ENDOTOXEMIA

ENDOTOXEMIA
Gram-negative bacteria have an outer membrane that contains highly toxic components called
endotoxins or lipopolysaccharides (LPS). LPSs are large molecules composed of both lipids and
saccharides.
These molecules provoke powerful immune reactions. As inflammation is part of the immune response, whenever our immune system encounters lipopolysaccharides, inflammation always happens.
Even after the gram-negative bacteria have been destroyed, LPS still provoke an immune response. If enough of these remnants enter the blood, sepsis or blood poisoning is the result.
What the theory of endotoxemia proposes is that the chronic inflammation that underlies many illnesses is provoked and sustained by these endotoxins. Where the inflammation manifests itself depends on where these LPS fragments end up.

The only species of bacteria that should colonize the small intestine are friendly gram-positive
Lactobacillus.The only reasons gram—negative bacteria would colonize the small intestine is:
· because there has been a breach in the stomach or gastric barrier defense or
· these pathogens have migrated from the colon because of impaired peristalsis or weak ileocecal
valve, or the beneficial small intestinal gut flora population is disordered.

The more diverse your gut flora, the better your health is apt to be. Various disease states have been consistently associated with low bacterial diversity.

The gastrointestinal mucus layer is of tremendous importance in preventing metabolic endotoxemia.
Beneficial bacteria like A. mucininiphylla may increase mucus thickness, although we are still unclear about the mechanisms involved. It is not inconceivable that because A. muciniphila is a gram—negative bacteria, it may provoke mucus secretion due to a biological process known as hormesis.
In both Crohn’s disease and ulcerative colitis, colonies of A. mucinivhila are greatly depleted and replaced by other mucin-degrading bacteria.

Certain dietary habits that can compromise this very important physical barrier. One such habit is very low~carb or ketogenic diets – eating less than 50 grams of carbohydrates a day,
although issues may arise for some on levels below 100 grams a day. MUC2 mucins are partly
composed of sugar molecules and require that these carbohydrates either come from the diet, or are produced by the liver from non-glucose substrates in a process known as gluconeogenesis.
The more butyrate your bacteria produce as a result of fermenting prebiotics, the healthier the cells lining your digestive tract are going to be. And the healthier these cells, the less likely your body’s immune and hormonal systems will have to grapple with inflammatory cascades caused by increased intestinal permeability. Bifidobacteria are especially prolific at producing butyrate.
A diet devoid or nearly devoid, of the prebiotic fibers beneficial organisms thrive on is highly likely to increase the risk of gut pathogens colonizing sections of the gut wall. And a diet lacking fermented foods rich in beneficial organisms that can help replenish and strengthen existing gut flora colonies is also one that would encourage the development of dysbiosis over time.

Prolonged exercise increases core body temperature. As core temperatures approach 39 C (102 F),
temperatures along the intestinal tract can reach 4l C (l06 F) or higher, and lead to damage of the epithelial layer lining the digestive tract.Intestinal temperatures over 40 C (104 F) have been shown to damage intestinal cells, shrink intestinal villi, and are capable of causing massive bleeding. The increase in intestinal permeability causes translocation of lipopolysaccharides (LPS) from gram-negative gut pathogens first to the liver, and if
severe enough, to systemic circulation. This cascade of events, however, is not solely mediated by exercise intensity. Another important factor is ambient temperature.
In a cool temperature/warm temperature study, intestinal permeability occurred during both phases of the trial, these changes in gut—barrier function could not wholly account for the increases seen in LPS concentrations during the hot treadmill run. Instead, what these researchers found was that these participants had a harder time clearing endotoxins. (athletes seems to develop adaptations) There is research centered around increasing heat shock protein (HSP) levels in athletes to lessen the effects of exercise—induced endotoxemia. HSPs are intracellular molecular complexes that aid in the synthesis of proteins and cell maintenance.
One HSP in particular, HSP70, prevents the breakdown of the tight junction protein occludin. It also protects intestinal cells Hom hydrogen peroxide and damage caused by low cellular oxygen.
Several agents have been tested to increase HSP70 levels, but with mixed results. Cow milk colostrum was shown to up-regulate HSP70 in one study. (Q However, another study found that colostrum actually increased intestinal permeability (2). That said, dairy proteins have been shown to increase gut—barrier function as I wrote here.

Zinc has also been proven to prevent increased intestinal permeability after the ingestion of
nonsteroidal anti—inflammatory drugs (NSAIDs).Glutamine amino-acid supplementation in rats has been shown to increase the expression of HSP70 and reduce intestinal permeability. g ll ) Glutamine has been used for years to treat IBS and IBD.
Now I want to talk about some that increase permeability, and are best avoided when engaging in
intense exercise.
Quercetin, a plant-derived flavonoid, has been shown to block increases in HSP70. {l2 g Foods high in
quercetin include apples, blueberries, cherries, cranberries, and onions.
Polyunsaturated fat (PUFA) consumption should also be minimized. PUFAs are easily prone to
oxidation. These fats will increase intestinal permeability by promoting lipid peroxidation in intestinal
cells, not to mention lipid peroxidation in liver cells under inflammatory stress.
This also holds true for omega—3 PUFAs as they are even more unsaturated than omega—6s and
therefore more susceptible to oxidation. If you are physically active, saturated and monounsaturated
fats are far less likely to promote endotoxemia than are PUFAs.
Fructose-heavy sport drinks are very popular among the physically active. However, fructose rapidly
breaks down ATP to AMP resulting in elevations of hydrogen peroxide, which increases gut
permeability.
Finally, I need to mention gluten-grains.

l Low thyroid function also results in a variety of digestive complaints. In the throat, it commonly causes
oropharyngeal dysphagia, the medical term for difficulty in swallowing. It can also contribute to hiatal
‘ hernias.
It can cause heartburn or gastroesophageal reflux disease (GERD). This shouldn’t be too surprising as
low thyroid function will result in delayed stomach emptying. (Q) Couple this with too much dietary
fiber that swells when in contact with gastric juices or general overeating, and the result can be GERD.
Low stomach acid production is another symptom of depressed thyroid function. QQ) Low stomach acid
will cause incomplete breakdown of protein increasing the risk of protein deficiency disorders. Persons
with low stomach acid often complain of problems digesting protein—heavy meals.
As I explained in this post, stomach acid serves not only to break down protein, it also kills potentially
harmful swallowed bacteria. Therefore, low stomach acid will predispose to small intestinal bacterial
overgrowth.
Appetite is usually reduced in those with hypothyroidism, but weight gain is common due to fluid
retention, and if untreated over a long period, to lowered resting metabolism. Complaints of abdominal
discomfort and bloating are also common.
Of major concern is the decrease in peristalsis or intestinal motility. Constipation is the major
gastrointestinal complaint in this population.
As I wrote in my SIBO series, the number-one cause of SIBO is impaired peristalsis. Just as thyroid
hormone dysfunction impairs gastric barrier function increasing the risk of SIBO, reductions in
intestinal motility will also predispose someone to developing SIBO, but from gram-negative bacteria
migrating up from the colon.
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In a Finnish paper; like a number of papers since, the association between serum endotoxin and
diseases we categorize as part of the metabolic syndrome was found to be a very strong one.
In the study these who went on to develop diabetes also had consistently higher endotoxin levels than
those that didn’t.
So again I must emphasize that there is another maj or route that gut pathogens use to reach circulation:
the paracellular route between gut epithelial cells. This route, not chylomicron formation per se, is the
pathological state when it comes to endotoxin translocation.
Any hypothesis about diabetes that does not reference increased intestinal permeability and the liver is
incomplete. Endotoxemia is not about the normal formation of chylomicrons in the absence of gut
dysbiosis. Otherwise, all fat, from saturated to polyunsaturated or monounsaturated fat, must be
j implicated as they all contain long-chain fatty acids and form chylomicrons when absorbed.
Chronic endotoxemia equals chronic inflammation equals lots and lots of free radicals. In a liver
subjected to oxidative stress, it is sheer dietary lunacy to recommend substituting saturated fat with
polyunsaturated fatty acids (PUFAs). These fats, when incorporated into cellular lipid structures,
including those in the liver, are most prone to lipid peroxidatiog when subjected to free radicals.
You correct a lopsided ratio Omega 3—6 ratio by reducing your omega—6 consumption. That requires
substituting saturated and monounsaturated fats for PUFAs.
Yes, omega-3s are anti-inflammatory, but that’s because they suppress immune function. If your body
is trying to fight a gut infection, what sense does it make to suppress the very system responsible for
fighting it?{ In a study of young healthy men and women: The first 24 hours consisting of an intravenous saline drip
followed by a one—time intravenous infusion of lipopolysaccharide (LPS) followed by another 24-hour
study phase that measured a variety of inflammatory markers and blood glucose metrics.
Results Not surprisingly, the endotoxin caused an immune response that the subjects experienced as an
increase in temperature, heart rate and white blood cell count, which resolved 8 to I2 hours after LPS
exposure.
But these were not the only effects observed:
Plasma levels of tumor necrosis factor (TNF) and interleukin 6 (IL—6), both cytokines, increased rapidly
shortly after endotoxin exposure.
Other inflammatory markers like MCP-l and C—reactive protein, free fatty acids and the hormones
cortisol and growth hormone spiked as well.
Sustained increases in free fatty acids or lipid toxicity is recognized as a cause for the loss of pancreatic
beta cell function leading to insulin—dependent diabetes.
The increases in both cortisol and growth hormones also grabbed by attention.
the most important finding of the study was that sensitivity to insulin in liver, muscle and fat cells
decreased by 30% Hom baseline in these healthy subjects.
Insulin sensitivity decreased and a measure of insulin resistance increased. No change in pancreatic
function as displayed in the graphs on the right was noted.
So for the first time in human beings, researchers were able to show how LPS could initiate an
inflammatory cascade that caused transient insulin resistance after 24 hours without any effect on
pancreatic function.
To further support this hypothesis the authors noted:
· The common observation of inflammation and development of type 2 diabetes that may emerge
in patients during acute human infections and sepsis.
· Experimental animal models of endotoxemia that elicit both fat-tissue inflammation and
changes in blood lipids resembling those seen in metabolic syndrome.
· Animal experiments in which genetic and drug blocking of cytokine receptors suppresses the
inflammatory response to endotoxins and blocks the onset of insulin resistance.
· Endotoxemia in animal studies induces gene changes in fat tissue that are remarkably similar to
changes observed in the visceral fat of those afflicted with type 2 diabetes.
So now imagine a scenario of low—grade LPS translocation Hom the gut to systemic circulation day
after day, year after year. How long would it take to develop insulin resistance that manifests itself as
type 2 diabetes or cardiovascular disease?
That would depend on the genetic predisposition of the person or animal, the amount of pathogens that
have taken up residence in the gut and the rate these endotoxins cross the gut wall.
Assuming this hypothesis is verified, does this mean LPS is the only cause of insulin resistance?
Perhaps but I doubt it. Once you have impaired gut barrier function anything that appears in the gut
lumen can potentially enter the blood stream and play a complimentary role: yeast, gram-positive
bacteria, viruses, food molecules or xenobiotics like heavy metals or pollutants.
The analogy I like to use is of an open sore anywhere on your skin. Once there, your blood stream is
vulnerable to whatever else happens to come along.j Remember that while your digestive tract is inside of you, as far as your body is concerned, its contents
are as much outside of you as anything your skin comes in contact with. And there is no possible way
to keep that internal “skin” healthy without the hiendly gut microbes that make it and the lumen their
home. Disturb them and you can rest assured that sooner or later inflammation and endotoxemia will
follow.
It appears, therefore, from studies in rodents and humans that it is endotoxemia that is causing
inflammation in the liver and at the root of liver disease. Choline deficiency no doubt plays a role by
inhibiting the export of fat from the liver, increasing inflammation and perhaps handicapping the liver’s
ability to detoxify these pathogens.
By administering probiotics to correct gut dysbiosis, endotoxemia is stopped or reversed and so is
further damage to the liver.
The way endotoxins cause liver damage can be summarized this way:
· Altered gut flora leads to
· Increased gut permeability which leads to
· Increased LPS! gut toxins which leads to
· Increased activation of the immune system which leads to
· Increased cytokine (immune signaling protein) production which leads to
· Liver inflammation and injury which leads to
· Increased systemic inflammation and organ injury.
The next four studies measured the effect of prebiotics on glucose concentrations after eating
(postprandial). Two of the four studies reported significant declines in blood glucose on both normal-
weight and obese subjects. Q) (Q) Following this analysis, statistical significance was still retained.
Of the three studies that measured postprandial insulin levels, two demonstrated significant reductions
following prebiotic supplementation in participants that were overweight or had very high cholesterol
levels. Combined analysis of these three trials continued to show a statistically significant reduction in
postprandial insulin levels.
None of these positive results surprise me in the least given the role gut dysbiosis plays in the cause of
metabolic syndrome. Translocation of gut pathogens, especially gram-negative bacteria, across the gut
wall will always initiate the Inflammatory-Cortisol Ballet.
Once this occurs, any hope of keeping glucose, insulin, blood lipids, inflammation, nutrient status,
metabolism, hunger, and cortisol levels under control flies right out the window. Evidence continues to
mount that metabolic syndrome is just another fbrm of Pseudo-Cushing’s. Medicine continues to miss
the boat in recognizing this by failing to account for cortisol generation within cells, including, but not
limited to, both adipose and liver tissue.
It is true that the hypothalamic-pituitary—adrenal axis is acutely stimulated by translocating gut
pathogens leading to transient cortisol spikes, especially in the postprandrial state. However, it is
chronic activation of the cortisol—cortisone shunt via this system’s interaction with inflammatory
cytokines that underlies development of insulin resistance and elevated circulating hee fatty acids
characteristic of metabolic syndrome.I Foods That Irritate Your Digestive Tract or Harm Your Gut Flora
Nightshade Vegetables
Edible nightshades contain alkaloids that can be very irritating to the gastrointestinal mucosa, and
because of this are implicated in gut-wall inflammation and leaky gut.
Now that I have given up gluten and cut back on drinking alcohol, the number—one dietary reason I
have trouble getting to or staying asleep is because I had too many nightshades for dinner. I like
potatoes but they disturb my sleep unlike other starchy tubers like sweet potatoes or yams. A lot of
people are also very sensitive to peppers especially as they age.
Excess Dietary Fructose
Fructose makes up half of the sucrose or sugar molecule. Also found naturally in fruit and maple syrup,
it’s what is responsible for the sweet taste of sugar. Fructose is quickly transported to the liver because
it is quite damaging to protein structures in the body, readily forming advanced glycation end products
or AGEs.
Fructose has the unique property of rapidly breaking down adenosine triphosphate or ATP in cells that
use oxygen, including those cells capable of absorbing fructose in the digestive tract. By doing so it
also rapidly elevates reactive oxygen species or free radicals to a point that overwhelms the cell’s built-
in defenses to neutralize them.
Getting your fructose from fruit is normally not an issue because it comes packaged with fiber,
antioxidants and vitamins that help counteract its oxidizing effects on cells while limiting the amount
you can eat. While eating two apples can be quite satiating, removing its fiber and making juice from it
can allow you to easily drink the fructose equivalent of four or more apples at one go.
Getting your fructose from refined sources like sugar and high fructose com syrup is even worse as not
only is it devoid of fiber that might limit its ingestion, it is also devoid of any antioxidants that might
counter its ill effects on intestinal cells. As it increases oxidation and inflammation in the small
intestine, it will promote the growth of pathogens by reducing beneficial Lactobacillus bacteria.
Fructose will also reduce colonies of bifidobacteria in the colon. Refined sugars should be limited to
avoid promoting endotoxemia and disturbing sleep.
Omega 6 Vegetable Oils
In the gut, excess omega 6 fatty acids will increase oxidative stress and inflammation thus promoting
endotoxemia. Polyunsaturated oils are extremely prone to forming free radicals when exposed to heat
and high pressure. As most industrial seed oils are produced using both, they are already full of free
radicals when you buy them.
If used for cooking, the damage is compounded further. By their very chemical structure, saturated fats
are the most stable to heat and resistant to oxidation, followed by monounsaturated fats like olive oil.
Omega 3s, on the other hand, are antidnflammatory and may help calm your digestive tract in the
absence of other inflammatory substances like alcohol, gluten, fructose and omega 6 vegetable oils.
However, I recommend you obtain your omega 3s in whole foods rather than in a capsule. Knowing
what I know about how nutritional supplements are handled in warehouses and in transit, taking fish oil
capsules is a bit of a gamble due to their very delicate structure.i Gluten Grains
q Speaking from personal experience, nothing apart from binge drinking, induces drowsiness like eating
gluten grains, especially when combined with sugar.
Gluten is high in excitatory glutamic and aspartic acid, so you would think the opposite would be true.
It’s glutamic acid, by the way, that makes so many freshly baked wheat products so flavorful.
There are several reasons for this. Gluten releases five different opioid protein fragments or peptides
when digested: A4, A5, B4, B5 and C. Besides their well—known pleasurable and addictive properties,
opioids are quite sedating. Beds figured prominently in opium dens for a reason. These opioid peptides
put the “comfo1t” in comfort foods.
One gluten opioid, A5, stimulates insulin production. So not only does the carbohydrate portion of
gluten grains promote the release of insulin, so too its protein content.
Along with gluten opioids, another compound called adenosine is also produced. Adenosine is a
calming neurotransmitter that slows not only digestive peristalsis, but pretty much all neuronal circuits.
Finally, wheat germ agglutinin (WGA), gluten’s natural plant pesticide, binds readily to insulin
receptors in fat and liver cells. In small concentrations, it enhances the actions of insulin in shuttling
glucose into cells and out of the bloodstream. In larger concentrations, however, it prevents the binding
of insulin to cell receptors thus inhibiting glucose nom entering. This causes blood—glucose levels to
rise further, which calls forth a more pronounced insulin response and subsequent blood sugar crash
that results in intense sleepiness and/or hunger.
So why not recommend eating gluten for an insomniac?
Because all of these tranquilizing properties mask its harmful effects on the gut wall. Moreover, as
explained in my post on plant lectins, natural pesticides like WGA are likely toxic to our beneficial
gram—positive gut flora. Eating gluten and WGA compromises gut barrier function and increases
inflammation, which fuels insomnia. And since it also inhibits peristalsis, it predisposes to SIBO and all
the negative effects on health that flows from that.

CORTISOL
The Gnt—Brain Axis: How Endotoxemia and Leaky Gut Affects the Hypothalamic-Pituitary-
Adrenal Axis
The HPA axis is a negative-feedback circuit between the hypothalamus, the pituitary gland and the
adrenals. Using hormones and the nervous system, these structures are in constant communication with
one another to regulate certain bodily systems.
The hypothalamus is an almond-sized part of the brain that has the chief Hinction of linking the central
nervous system to the endocrine system via the pituitary gland. It produces a number of hormones that
target distant tissues and the anterior pituitary gland.
The pituitary gland is a pea~sized protrusion attached to the hypothalamus composed of the posterior
and hormone—producing anterior pituitary gland. It is known as the master endocrine gland and along
with the hypothalamus is responsible for a number of physiological ftmctions, including growth rate,
appetite and weight regulation, blood pressure, milk production, mood, sleep, reproductive hormones,
fertility, uterine contractions, kidney ftmction, thyroid function, thirst, water balance and body
temperature.
The adrenals are two hormonal glands that sit atop each of your kidneys. Each gland has an inner
section called the medulla, and an outer section called the adrenal cortex.
The adrenal medulla is where the fight or flight hormones epinephrine (adrenaline) and norepinephrine
are produced.
The adrenal cortex is itself divided into three separate zones that each produce different hormones.
The outermost layer of the adrenal cortex is called the zona glomerulosa and the main lrormone
produced here is aldosterone. Aldosterone is the main hormone regulating blood pressure by its actions
on the kidneys. The more aldosterone produced, the higher your blood pressure.
The innermost layer of the outer cortex is called the zona reticularis and here androstenedione, a
precursor to reproductive hormones, is produced from cholesterol.
Sandwiched between the outer and inner layer of the adrenal cortex is the zona fasciculata. Here are
produced what are known as the glucocorticoids, a class of steroid hormones. These hormones regulate
glucose metabolism throughout the body hence their name.
Another important ftmction of these steroid hormones is to reduce inflammation by suppressing
immune function. Remember, inflammation is how the immune system handles infections and threats;
however, too much inflammation can cause damage, some of it irreversible, to surrounding tissue and
cellular structures. For this reason modem medicine uses these types of steroids to treat chronic
inflammatory conditions.
Of the glucocorticoids, cortisol is by far the most important. Cortisol has a number of functions when
released in the body:
· Metabolism: when cortisol production is increased, glucose output in the liver goes up and
glucose uptake by muscle, fat and other tissue goes down resulting in a rise in blood-glucose
levels. In order to increase glucose production in the liver, it breaks down protein and fat in
muscle, fat, comiective and lymphoid tissue so the liver can produce glucose from these
building blocks. Doing so mobilizes energy for the brain and the heart which is good in an
emergency, but is harmful to health if cortisol production is chronically raised over long periods
of time.
· Blood Pressure Regulation: cortisol maintains the responsiveness of the smooth muscle tissue of
blood vessels to other hormones responsible for proper blood pressure regulation. Without it
you would experience severely low and potentially life—threatening blood pressure. However,
too much can chronically raise blood pressure.
· Immune System: cortisol inhibits immtme function by suppressing precursors to prostaglandins,
lowers nitric oxide and decreases the number of immune T4 cells and cytokines. This is good in
the short term to shuttle energy from the immune system to the brain and heart, but not good
over the long term if you need to ward off infections.
· Central Nervous System: cortisol directly impacts the electrical activity of neurons including
those responsible for memory. It decreases REM sleep but increases shallow sleep or time spent
awake which is good if there is an extemal threat. However, chronically elevated cortisol is not
good if you need sleep.
What has become clear over the last decade from the results of numerous rodent studies is that this
HPA axis is affected by gut pathogens as illustrated in the following graphic:
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Hypnthalamus
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Adrenal Cortex li S Gut Pathogens
Courtesy: Regulation 0f the stress response by the gut micr0bi0ta
In the lower-right-hand corner we notice gut pathogens that have breached the intestinal gut wall and
have provoked an immune response represented by the green arrow pointing towards the circles labeled
immune system. These pathogens, by the way, are none other than gram-negative bacteria and their
cell-wall remnants lipopolysaccharides (LPS).
Let me interj ect that gut pathogens are not the only substances capable of provoking an immune
response. Gluten, alcohol, plant lectins, nightshade vegetables, other food proteins, Candida albicans,

i viruses—all can produce immune stimulation in the presence of compromised gut barrier ftmction. Since
gluten grains produce inflammatory gluten peptides upon digestion and contain wheat germ agglutinin.
they are particularly effective at causing gut permeability and inflammation. So too omega-6 oils.
Each of these factors can amplify the effects of the other. The key point here is that anything that
increases intestinal permeability will provoke an immune response. However, I’ll just concentrate on
the immune response provoked by gram-negative bacteria for now.
You’ll notice two green arrows leading away from the immtme system. Let’s first look at the arrow
pointing towards the hypothalamus.
Here we notice an increase in the production of the cytokines interleukin 1 and 6 affecting the
hypothalamus, although there are other cytokines not shown that also impact it like tumor necrosis
factor alpha. Cytokines, as you may recall, are signaling proteins used by the immune system to
regulate inflammatory responses.
In response to these immune signals, the hypothalamus produces the hormones CRH (corticotrophin—
releasing hormone) and AVP (arginine vasopressin) that then act on the anterior pituitary gland. Keep in
mind that these inflammatory cytokines can, over time, damage the hypothalamus potentially affecting
any and all systems regulated by it. Moreover, notice that serotonin (5-HT) and noradrenaline (NA)
also cause the hypothalamus to produce CRH and AVP.
The pituitary, in response to both CRH and AVP, produces adrenocorticotropic hormone or ACTH.
ACTH directly acts on the adrenals to increase cortisol production. The more ACTH produced the
higher the production of cortisol.
Once cortisol is produced it signals back to both the hypothalamus and pituitary gland to suppress the
production of CRH, AVP and ACTH to curtail its further production. This is represented by the red
arrows and completes the negative-feedback loop.
Finally note that endorphins, which are produced when exercising, will also decrease cortisol
production by acting directly on the hypothalamus. This is one reason exercise is good for you.
However, the immune system does not only stimulate cortisol production via cytokine signaling. It also
increases cortisol via the synthesis of prostaglandin PGE2. This arm of the immune system is
represented by the second green arrow emanating from the immune system in the diagram.
Therefore, the more endotoxins provoke an immune response, the more cortisol will be produced. And
since the immune response affects both the HPA axis and the adrenals directly, the more likely it is that
the signals responsible for lowering cortisol will be overwhelmed by the signals that increase it.
While this diagram only details the effects of endotoxemia on the production of cortisol, I need to stress
that the increases in ACTH produced by the actions of both the hypothalamus and the pituitary gland
and the direct stimulation of the adrenals by prostaglandins impacts all hormone-producing areas of the
adrenal glands, not just that producing cortisol. This has implications for reproductive hormone
production, blood pressure regulation, thyroid function, and regulation of the fight or flight response.
Another point I want to make is that stress itself causes “leaky gut”. Increased cortisol will lead to
openings in the tight junctions that span the distance between the cells lining the gut wall. Just as gluten
or pathogens open these gateways, so too cortisol.
As seen in the following diagram, cortisol causes intestinal permeability which then directly impacts
the HPA axis via the production of cytokines as seen on the right. However, note that inflammation also
acts upon the liver and reduces tryptophan levels in the brain:

Stress Altered 5-HT —s $CRFfAVP sx
1 tryptophan / l V I B,
Adrenal Colin:
/· T wu; $.IL—6 1
l M l Ccrtisol
Liver epithelium
Gui ‘ p, if Entert:
Parhnaens i’ V W2`; . mi¤r¤bi¤la
Probicitics
Courtesy: Regulation of the stress response by the gut microbiota
Tryptophan is an essential amino acid that is a precursor to the neurotransmitter serotonin (5 -HT).
Serotonin produced outside of the gut is used to regulate mood and appetite. lt is also important in
sleep regulation as melatonin is made from it. Serotonin is also involved in cognitive functions,
including memory and learning. Alter tryptophan and you alter serotonin and everything it regulates.
Finally notice that probiotics block all of this mayhem by strengthening gut barrier defenses and
preventing bacterial translocation.
Improper breaching of the gut wall by food macromolecules, parasites, bacteria, yeast, and viruses will
always provoke a defensive response from the body. lt is for this very reason that the majority of our
immune cells are located along the length of the gastrointestinal tract.
For example, bacteria that are beneficial to our health and survival when confined to the lumen or gut
wall turn pathogenic when they flood into the bloodstream because of intestinal perforation.
Conversely, organisms like Candida albicans, Clostridia dyjicile, and Klebsiella pneumoniae can exist
in our digestive tract for a lifetime causing us no problems whatsoever, as long as they are kept in
check by friendly gut flora and prevented from reaching systemic circulation.
I’ve explained how the membrane that surrounds gram—negative bacteria (lipopolysaccharide; LPS) is
tmiquely effective in initiating and maintaining chronic immune activation should these bacteria breach
the gut wall. l’ve also detailed how these inflammatory reactions can activate what is known as the
hypothalamic-pituitary-adrenal {HPA) axis leading to cortisol release.
However, activation of the HPA axis is not the only way endotoxins, and the irnrnune reactions to them,
affect cortisol concentrations. There is another pathway that has provoked great interest among
researchers. I will introduce you to that pathway in act two.
What’s important to remember is that interactions between the immune and hormonal systems are not
unidirectional. Not only do inflammatory cytokines affect cortisol secretion and its metabolism, cortisol
also shapes immtme function. Indeed, one of the major uses of synthetic cortisol-like medications is to
tamp down inflammatory immune responses.

To use a metaphor, cortisol is an active dance partner of inflammation and the cytokines that drive
immune responses. It often moves left when inflammation moves right, back when the other moves
front. y
This dance is extremely complex and not always balanced. There are times when the anti-inflamrnatory
actions of cortisol hold sway, and yet other periods when inflammation is in firm control of the
choreography much to the detriment of the body and its various organs.
While the actions between the two can be mainly described as oppositional, there are times when their
effects are synergistic. Adding to this ballet’s complexity is the fact that rarely are these performers
alone on stage. Both are accompanied by other hormonal and immtme partners who collectively shape
the ebb and flow of immune activation, function, and hormonal responses.
Many effects caused by cortisol excess camiot be entirely cut off from an immune system that often
drives or counters these processes. Nor should we forget the effect that intense psychological stress has
. on cortisol release. That stress is more than capable of initiating disruptions in both intestinal-barrier
function and composition of native gut flora populations; and this alone can spark inflammatory
cascades.
In other words, what you’re about to read can not always be blamed solely on cortisol and other
glucocorticoids. Disentangling where the actions of these agents end and where those of inflammation
begin can be extremely difficult.
What Is Cortisol?
Cortisol is a steroid hormone produced in the Zona fasciculata ofthe adrenal glands. lt is more formally
known as hydrocortisone.
Other hormones produced by the Zona fasciculata are the androgens: androstenedione, DHEA, and
DHEA sulfate. These serve as precursors to testosterone and dihydrotestosterone.
All steroid hormones are derived from cholesterol. While low-density lipoprotein (LDL) cholesterol is
considered to be the main substrate for cortisol synthesis, recent research suggests that high—density
lipoprotein (HDL) is more important to its formation.
Cortisol is classified as a glucocorticoid. The name derives from theirability to regulate glucose levels
ir1 the blood, namely by increasing them in opposition to insulin’s action of lowering blood—sugar
levels.
Broadly speaking, glucocorticoids are steroid hormones able to bind to glucocorticoid receptors (GR)
expressed in a large array of cells and tissues. However, these aren’t the only receptors that
glucocorticoids bind to.
As mentioned, glucocorticoids have powerful anti-inflammatory effects that modem medicine has
utilized to create a number of synthetic corticosteroids for use in autoimmtme and inflammatory
conditions like rhetnnatoid arthritis, ulcerative colitis, lupus, allergies, etc.
Cortisol is also popularly referred to as the stress hormone, although other hormones are involved in
the fight or flight response like adrenaline and norepinephrine. Typically, however, when people are
waming about the hazards of chronic stress, it’s cortisol they’re mostly referring to even if they’re not
aware of it.
The use of synthetic glucocorticoids, like any hormone-replacement therapy, causes suppression in the
body’s production of said hormone, in this case cortisol. As a result, stopping these drugs abruptly can
lead to a condition known as adrenal fatigue.

This breakdown causes an increase in the glucogenic amino acids necessary for accelerated production
of glucose in the liver. And while suppressed in peripheral tissue, protein synthesis is stimulated in the
liver.
ln adipose tissue, elevated glucocorticoid levels increases breakdown of stored fat (lipolysis). This
causes an increase in glycerol levels which is also used by the liver to produce glucose. Lipolysis also
causes an elevation in Hee fatty acids, so-called because they are no longer bound to their glycerol
backbone. They also cause a rise in plasma triglyceride levels.
Ironically, while lipolysis is stimulated by glucocorticoids like cortisol, a classic outcome of elevated
glucocorticoid levels is weight gain and obesity. So while cortisol acts to break down fat to increase
production of glucose, it also increases the propensity to pack on the pounds, and in the worst way
possible-—as visceral fat.
Studies in animals and humans have shown that elevations in stress and the stress hormone cortisol
consistently leads to stimulation of the appetite centers in the brain. Stress activation also has
depressive effects on metabolism. This increase in calories ingested against a decline in calories
expended accounts for the propensity to gain weight in those experiencing elevations in both serum and i
tissue glucocorticoid concentrations.
With substrates from both muscle and fat now readily available due to the catabolic actions of
glucocorticoids, a dramatic increase in the liver’s production of glucose occurs. This is achieved by a
process known as gluconeogenesis.
This is mainly brought about because glucocorticoids call forth a dramatic increase in two liver
enzymes necessary for this to occur: glucose—6—phosphatase and phosphoenolpyruvate kinase.
Not only is production of glucose raised, but so too the deposition of glycogen in the liver. Glycogen is
the polysaccharide storage form of glucose.
To prevent insulin hom countering these effects by shuttling glucose into peripheral cells, cortisol and
other glucocorticoids actively inhibit glucose uptake by muscle and fat tissue. Glucocorticoids also
enhance the action of other hormones like the catecholamines (adrenaline, norepinephrine, dopamine)
and glucagon that also act to cotmter insulin’s action in peripheral tissue.
The result of all of this is insulin resistance. The higher production of glucose by the liver, combined
with increased resistance to the effects of insulin, causes blood glucose levels to rise and stay elevated
as long as glucocorticoids remain biologically active.
The pancreas, however, continues to pour out insulin in a futile attempt to bring down blood—glucose
levels. But the signal goes rmheard, both in peripheral tissue and in the liver where insulin would
normally act to shut oif gluconeogenesis. Thus diabetes can be an outcome of glucocorticoid excess.
When it comes to who has the upper-hand, glucocorticoids, catecholamines, and glucagon consistently
trump insulin.
Our survival depends on our ability to fight or take flight when confronted by external threats. Cortisol,
catecholamines, and glucagon are required to fuel these responses.
Under such conditions, the actions of insulin are clearly counterproductive. An increase in blood sugar,
not its diminution, is what is needed to supply quick energy to the brain and muscles to power these
reactions
But extemal threats are not the only perils faced. Intemal threats from increased intestinal permeability
and translocating gut pathogens, for example, also elicit similar hormonal reactions due to inrmrme
activation.

So when it comes to determining the hierarchy of hormones, it should be fairly obvious that while
cortisol opposes the actions of insulin, and insulin opposes the actions of cortisol, when the body is
under tl1reat—acute or chronic, external or intemal—it is cortisol that grabs the lead role.
Skin and Connective Tissue
In skin and connective tissue, glucocorticoids inhibit both DNA synthesis and cell division reducing
production of collagen. In those experiencing chronically elevated cortisol levels, the skin on the back
of the hand can become quite thin and takes on a wrinkled appearance that resembles crumpled
cigarette paper.
Easy bruising of the skin with minor trauma is also a pervasive side effect. Acne is also common, with
outbreaks appearing on the face, chest, and back.
Bone
Glucocorticoids directly inhibit bone formation. In youth, cortisol excess can stunt growth.
Nevertheless, due to an increase in load-bearing weight from being overweight or obese, a decline in
bone—mineral density is typically averted before reaching adulthood.
In adults, osteopenia and osteoporosis are very common outcomes of chronic glucocorticoid excess. In
those on synthetic corticosteroid therapy for longer than twelve months, fully 50% will go on to
develop osteroporosis.
A small part of this group will go on to develop a condition known as osteonecrosis or avascular
necrosis. This side effect produces a very rapid breakdown of bone that primarily affects the hip,
leading to pain and collapse. Osteonecrosis can affect people at any age, and has been documented to
occur on relatively low doses of corticosteroids.
Another result of glucocorticoids on bone metabolism has to do with calcitnn. These tgents inhibit
absorption of calcitun from the digestive tract and accelerate excretion of the same in urine.
Because of induced low calcitun or hypocalcemia, the parathyroid glands kick into high gear to correct
the imbalance. Parathyroid hormone also causes bone to be broken down to raise levels of calcium in
the blood.
Blood Pressure
Glucocorticoids reliably increase blood pressure. First by increasing sensitivity to agents like the
catecholamines and angiotensin H. Secondly, by decreasing nitric oxide dilation of smooth muscle cells
in the vasculature.
Glucocorticoid excess, along with certain kinds of inflammatory cytokines, can down—regulate an
enzyme that normally prevents cortisol from binding to mineralocorticoid receptors (MR) in the
kidneys. Activation of these receptors is responsible for sodium retention and potassium loss.
Interestingly, glucocorticoids have a higher affinity for mineralocorticoid over glucocorticoid receptors.
Immune System
Glucocorticoids have quite powerful anti-inflammatory effect. Now, as I wrote in relation to omega 3s
in my post on polyunsaturated fats, whenever you read the word anti-inflammatory, you should
automatically interpret this to mean irmnune suppressing. Plainly speaking, glucocorticoids are anti—
inflammatory because they suppress certain immune functions.
The broad effect glucocorticoids have on immune cells is well beyond my ability to explain them in a
single blog post. Suffice it say that these effects are wide—ranging, and there are still many questions
left unanswered about how they are produced.

This illustration comes from a paper entitled: The kaleidoscope of glucocorticoid effects on immune
system. As can be gleaned from this illustration, these effects impact a large variety of immtme cell
types and the signaling proteins some of these cells produce.
Most of the effects are suppressive as indicated by the trtmcated red arrows. Moreover, note that anti-
inflammatory Treg cells are stimulated by these agents.
However, I want to point your attention to the cell type seen in the upper-right-hand section that is
labeled MCD and is colored bright orange.
This represents macrophage cells. Their name derives from the Greek for ‘big eaters’, and that is
precisely what they do. They eat or phagocytose cellular debris or pathogens, either as stationary cells
like resident Kupffer cells in the liver, or as mobile immune cells drawn to the site of an infection.
Macrophage activity is either stimulated or inhibited by glucocorticoids depending on their
concentration. This illustrates that cortisol can augment inflammatory immune reactions under certain
conditions, and therefore does not universally act in an immune-suppressive marmer.
Needless to say, these powerful immune—shaping effects can dramatically dial down inflammation.
However, these same effects also increase susceptibility to catching things like the cold, flu, or
tuberculosis. This explains the common association seen between high—stress levels and increased
susceptibility to infection.
Apart from viral and bacterial infections, fungal infections of the skin, nails, and bowel are also a
common occurrence in those on glucocorticoid medications or experiencing chronically elevated
endogenous cortisol production. Susceptibility to wound infections also occurs, while wound healing is
delayed.
Central Nervous System .
Glucocorticoids can have pronounced effects on the brain and mood. Recall that cortisol and most other
glucocorticoids have a high affmity for both glucocorticoid and mineralocorticoid receptors. Both types
of receptors are expressed in the brain, including the hippocampus, hypothalamus, cerebellum, and
cortex.
Glucocorticoids are well-known for causing the death of brain and central nervous system cells or
neurons. For this reason, there is great interest in studying glucocorticoid excess as a precipitating
factor l1’1 impaired cognitive function, neurodegenerative diseases, and Alzheimer’s.
In those diagnosed with Cushing’s syndrome, about 50% report some mood or psychiatric disorder.
Some of the disorders reported are depression, fatigue, paranoia, anxiety, overt psychosis, insomnia,
irritability, apathy, and euphoria. Again, how much of this is due directly to glucocorticoids and how
much is due to inflammatory immune activation that often accompanies their presence is yet to be
determined.
Memory and cognitive ftmction are often impaired in those experiencing higher glucocorticoid levels.
Feelings of being spaced out and having a hard time concentrating are often seen in this group.
Eyes
Glucocorticoids raise pressure in the eyes. Combined with genetic predisposition, these hormones are
capable of initiating development of glaucoma.
Cataracts are also a known side effect of elevated glucocorticoid levels. No doubt this has something to
do with chronic elevations in blood glucose and free fatty acids as cataracts are also quite common in
those with pre- or full-blown type-2 diabetes.
Gut
Long—terrn use of glucocorticoids increases the chance of developing peptic ulcers. Glucocorticoids
increase triglyceride levels. As hypertriglyceridemia is a risk factor for developing pancreatitis, those
on long-term glucocorticoid therapy are at higher risk of developing this disorder.
Glucocorticoids consistently increase intestinal permeability and endotoxemia. One hypothesis holds
that effects on mast cells lining the digestive tract is the reason for this occurrence. (Q
Another theory holds that their general immune—suppressing actions can permit the out-of—control
growth of pathogens like Candida albicans and gram—negative bacteria in the digestive tract. This
could conceivably allow these pathogens to crowd out beneficial gut flora, and compromise ir1testinal—
barrier function by initiating inflammatory responses at the level of the gut wall.
Another mechanism is disturbance to intestinal motility due to depressed thyroid hormone metabolism
that predisposes to small bowel infection. I describe why below. _
Whatever the mechanism(s), glucocorticoid’s ability to disrupt gut-barrier function, intestinal
movement, and gut flora populations can initiate and sustain a cycle of gut dysbiosis, endotoxemia,
inflammation, and chronic cortisol secretion that can make resolving gastrointestinal disturbances very
difficult.
Metabolism
Glucocorticoids reliably suppress thyroid hormone function and metabolic rate. Some of this effect is
due to direct inhibition of the pituitary gland’s secretion of thyroid-stimulating hormone (TSH).
However, while this is mainly true for acute glucocorticoid spikes brought about by the rapid onset of
infection, chronic glucocorticoid excess is more likely to have tissue-specific effects on thyroxine (T4)
conversion to its more biologically active triiodothyronine (T3) form.
Glucocorticoids also down-regulate peripheral T3 receptors and increase levels of biologically inactive
reverse T3. This explains why euthyroid sick syndrome is commonly seen in those diagnosed with
Cushing’s syndrome.

Declines in metabolic rate will cause gastrointestinal issues like constipation, delayed stomach
emptying, and gastroesophageal reflux disease (GERD). It will also predispose to development of small
intestinal fungal and bacterial overgrowth (SIFBO) as slowed intestinal movement can lead to
migration of predominantly gram-negative bacteria from the colon into the small intestine.
Reproductive Function
Glucocorticoids suppress gonadotropin—releasing hormone (GnRH). GnRH is released by the
hypothalamus and causes the pituitary to release luteinizing honnone (LH) and follicle—stimulating
hormone (FSH).
In women, LH stimulates secretion of progesterone and estrogen. A surge in LH in the mid-menstrual
cycle is responsible for ovulation. In men, LH stimulates testicular cells to produce testosterone.
FSH in women stimulates maturation of ovary follicles. In men, this hormone is important for
maintaining production of viable sperm.
Disruption in GnRH secretion is therefore an important cause of infertility in both men and women.
This explains why psychological stress is often associated with difficulties in becoming pregnant.
Glucocorticoid excess also delays onset of puberty in young girls. It also causes the absence of
menstrual cycles in women of reproductive age; a condition known as amenorrhea.
Blood Lipids
Glucocorticoids increase blood levels of LDL cholesterol and triglycerides. However, they lower blood
concentrations of HDL.
As mentioned, the prevailing view had been that LDL served as the main substrate for cortisol
synthesis. It now appears that HDL is the preferred source.
This would suggest that reductions in HDL may be partly explained by an accelerated conversion of
this lipid to cortisol. This would further imply that the typical pattern seen in those diagnosed with
metabolic syndrome of high LDL cholesterol, high triglycerides, and low HDL may be an outcome of
cortisol activation.
The well-known fact that those suffering from Cushing’s syndrome and Cushing’s disease experience
higher rates of heart disease than the general population speaks to the role stress hormones play in the
genesis of this disorder. Moreover, given the reality that increases in glucocorticoid levels rarely, if
ever, occur without concurrent immtme activation, implies that both are intimately involved in the p
onset of cardiovascular disease.
In the first act we saw what happens when cortisol is low, as in adrenal insufficiency, and what occurs
when cortisol is high, as in Cushing’s syndrome.
But it’s now time to introduce the other members of our inflammatory-cortisol ballet. The other partner
in this dance is the immtme system, specifically immune cells and their inflammatory cytokines.
Immune Cells and Cytokines
Broadly speaking, cytokines are small proteins secreted by a variety of cells that affect the behavior of
other cells. When we’re talking specifically about the immrme system, we’re mainly talking about how
these proteins coordinate an immtme response when a pathogen or pathogens are detected.
There are different types of cytokines released by many types of immune cells, and there is no possible
way I could do justice to this subject in a blog post. The immune system is extremely complex and can
easily constune a lifetime in study.
Therefore, I’ll be concentrating on one cell type above all others. It certainly isn’t the only hoofer in
this ballet, but it does have a starring role. And that dancer was briefly introduced to you in the first act
as the macrophage cell, he of the very big appetite. g
Macrophage cells are part of our innate immune system, although they also take part in the adaptive
immune response. The innate immune response is that part of the immune system that serves as our
first line of defense. Well, it’s our first line of defense if we disregard both our visible skin and our
internal skin i.e., the skin cells that line our respiratory system and gastrointestinal tract.
Macrophage cells are also known as sentinel cells, and they’re called that because they reside under the
surface of the skin, ltmgs, sinuses, oral cavity, stomach, and intestines—in other words areas next to the
outside world, which if breached by pathogens can present a threat to our health and very survival.
All macrophages can exist in three different states of readiness. The lowest state of readiness is the
resting state.
In this state macrophages sample the area around them sniffing, as it were, for any trouble. They also
eat or phagocytose cellular debris.
Every second of our lives, about one million cells die. That’s a lot of cellular debris the body needs to
clean up. And that cleanup is done by macrophages that act not only as sentinels, but as garbage
collectors.
How do they know which cells should be eaten and which ones left alone? Well, cells that have reached
the end of their life send out signals that attract these garbage collectors. When close, macrophages are
able to read devour me signs displayed on the surface of these dying cells, and that’s precisely what
macrophages proceed to do.
Macrophage cells are pretty long-lived as far as immune cells go. They can easily live for months and
spend a good chunk of their time eating our cellular trash.
However, macrophages not at rest come in two types. Type one is a killing machine and described
below. Type two macrophages aid in wound healing, and tissue and muscle repair. These macrophages
help end the inflammatory process initiated by the first type.
When pathogens of any type breach the gut wall, a normal occurrence in gut dysbiosis, so—called naive
macrophage cells receive a signal that something’s not right. They become activated as type one
inflammatory macrophages. In this state, they start taking bigger gulps of their surrounding
environment.
This activation typically occurs in response to a cytokine known as interferon gamma (INF -y). This
cytokine is mainly produced by helper T cells and natural killer cells. INF -y not only activates type one
macrophage cells, it can also cause these same cells to produce other cytokines that make both T cells
and natural killer cells continue to release INF-y to keep the inflanrnnatory cascade going.
But there is another state where type one macrophages become hyperactivated. This state is entered
when these cells directly encounter an invader. Remember lipopolysaccharide (LPS), the outer cell wall
component of grarn—negative bacteria? Macrophages can bind LPSs on their cell walls, as well as
mannose, a common carbohydrate component of other pathogens like Candida albicans, viruses like
the flu or PHY gram—positive bacteria, and parasites.
When hyperactivated, these formerly cahn garbage collectors are turned into killing machines. They
become larger, and their appetite really grows as they eat invaders left and right.
In this state they produce a very powerful cytokine by the name of tumor necrosis factor alpha (TNF-
or). This cytokine is so named because it can kill tumor cells and cells infected by viruses. This cytokine
can also cause other immune cells to release substances that kill pathogens and infected cells.
Furthermore, macrophages can produce cytokines by the names of interleukin 1 (IL-1) and interleukin
6 (IL-6). It is therefore very common to find IL-1, IL—6, and TNF-or present together during an immune
threat.
Inside of these large, eating killing machines, reactive oxygen species like superoxide anion and
hydrogen peroxide are produced. Hydrogen peroxide is a very powerful anti-bacterial agent. Also
produced are reactive nitrogen species like nitric oxide and peroxynitrite—all toxic to bacteria.
When macrophages are overwhehned by an attack, they send signals for another type of immtme cell to
join the battle; neutrophils. These cells circulate in blood and are attracted to the site of an infection.
Neutrophils are professional killers once activated. Because of that, you don’t want too many of these
hanging around for prolonged periods, or you risk some serious damage to surrounding tissue and
organs.
In fact, the substances emitted by neutrophils, including TNF—0t and IL-1, can literally liquefy both cells
and connective tissue. For that reason, these cells have a life of only about five days, after which they
are programmed to kill themselves.
I want to briefly highlight some of the different types of inflammatory cytokines that are secreted by
activated macrophage cells:
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Note that all but one of these cytokines are secreted by activated macrophages. On the right, we can
read what tissues and other parts of the immune system these cytokines aiifect. NK stands for natural
killer cells, and MI—IC stands for major histocompatibility complex. MHC proteins act like billboards
alerting immune cells to what is going on inside an infected cell.
Cytokines often overlap in the effects they have on cells and tissues, so there is a bit of redundancy
built into the system. Note that LL-1 and TNF-or both act on the vasculature, causing inflammation.
While it would be incorrect to treat these cytokines as interchangeable, we can say they share some
commonalities as seen in the following chart:

Endogenous pyrogen fever + + +
Synthesis of acuteohase
proteins by liver + + +
increased vascular permeability + + +
increased adhesion molecules
on vascular endothelium + e —
Fibroblast proliferation + + —
Platelet production + — +
Chemolone induction (eg., IL-8) 4- + —
lnciuerlon of lL-5 + + —
T·cell activation + r +
B-cell activation + + +
increased immunoglobulin
synthesis — – +
Plus signs show that the cytokine in question has an effect, where a negative sign shows the opposite. I
won’t be detailing what these effects are, but wanted to show you that many of these actions overlap.
I want to focus on TNF—0t because it is a very powerful pro-inflammatory cytokine that is always
produced when bacteria, especially gram-negative bacteria, breaches the gut wall. This cytokine derives
its name from an observation made by a surgeon called William Coley at the turn of the 20th century.
What Dr. Coley observed was that when some of his cancer patients developed a certain type of
bacterial infection, their tumors would begin to die. In the belief that he might have stumbled upon a
cure for cancer, he began injecting what were called “Coley’s toxins” into patients. While it did induce
tumor death, there were a significant nturrber of side eifects making his cure highly unsuitable.
And the reason why was because “Coley’s toxins” were what we now call lipopolysaccharides.
However, it wasn’t the LPSs that had this effect, but the release of TNF—ot.
The name ttunor necrosis factor didn’t come into use until much later. This cytokine was originally
named cachexin. W’hy? Because it caused cachexia when secreted in large amounts.
Cachexia is a wasting away of the body due to illness, and TNF—ot appears to be the proximate cause of
this debilitating condition. This discovery was iirst made when infected rabbits were observed to lose
half their body weight after a two—month infection.
Both TNF—<1 and IL-1 reduce the desire to eat, so both are classified as anorexic cytokines. They also ramp up metabolic rate, both as a consequence of fueling the energy requirements of an activated immune system, and as a result of inducing increases in body temperature to fuel fever. Note that both actions are opposite to what cortisol does, namely increase appetite and slow metabolic rate. In fact, many of the actions of TNF-ot oppose those of cortisol and vice versa. Where chronic cortisol release raises blood pressure, inflammatory cytokines if unchecked can cause life-threatening drops in blood pressure. Cortisol increases blood glucose levels, while TNF-or can lead to very low blood-glucose. Cortisol excess causes elevations in LDL cholesterol, TNF-ct causes a decrease in the same. Ll) But while LDL levels decrease, the LDL particles that are left tend to be of the small, dense variety, which are considered more atherogenic. One area where TNF-or and cortisol seem to have synergistic effects is in the genetic expression of adipose or fat tissue. Both promote pathways that cause adipose cells to differentiate into a type that causes the body to accumulates fat as visceral fat, and not as less metabolically active subcutaneous fat. Both also cause fat breakdown. However, in those with either elevated sertun and/or cellular cortisol levels, this fat breakdown is overcompensated for by stimulation of eating behavior that results in overall weight gain. In situations where TNF-ot is not adequately opposed by endogenous cortisol secretion or metabolism, the anorexic effect of this cytokine, along with IL-1, leads to an overall decrease in appetite. When coupled with the overall catabolic actions of both TNF—0t and whatever cortisol is being released, a condition akin to anorexia is typically observed. I’ve simplified things a bit; however, my purpose is to get you to understand how wide—ranging these immune reactions are in response to invading pathogens, including those caused by increased intestinal permeability. Now the immune system has a number of mechanisms to make sure these reactions are self—limiting to prevent damage to healthy cells and tissue. For example, the type 2 macrophages I spoke of earlier are involved in ending these inflammatory cascades and promoting healing. However, as in the case of autoimmune disorders, these mechanisms don’t always work. Once again, for the sake of brevity, detailing what those immune mechanisms are is far beyond the scope of this post. · But as I’ve already hinted, these anti-inflammatory mechanisms are not strictly limited to the immtme system. The hormonal system is also involved in keeping a lid on these processes, with cortisol as the primary counterweight to uncontrolled immune activation. Inflammatory immune activation always calls forth compensatory anti-inflammatory responses that lead to an increase in cortisol secretion, and its conversion from inactive forms to active ones. It appears strange that the body increases the secretion and metabolism of an anti-inflammatory substance like cortisol (which can potentially lead to all the side effects I covered in the first act) at the same time its own immune system is busy creating inflammation to kill invading pathogens. Why would the body take back with the right hand what it gives with the left? Because runaway inflammation can kill you. In the case of bacterial sepsis, for example, it’s not the infection that kills the patient, it’s the runaway immune response—inflammatory cytokines, reactive oxygen species, reactive nitrogen species—that can cause severe tissue damage and organ failure. In fact, sepsis patients who for whatever reason are least able to produce cortisol in response to acute immune activation are also less likely to survive this life-threatening condition. Q) Known as critical illness—related corticosteroid insufficiency, this inability of the body to tamp down a runaway immune response contributes to the high mortality rate in this group of patients. In the first act I wrote: “To use a metaphor, cortisol is an active dance partner of inflammation and the cytokines that drive immune responses. It often moves left when inflammation moves right, back when the other moves front.” And indeed, that’s precisely what cortisol does. The ‘yin’ to inflammation’s ‘yang’, cortisol, like so much else in the body, has more than one role to play. While it clearly can cause us problems when in excess, it also protects us from an immune system that if left unchecked, can run amok and kill us. In a nutshell, when there is immtme activation, cortisol is working right along with it to keep things under control. There can be no gut dysbiosis without immune activation. And there can be no immune activation without compensatory cortisol release and/or metabolism. Imbalances can occur between inflammatory immtme responses and the anti—inflammatory actions of cortisol. I’ve already hinted at two instances in those exhibiting anorexia and those septic patients who fail to pull through their infections. I’ll have more to say about this in the next act. In addition, I’ll briefly explain how cortisol is regulated, and how infIammatory—immune responses call forth cortisol secretion from the adrenals. And within cells, we’ll see how inflammation, with the aid of ll[?»-hydroxysteroid dehydrogenase type 1, amplifies the many acts of Cortisol. In today’s post, I’ll be concentrating on how cortisol is regulated by the body, and how these regulatory systems are shaped by immune activation. There is a happy meditun where hormone concentrations within a defined lower and upper limit result in the best health outcomes. However, go outside those boundaries for extended periods and bad things begin to happen as we saw with both adrenal insufficiency and cortisol excess. Some of you may have noted how similar the symptoms of glucocorticoid overload are to syndrome X or metabolic syndrome. Metabolic syndrome has many of the same symptoms as Cushing’s syndrome: abdominal obesity, elevated blood pressure, high fasting blood glucose, raised triglyceride levels, high LDL and low HDL cholesterol levels. F or a while now, some researchers have defined metabolic syndrome as a form of Cushing’s syndrome. However, where Cushing’s patients consistently display elevations in plasma cortisol, persons with metabolic syndrome typically do not. Nevertheless, disturbances in daily plasma cortisol levels have been regularly noted in this group. And women with metabolic syndrome have higher urinary excretion of cortisol metabolites. I believe there is a good explanation for these observations. However, before I get to that, I really need to cover how cortisol is regulated by the body. The Hypothalamic-Pituitary—Adrenal (HPA) axis Whenever the brain perceives stress, including the stress of infection, corticotropin releasing hormone (CRH) is secreted by the paraventricular nucleus of the hypothalamus. This hormone then travels to the pituitary where it acts on receptors in the anterior lobe of this gland. In response, the pituitary releases adrenocorticotropic hormone (ACTH). ACTH acts by binding ACTH , receptors in the adrenal glands. This m turn stimulates secretion of cortisol. Free, unbound cortisol is t now able to attach to receptors in a variety of sites throughout the body. The increase in plasma cortisol concentrations reacts back on the brain not only to inhibit further release of CRH by the hypothalamus, but also of ACTH from the pituitary. In other words, a rise in plasma cortisol calls forth a decrease in the hormones that caused the adrenals to secrete it in the first place. However, if there is a pituitary tumor as in Cushing’s disease, this feedback loop is never closed. Instead, the pituitary gland continues to pump out ACTH oblivious to signals that cortisol is already at high levels. In other cases, tumors that are not part of this HPA—axis can also release ACTH to stimulate cortisol release. For example, some small-cell lung carcinomas do this. However, it’s well beyond the scope of today’s post to explain the many ways this axis can be affected by tumors. However, the I—IPA—axis isn’t the only way cortisol is regulated by the body. For that, we need to look at another system, this one having to do with the metabolism of cortisol within cells. The Cortisol-Cortisone Shunt {rig J f” · ei .; · inns-·¤=’!!!’C-nr-. `_._ vv I A rg » ‘‘ ` 5 ` ‘ ’ _ ‘‘` v_ `lI,E~HSC?’l __.` U V ` ( A { 1,; ; l . o 3 T1;Z;i‘l.!. { * EA; :°` ¤}..‘ if- Hi = · ,;*1**; Q; arti:}. ‘ if ·· $:’l;25.· “T.s V Courtesy: Greenspan S Basic & Clinical Endocrinology 9th Ed Recall that cortisol bound to a protein might as well not exist as far as the body is concerned. Bound cortisol is biologically inactive. But there is another way for the body to inactivate cortisol, and that is by converting it to cortisone. Cortisone is also biologically inactive. But why would the body do this’? Cellular enzymes exist that can not only convert active cortisol to inactive cortisone, but can reverse the process by changing cortisone back to cortisol. These enzymes are IIB-HSDI and IIB-HSD2. Both are shown in the two yellow ovals of this graphic. These abbreviations, by the way, stand for IIB-hydroxysteroid dehydrogenase type I and IIB- hydroxysteroid dehydrogenase type 2. Let’s start with the type 2 thing first. The burgtmdy blob on the right represents the kidneys, and attached to the kidneys are the adrenals, site of cortisol production and release. What you’re seeing illustrated here is that cortisol is converted from its active form to cortisone by ll B- HSD2 within kidney cells. Also seen here is that kidney tissue expresses mineralocorticoid receptors. See the box in the lower center part of this illustration? The one that starts with kidney colon, etc.? Those are sites that contain mineralocorticoid receptors. This isn’t an exhaustive list by the way, but good enough for today’s purposes. Recall that cortisol not only binds to glucocorticoid receptors, but also to mineralocorticoid receptors. And cortisol has a higher aitinity for mineralocorticoid than for glucocorticoid receptors. Binding to these receptors can mimic the actions of aldosterone. Aldosterone is another hormone produced by the adrenals involved in blood pressure regulation. Aldosterone plays this role by acting on the sodium, potassium, and water retention system in the kidneys. Dysregulation of this system by this hormone is a major contributor to hypertension. If l1B—HSD2 did not convert cortisol to inactive cortisone in kidney cells, cortisol would bind to these I receptors causing a chronic increase in blood pressure. So 11B-HSD2 plays a very critical role in preventing cortisol from doing this. However, when plasma cortisol levels are high, the inactivating function of l1B—HSD2 can be overwhelmed leading to chronically high blood pressure. Cortisone can be converted back to cortisol by the enzymatic actions of IIB-HSD1. This is seen on the left-hand side of this graphic where the liver is represented. The overwhelming majority of this enzyme’s action, but by no means all, occurs here. In the liver, cortisone is reconverted to cortisol and the free hormone is once again capable of binding to both glucocorticoid and mineralocorticoid receptor sites throughout the body. See the box in the upper—left-hand corner? These are some of the tissues that express glucocorticoid rec Jptors. But again, this list is by no means exhaustive. OK, so what I want you to take away Hom all this is that the cellular enzymes IIB-HSD1 and 11B- HSD2 have opposite actions when it comes to cortisol metabolism. All things being equal, if 11B—HSD1 enzymatic activity is predominant, more cortisol will be generated from inactive cortisone within cells and tissue. Conversely, if there is more l1B—HSD2 activity, the opposite occurs.L HY Immune Activation and Cortisol Secretion snaupuzna itz? 1-typothalamus cm-i u.-1 Aw u.-6 \ Anterior C¤rI¤¤|’ I ··r.V Immune System rg nne »t ··¤¤= 2;, n·ei Adrenal Cortex l Gut Pathogens Many of you are already familiar with this graphic from my post The Gut—Brain Axis: How Endotoxemia and “Leaky Gut” Impact the Hypothalamic-Pituitary-Adrenal Axis. There is no need for me to once again explain what I covered in that post, other than to say that this graphic is missing a very, very important player, namely tumor necrosis factor alpha (TNF-ot). In the green box where you see the cytokines interleukin 1 (IL—l) and interleukin 6 (HJ6) represented, TNF-rx should also be listed. It, like IL-1 and IL—6, acts directly on the hypothalamus to cause the release of CRH. This activation of the HPA—axis is, however, self-limiting because of the feedback loop I mentioned above. So in gut dysbiosis, one can argue that stimulation of this axis is apt to occur acutely and not chronically, with digestion of food and drink being a precipitating factor. Note also in this graphic that the inunune system acts on the adrenals by producing what is known as prostaglandin E2 (PGE2). Prostaglandins are lipid compounds produced from certain polyunsaturated fatty acids (PUFAS). In the case of PGE2, that fatty acid is arachidonic acid, an omega 6 PUFA. Immune cells like monocytes and macrophages produce large quantities of PGE2 when activated by bacterial toxins from the gut. Immune neutrophils also produce PGE2s, but in moderate amounts. So this is another way the adrenals can be stimulated to secrete cortisol when pathogens breach the gut wall. Immune Activation and the Cortisol—Cortis0ne Shunt However, immtme activation from a leaky gut does not only impact the adrenals via the HPA axis or PGE2 generation. Pro-inflammatory cytokines like TNF -a and IL—l also lead to an increased expression of the intracellular HB-HSDI enzyme that converts inactive cortisone to active cortisol. Q) Now, what’s important to remember is that this conversion is taking place within cells, not outside them. In other words, where stimulation of the HZPA axis and increases in PGE2 formation are likely to be noticeable as elevations in plasma cortisol when measured by a saliva, blood, or urine test, what occurs within cells cannot be detected by these same tests. The only way to note an increase in 11B- HSD1 enzymatic activity would be by tissue biopsy. And this means that if a standard test for cortisol d0esn’t register systemic elevations in this hormone, that doesn’t mean that intracellular concentrations are not high. On the contrary a lot of recent research has shown that an increased conversion of cortisone to cortisol within cells may be the key to Lmraveling the mystery of metabolic syndrome. In rodents, inhibition of or genetic deficiency in 11B-HSDI improves insulin sensitivity in the liver and fat tissue. It also slows production of glucose by the liver, changes the lipid profile of these rodents to one that is “heart healthy”, reduces or reverses accumulation of fat in the liver, and causes fat to be stored as less dangerous subcutaneous fat and not pro—inflammatory visceral fat. (LQ) fg) LQ) LQ) Conversely, mice genetically bred to overexpress this same enzyme in their fat tissue become obese, develop high blood pressure, show a lipid profile conducive to heart disease, and are insulin resistant. (Q) Mice who are bred to selectively overexpress 11B—HSDl, but only in the liver, do not become obese. However, they exhibit insulin resistance, develop fatty livers, hypertension, and an atherogenic cholesterol profile. (LQ). In humans with type 2 diabetes, inhibition of 1lB—HSD1 also lowers plasma glucose levels and cholesterol markers for heart disease. Inhibition has also shown promise in reducing high blood pressure. (Q’) §_l§) (Q) This improvement in blood pressure is no doubt due to less cortisol attaching to the mineralocorticoid receptors in the kidneys. TNF-or also induces a decrease in 115-HSD2, the enzyme that converts cortisol to inactive cortisone. This too would affect the kidneys’ regulation of blood pressure. As we said before, this up-regulation of cortisol metabolism is good as a way to counterbalance immune activation. The anti-inflammatory actions of cortisol also aid in the eventual resolution of the immrme response. But if acute immune activation doesn’t resolve, then we have chronic immune activation, and along with it comes the potential for chronic conversion of cortisone to cortisol within a whole host of tissues: the liver, muscles, kidneys, fat, arteries, central nervous system, etc. This suggests that metabolic syndrome is just another form of glucocorticoid excess, but one that is more likely to affect the cortiso1—cortisone shunt rather than the HPA-axis. It is for this reason that plasma cortisol concentrations can appear normal in those who have type 2 diabetes or are morbidly obese, yet within cells generation of cortisol remains elevated. And with its elevation, many of the effects of glucocorticoid excess become obvious.The kaleidoscope of glucorticoid efzcts on immune system $20) I’ve reprinted this chart from the first act illustrating the myriad effects glucocorticoids like cortisol have on immune cells, including macrophage cells represented in the upper-right-hand corner in orange and labeled MCD. What I want to emphasize is how low doses of cortisol, and that includes cortisol generated within cells, augments the inflammatory actions of these immune cells. Secretion of inflammatory cytokines by these macrophages induces an increase in the 6 izymatic actions of llB—HSDl, that in turn causes cortisone to be converted to cortisol. And that reacts back on these same macrophages to cause them to release even more inflammatory cytokines. This feed-forward system is prevalent in many tissue types, but seems particularly active in visceral, as opposed to subcutaneous, fat. This turns this type of adipose tissue into a chronic generator of both cortisol and inflammatory cytokines. I have argued from the start that gut dysbiosis is often the source of the irmnrme activation and consequent cortisol release and metabolism that underlies many chronic disease states. This hypothesis of gut dysbiosis setting in motion the inflammatory-cortisol ballet can explain why diet can have such a profound effect on health. We can predict that those foods and drinks that nourish beneficial gut flora, and by doing so support gut wall integrity, would be expected to inhibit this inflammatory cascade. Conversely, those foods and drinks that damage these organisms, and by doing so compromise gut wall integrity, would be expected to increase the ntunber of times this “ballet” is performed as well as its duration. Psychological Stress Now, no one should take this to mean that I’m discounting the role psychological stress plays in the onset of disease. Far from it. The research is pretty clear that chronic psychological stress increases the risk for many diseases, including cardiovascular disease. Psychological stress is more than capable of negatively impacting the health of our gut bacteria as well as compromising gut-barrier function. Someone who also sulfers from gut dysbiosis is at a far greater disadvantage when it comes to handling the stresses of life than someone who doesn’t. For in such situations, any psychological stress is piled on top of an irmntme and hormonal system that is already chronically activated. As I’ve blogged before, gut dysbiosis and the inflammatory-cortisol cascade provoked by this, negatively affects emotional well-being and the ability to handle the challenges of everyday life. It is not in the least bit unusual to note improvements in mental health and outlook in those who successfully overcome their gut issues. Never forget that the gut—brain axis is a two—way street. 4: wk is >¥ wk :2
The inflammatory-cortisol ballet can explain many of the disparate symptoms seen in those suffering
from various forms of gut dysbiosis.
For example, let’s consider someone with confirmed metabolic syndrome. They are obese, have
elevated fasting blood glucose, high triglyceride levels, high LDL levels, sulfer from hypertension,
osteopenia, and insomnia. In other words, they manifest many of the symptoms of cortisol excess we
read about in act one.
In this situation, inflammation, or to be more precise, inflammatory cytokines like TNF -0t, IL-], and
Hi—6 are causing an increase in intracellular cortisol metabolism separate and apart from any transient
cortisol spikes from stimulation of the HPA—axis. And this immune activation is being caused in
response to lipopolysaccharides (LPSs) and other gut components (yeast, gram-positive bacteria, etc.)
coming through the gut wall due to increased intestinal permeability.
Now inflammation is clearly driving cortisol secretion and metabolism. However in this case, what is
most noticeable are the actions of Cortisol, not those of Inflammation. In other words, the symptoms of
glucocorticoid excess are in the forefront, yet the underlying immune activation that’s driving the entire
process is hidden from view.
Now what if we really cranked up gut permeability? Would the results be the same?
Let’s say we look at another person, a heavy drinker, say they consume at least a fifth of whiskey per
day. And let’s also say that this person is a heavy cigarette smoker, on the order of two to three packs a
day. You can tell they’re heavy smokers by looking at the yellowed and rotting teeth in their mouth, a
sure sign of oral dysbiosis.
Due to their oral dysbiosis, many of these mouth pathogens are swallowed daily. Given how binge
drinking reliably raises stomach acid pH, many of these bacteria happily make their way to the gut
tmdisturbed. Here they displace beneficial bacteria, adhere to the gut wall, and with the help of
alcohol’s metabolite, acetaldehyde, cause their host’s gut to resemble a sieve. In other words, they too
have gut dysbiosis but on another level entirely.
As in the case of the person with metabolic syndrome, cortisol is being released from the adrenals in
response to translocating gut pathogens and irmnune activation. And the same goes for conversion of
cortisone to cortisol within cells. But this person’s immune system is really pumping out copious
amounts of cytokines to deal with the bacterial onslaught.
In this case, unlike in our first example, we are more apt to notice the actions of Inflammation rather
than those of Cortisol.
And indeed, the smoking alcoholic is extremely gaunt and pasty looking. The reason for this is that his
body is undergoing a form of cachexia. Partly caused by the anorexic effect these inflammatory
cytokines have on appetite, but also due to sped up metabolism and overall catabolism. Any
compensatory weight-enhancing effects cortisol would normally have—increase in hunger and slow
down in metabolic rate due to euthyroid sick syndrome—are swamped by the intense inflammatory
response.
Yes, Cortisol is still working like mad. However in this case, Inflammation is outdoing it, and Cortisol
just can’t keep up, let alone rein it in.
Should our alcoholic smoker never attain sobriety, or die an accidental death, pneumonia, cirrhosis, or ¢
cancer will kill him.
This imbalance between immune activation and the anti—inflammatory actions of cortisol may also
explain why reducing, yet not entirely eliminating, increased intestinal permeability can paradoxically
result in weight gain for some ex alcoholics and/or smokers. The weight—enhancing effects of cortisol
now come to the forefront, while the anorexic effects of inflammatory cytokines recede.
Of course, genetics also plays arr important role in how this all goes. For example, in people who are
efficient at producing cortisol in response to immune activation, the effects of glucocorticoid excess
would be more apparent than in low cortisol responders. And ii as in the rodent study I cited above, the
IIB-HSD1 enzyme is overexpressed in the htunan liver, but underexpressed in fat cells, metabolic
syndrome would be noticeable, but without the typical weight gain seen in most people with this
disorder.
STRESS
The ability of translocating gut pathogens to stimulate this axis is central to understanding how
elevations in glucococorticoids, like cortisol, will negatively impact basal metabolic rate. In response to
gut pathogens breaching the gut wall, the irrmiune system produces inflammatory cytokines
and prostaglandins to stimulate the production of cortisol.
Increases in cortisol, whether caused by endotoxemia or psychological stress, always compromises gut-
barrier function, both in the small intestine and colon. And once gut dysbiosis sets in, the chronic stress
response this elicits will continually stimulate increased intestinal permeability and cortisol release in a
feed—forward manner. Thyroid hormones and metabolic rate will also be impacted.
The hypothalamus is the primary regulator of metabolic rate and does so through the hypothalamic-
pituitary-thyroid axis. The hypothalamus secretes thyrotropin—releasing hormone (TRH) in a pulsatile
fashion throughout the day. TRH, in turn, signals the pituitary gland to release thyroid-stirnulating
hormone (TSH). TSH causes the thyroid gland to release two forms of hormone, thyroxine, known
more cormnonly as T4, and triiodothyronine, known as T3. Of the two types, T3 is from three to four
times more metabolically active than T4.
Both types of thyroid hormone require iodine derived from diet for their production. Therefore, not
getting enough iodine from your diet can impair synthesis of these vital honnones as can malabsorption
caused by small gut dysbiosis. The enzyme responsible for converting T4 to T3 requires selenium, so
low levels of this element due to low dietary intake or malabsorption will also interfere with thyroid
hormone synthesis. Other elements like bromine can interfere with this system, but I’ll forgo discussing
this for now.
The thyroid produces anywhere from 70% to 80% of T4 and 20% to 30% of T3. As previously
mentioned, a certain quantity of T4 is converted in various peripheral tissues and organs to the more
metabolically active T3 in a process known as deiodination. Of the organs responsible for this
conversion, the liver and kidneys rank first and second. Note that both these organs are also responsible
for the majority of detoxification ftmctions in the body, and would be most vulnerable to damage
caused by translocating gram-negative bacteria and their cell—wall remnants, lipopolysaccharides.
Thyroid hormone increases metabolic rate, secretion of growth hormone and catecholamines. The
catecholamines include dopamine, norephinephrine, and adrenaline.
Now this is an admittedly simplified overview of thyroid hormone synthesis and function. For example,
there are differences between the amount of free or bound thyroid hormone in blood serum, the
production of transport proteins by the liver, the level of metabolically inactive reverse T3, the extent
and health of various thyroid receptors throughout the body, and the rate thyroid hormone is degraded
and excreted.
And a lot can go wrong with this system, including autoimmtme disorders like Graves’ disease
(overactive thyroid) or Hashimoto’s thyroiditis (underactive thyroid). Nevertheless, even when the
hypothalamus, pituitary and thyroid gland are all working properly, chronic stress and LPSs will
depress metabolic rate.
It is well doctunented that acute cortisol release as occurs in sepsis, can directly depress secretion of
TSH from the pituitary gland and suppress downstream thyroid hormone release and conversion. Q_)_
While chronic endotoxemia appears to spare direct damage to the hypothalamic-pituitary-thyroid axis,
at least initially, it does lower metabolism by promoting euthyroid sick syndrome (ESS).
In this syndrome, levels of both TRH and TSH are normal, as are production of both T3 and T4 by the
thyroid gland. In fact, clinical tests that fail to directly measure levels of serum T3 or reverse T3 will
typically show no abnormalities in someone experiencing ESS.
The mechanism for metabolic derangement in euthyroid sick syndrome appears to be two-fold. First,
translocating LPSs will directly down-regulate thyroid receptor activity. Q.) All hormones require
properly functioning receptors to affect biological processes. By interfering with receptor activity in the
liver, lipopolysaccharides prevent these thyroid hormones from carrying out their ftmrtions even when
their levels are in the normal range.
Secondly, stress hormones directly reduce the conversion of T4 to T3 in the liver, kidneys, and other
peripheral organs. They do so because one of the functions of glucocorticoids is to shuttle energy to the
brain and the heart in emergencies. Chronic stress, however, is a never—ending “emergency” that causes
chronic stimulation of the HPA axis and cortisol release. QL
Another cause of euthyroid sick syndrome is malnutrition brought about by starvation, fasting, or as I
described here, malabsorption. lf you are not properly digesting and absorbing nutrients from food
because of small gut dysbiosis, your body is under stress, and stress will cause depression of metabolic
rate. Add in endotoxemia and the stress response is further amplified.
Following are some common symptoms seen in those experiencing euthyroid sick syndrome:
· dry skin
· low basal metabolic rate
· insomnia
· constipation
· heart rate under 60 beats per minute (bradycardia)
· hypothermia or feeling cold, especially in the extremities
· absence of menstrual periods in women of reproductive age (amenorrhoea)
· difficulty losing weight even with calorie restriction
· having low energy, feeling tired
Many people who battle weight issues are very familiar with this list of symptoms. It’s not uncommon,
for example, for people experiencing endotoxemia- and/or malnutrition-induced euthyroid sick
syndrome to have cold hands and feet. I’ve known many people who can’t tolerate sitting near or under
a fan even on a hot day because they can’t tolerate any amotmt of cold. And many of these same people
suffer from constipation and chronic fatigue.
While elevated cortisol levels cause a breakdown of tissue to fuel a rise in glucose production in the
liver, it simultaneously depresses fat burning (lipolysis) by inhibiting the release of growth hormone
from the pituitary gland. While acute endotoxemia can stimulate growth hormone release ir1 the short-
term, chronic endotoxemia arrests its secretion.
Growth hormone stimulates cell growth and regeneration in humans. It’s what is responsible for the
rate of growth in children and young adults. Growth hormone is an anabolic agent whereas cortisol is a
catabolic agent. It builds up your muscles while cortisol breaks them down. Some important functions
of growth homrone apart from stimulating height in children include:
· increasing growth of muscle mass
· promoting breakdown of stored fat for use as fuel
· increasing bone density and buildup by retaining calcium
· increasing synthesis of protein
· stimulating growth of all internal organs except the brain
· stimulating the immune system
· maintaining the proper functioning of pancreatic cells responsible for blood glucose control
Chronic stress will inhibit all of this. Trying to lose weight and build muscle (not to mention bone) will
be very difficult to do when chronic stress is inhibiting the secretion of growth hormone.
Stress hormones also reduce gonadotropins. Gonadotropins are hormones that regulate reproductive
development and function. The two principal types of gonadotropins are follicle-stimulating hormone
(F SH) and luteinizing hormone (LH).
In women, FSH and LH work together to start ovulation, making both hormones absolutely vital for
reproductive function. In men, FSH is important for proper sperm formation and LH is responsible for
the production of testosterone in the testes. As sex hormones also increase lipolysis and promote
growth of muscle mass, inhibition of these biological agents will make fat loss harder to achieve.
In fact, increased weight gain is a common finding in those with Cushing’s syndrome. Cushing’s is
caused by a tumor on the pituitary gland that causes increased release of adrenocorticotropic hormone
(ACTH). This in turn increases the production of cortisol by the adrenals. Cushing’s patients typically
have decreased lean body mass, increased visceral fat, osteoporosis, and depressed immune function.
To sum up, increased HPA axis stimulation is associated with:
· central obesity
· insulin resistance
· hypertension
· high-blood glucose
· decreased lean-muscle mass
· inability to breakdown stored fat for use as fuel
· allergic reactions
· migraines and headaches
· pain (abdominal, pelvic, low-back)
· cardiovascular disease

· osteopenia and osteoporosis
· protein breakdown
· immune system dysfunction
· pancreatic dysfunction
· severe chronic disease
· melancholic depression
· obsessive-compulsive disorder
· panic disorder
· anxiety
· excessive exercise (obligate athleticism)
· alcoholism
· malnutrition
· diabetes mellitus
· dry skin
· low basal metabolic rate
· constipation
· diarrhea
· insomnia
· daytime sleepiness
· heart rate under 60 beats per minute
· intolerance to cold
· absence of menstrual periods in women of reproductive age
· diiiiculty losing weight
· tiredness and fatigue
One last point. Appetite is either stimulated or inhibited by the stress response. One thing I left off this
list is anorexia. It too has been associated with raised cortisol secretion via a stimulated HPA axis.
Scientists are still investigating the precise mechanisms that influence how stress hormones affect
appetite, and why that varies from person to person.
How disease and inflammation cause sleep problems. `
In a healthy person experiencing normal levels of plasma cortisol and adjusted to a typical daytime
schedule, cortisol levels are lowest at around midnight or about two to three hours after falling asleep.
At this point, levels gradually begin to rise into early moming and dramatically increase after waking.
In most people, plasma cortisol jtunps about 50% thirty or so minutes after getting up from bed. This is
called the Cortisol Awakening Response.
Cortisol levels peak around 9 a.m. and as the day continues, begin to decline until again reaching their
lowest levels two to three hours after sleep commences.
What this means is that not only are the daily fluctuations in the level of melatonin important, so too
the variations in cortisol production. So we can also say that anything that alters cortisol production
during the evening and night will negatively impact sleep every bit as much as changes in melatonin,
serotonin and hypothalamic ftmction.
For today’s topic, it’s enough to emphasize that gut pathogens will provoke an immune response that
will increase levels of cortisol; both via cytokine stimulation of the hypothalamus and direct
stimulation of the adrenals by the prostaglandin pathway.

Cortisol directly impacts the central nervous system. It decreases REM sleep but increases shallow
sleep or time spent awake which is good if there is an external threat. However, chronically elevated
cortisol is not good if you need to get some sleep.
In a nutshell, increase levels of cortisol during the evening and night, and your chances of getting to
sleep or staying asleep are about as likely as meeting a unicorn.
Very low blood-glucose levels can also cause sleep problems. If blood sugar drops too low at night to
adequately supply brain and other cells, you may be jarred awake by a rise in cortisol to raise blood
glucose and initiate feeding behavior. This is what happens during starvation or glucose deficiency.
I consider insomnia the proverbial canary in the coal mine. It is highly associated with cardiovascular
disease, diabetes, obesity, cancer, skin diseases, gastrointestinal disorders, depression, anxiety, mood
swings and dementia. It often predates these diseases by years, if not decades. And the reason this is
true is because these disorders have a common cause—gut—derived inflammation.
I want to emphasize that translocation of gram-negative bacteria and their ce1l—wall remnants,
lipopolysaccharides (LPS), are not the only sources of inflammation from the gut. Overgrowth of yeast,
antigens from various foods, viral infections and intestinal parasites can all cause inflammation due to
compromised gut barrier function.
And in extreme breaches of the intestinal gut wall, even normally fiiendly gram-positive gut flora can
threaten our very existence.
One other point. This chronic inflammation has the potential to damage cells, including the cells in the
suprachiasmatic nucleus of the hypothalamus, site of your biological clock. How long it takes for this
to happen or how reversible this damage is, is anybody’s guess.
Tryptophan Metabolism
But the story doesn’t end here. Recall that melatonin is also involved in regulating our sleep—wake
cycle. And recall that the pineal gland requires serotonin to produce melatonin.
Allow me to reproduce two graphs to illustrate what this means for sleep:
SE. yered 5-HT -• ‘HZRFFAVP ·
{ tryptcvphan / ZE. if
Adrenal Caffe:
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Pathogens aj · . I micrubmta
Prubictics
Gut—derived inflammation not only affects the hypothalamic-pituitary—adrenal(HPA) axis as seen on theright—hand side of this illustration, it also directly increases the production of an enzyme called
indoleamine 2,3 dioxygenase or IDO in the liver.
IDO suppresses T—cel1 production, an immensely important set of immtme cells. One subset of T—cells,
natural killer cells, are your first line of defense against cancer. The more HDO produced, the more
compromised your immrme system becomes. This is a major reason increased cortisol levels depresses
immune function and why inflammation is associated with cancer.
But H)O is also important because it degrades tryptophan, the precursor of serotonin and serotonin’s
metabolite, melatonin, to kynurenine. The more tryptophan shuttled to the kynurenine pathway, the less
is available for the production of serotonin or melatonin. And the less melatonin produced, the less
likely you are to feel drowsy when it’s time to go to bed. While melatonin is inhibited by light, it isn’t
the only thing affecting melatonin for the worse.
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At the bottom of this chart, you can see how increases in the inflammatory cytokines IFN-ot, IFN—y and
TNF-ot, but not lL—4 or 11,-10, stimulates the production of [DO leading to a decrease in tryptophan
available for later melatonin production. Instead, tryptophan is converted to kynurenine, which
increases the production of both 3-hydroxy-kynurenine (3 —OH-KYN) and quinolinic acid (QUIN), both
of which easily cross the blood-brain barrier.
These metabolites are implicated in the following disorders:
· Parkinson’s disease
· Huntington’s disease
· AIDS-related dementia
· Alzheimer ’s disease
. · infections ofthe central nervous system
· malaria
· ischemia or blood supply restriction
· traumatic injury
· hypoxia at birth
· epilepsy V
· schizophrenia
3—OH—KYN generates lots of free radicals that damage cell components in the brain, including DNA,
and causes increased cell death or apoptosis.
QUINN also causes oxidative stress, depletes cellular energy and is an excitotoxin. Excitotoxins cause
an excessive release of excitatory neurotransmitters that damage nerve and glial cells eventually
resulting in cell death. It would not surprise me that the obsessive thoughts that rack the brain of many
an insomniac in the middle of the night are due not only to increased cortisol levels, but also increased
concentrations of quinolinic acid.
Nor would it be shocking that the hypothalamus itself including the cells of the “master” biological
clock, are similarly damaged by these toxic metabolites.
Melatonin is also a powerful antioxidant. By reducing its production, IDO not only im; acts sleep, it
inhibits the synthesis of a very powerful free radical scavenger.
Finally; recall that: “. ncommtmication between the gut and brain is not one way. Tratunatic events can
trigger intense stress that can impair gut barrier function by initiating an inflammatory response after
cortisol release from the adrenals, especially in the presence of already disordered gut flora.
This increased intestinal permeability can in turn cause a translocation of pathogens or other antigens
from the gut into systemic circulation that then sets up a positive-feedback loop: chronic inflammation
leading to increased HJO and cortisol production, leading to increased oxidative damage in the brain
and leaky gut, leading to more inflammation, etc.”
The stress involved by repeatedly failing to get a good night’s sleep will also contribute to this vicious
feed—back loop.
When Getting to Sleep is the Least of Your Problems
Not all inflammation results in sleeplessness. On the contrary, intense immtme responses can result in
the opposite: inability to stay awake or remain conscious.
Why would this be? Cortisol is always released in stressful situations and acute ilhiess is a stressful as
it gets. As I wrote in my post on the HPA axis,
“. . .when cortisol production is increased glucose output in the liver goes up and glucose uptake by
muscle, fat and other tissue goes down resulting in a rise in blood—glucose levels. In order to increase
glucose production in the liver, it breaks down protein and fat in muscle, fat, connective and lymphoid
tissue so the liver can produce glucose from these building blocks. Doing so mobilizes energy for the
brain and the heart which makes sense in an emergency. ..”
If this breakdown of tissue, also known as catabolism, exceeds the buildup of tissue or anabolism,intense tiredness will result, overwhelming the waking signals from cortisol.
Let’s say you come down with a very bad flu. Cortisol levels will increase as a result of your immtme
system’s response to the virus. However, a number of other things happen as well.
Your body will produce loads of white blood cells to fight the infection, and this requires a lot of
energy. Your vitamin and mineral stores will be depleted. Whatever glucose stores you had will be
broken down to feed the brain and other cells. Thyroid function will be impacted for the worse,
especially if you already have low function to begin with. IDO production in the liver will increase the
production of QUHQN which depletes cellular energy. And chances are, you’ll lose your appetite, or if
you do eat, you’ll throw it up or it goes right through further depriving your body of the nutrients it
needs.
Is it any wonder so many people lose a lot of weight after a serious infection?
Gut Flora and Insomnia –
If you have chronic insomnia and there are no obvious ilhiesses, external stressors, glucose deficiencies
or sleep hygiene issues to explain why, I can confidently say your answer lies here.
As long as this gut inflammation exists, you will have a very hard time getting a restful night’s sleep.
Your body is telling you something is seriously wrong.
Disordered gut flora or dysbiosis is the source of this inflammation. This dysbiosis can be from either
the small intestine or colon or both. Once your beneficial gut flora is disturbed for whatever reason——
diet, drugs, external stress, environmental pollutants, etc—the chances are high that pathogenic bacteria
and yeast will colonize the gut wall, compromise gut barrier function, translocate to systemic
circulation, provoke a chronic immune response and result in sleep disorders along with much else.
Determining where in your digestive tract the inflammation is coming from can be difficult. Small
intestinal bacterial overgrowth (SIBO) will cause dysbiosis in the colon. Since small intestinal
dysbiosis ALWAYS results in inability to properly digest food, undigested food will reach your colon to
be fermented by both friendly gut flora and pathogens that use it to fuel their growth.
Friendly gut flora is crucial to maintaining the integrity of the intestinal wall and keeping pathogens
from colonizing it. If your friendly gut flora is disordered, your sleep and health are essentially messed
up regardless of how “wholesome” or “Paleo” or “nutrient-dense” or “plant-based” your diet.
It will be impossible to tackle chronic insonmia caused by the hormonal and chemical imbalances
wrought by gut dysbiosis without correcting gut flora. Doing so requires prebiotics, probiotics, an
antiparasitic medication if you have parasites and perhaps an antibacterial if you have SIBO.
Eating fermented foods won’t cut it, not if you’re expecting rapid results. A healthy level of stomach
acid will kill 99% of ingested bacteria within five minutes and that holds true for friendly bacteria in
kefir or yogurt. I recommend fermented foods as part of a long-term diet strategy to support gut flora
populations but not as a short-term corrective.
I recommend that prebiotics be taken in the moming or during the day to avoid any unwanted gas or
bloating from interfering with sleep. Probiotics, on the other hand, should be taken before bedtime. In
fact, a good way to know if the probiotic you’ve chosen is doing you any good is if your sleep
improves while taking it. For some prebiotic and probiotic recommendations, click here.
Alcohol should also be minimized or avoided entirely during treatment. It will be very hard for your
liver to detoxify alcohol and gut pathogens at the same time. And alcohol is well known to cause sleep
disturbances among many other things as explained here.

Endotoxemia, Dysbiosis and Cardiovascular Disease
The holiday season sees more deaths from heart attacks than any other time during the year. (L)
I want to bring to your attention an Italian epidemiological study. This study followed 516 middle-aged
men and women aged 50 to 79 for five years. The researchers measured the levels of
lipopolysaccharides (LPS) in the blood plasma of these study participants.
They were looking to see if the development of atherosclerosis assessed by either ultrasound or an
actual heart or stroke event was increased in those with higher levels of LPS in their blood. What they
found was that those participants who had plasma LPS levels over 50 pg/ml had a three—fold increase
in developing atherosclerosis during the five-year study period. Both smokers and non-smokers with
low endotoxin levels had a low risk of developing vascular disease. However, smokers and ex—smokers
with elevated levels of plasma endotoxin had a l3—fold increase in heart and stroke disease risk. Q_)
In another study, individuals afflicted with inflammatory bowel diseases were at a higher risk of
developing coronary artery disease even though they had lower traditional risk factors (lower levels of
cholesterol, blood pressure, obesity and diabetes) than their age-matched controls. Q) Endotoxins and
dysbiosis are universal findings in those suffering from bowel diseases.
In the Wandsworth Heart and Stroke Study conducted in Britain across multiethnic groups, increases in
LPS correlated with higher cardiovascular disease risk. Q) Unlike the U.S., the black population of
Great Britain has the lowest cardiovascular disease rates. The white British and European population
have higher rates. Topping the list are Indian Asians with a 40% greater incidence of cardiovascular
disease than whites. From the abstract we learn that:
“Age—adjusted endotoxin levels were lower in women than in men and were highest in South Asians
and lowest in individuals of African origin than in whites. Endotoxin levels were positively associated
with waist, waist—hip ratio, total cholesterol, sertun triglycerides and serum insulin levc Ts and
negatively associated with serum HDL-cholesterol?
We know that the presence of LPS in blood plasma impacts the body in many negative ways.
Lipopolysaccharides:
· provoke a robust systemic inflammatory response,
· increase levels of inflammatory cytokines like tumor necrosis factor and interleukin 6,
· increase white blood cell counts, A
· increase the level of growth hormone,
· increase the levels of chemokines like MCP-l and fractalkine. These substances are involved in
recruiting T-cells and white blood cells to the site of injury and infection. MCP—l has been
implicated in rheumatoid arthritis, lupus, kidney and heart disease.
· trigger the increased production of the stress hormone cortisol by their impact on the
hvpothalamic-pituitarv-adrenal axis,
· negatively impact thyroid function, `
· increase transient heart rate at high doses,
· decrease levels of tryptophan,
· alter levels of serotonin,
· reduce melatonin, \_
· increase levels of toxic metabolites that injure brain cells via increased production of 3-
hydroxy—kynurenine and quinolinic acid, ”
· increase the odds of developing an autoimmtme disorder,
· increase levels of C-reactive protein, a marker for inflammation,
· increase the release of free fatty acids into the blood,
· increase levels of resistin, a hormone that promotes insulin resistance,
· increase hormone levels of leptin, a substance involved in long-term weight regulation,
· decrease insulin sensitivity and chronically raise blood glucose levels,
· increase fat-tissue inflammation and,
· induce genetic changes in fat tissue in animals similar to those observed in the visceral fat of
type 2 diabetics.
When LPS binds to the endothelial cells of arteries, it initiates the release of proinflammatory cytokines
leading to endothelial dysfunction, the formation and rupture of plaque, oxidation of LDL cholesterol,
and accelerates the formation of blood clots.
LPS increases the generation of reactive oxygen species or ROS. ROS are what are popularly known as
oxidants and the reason to include antioxidant-rich foods in your diet. While reactive oxygen species
are a normal byproduct of the cellular use of oxygen, too much ROS can cause lots of damage. At
higher levels in response to infection, reactive oxygen species promote cell death as a defense
mechanism to protect the body. Q) This then calls forth macrophages, a type of cell that eats and
disposes dead cellular debris.
LPS’s ability to disrupt the vascular system is a well-known effect of blood poisoning or septicemia. In
this severe form of infection, numerous proinflammatory responses occur including increased
production of molecules that clump cells together (cell adhesion molecules), increased production of
inflammatory cytokines, increased levels of oxidation, reduced integrity of arteries and veins, and
increased rates of cell death or apoptosis along the vascular wall. What’s true of septicemia is also true
for low-grade blood poisoning, aka metabolic endotoxemia as a result of gut dysbiosis. The only
difference is that in the latter case, it can take years or decades before the damage manifests itself as
heart disease or stroke.
You may have heard of foam cells. These cells are composed of macrophages, smooth muscle cells and
oxidized LDL cholesterol and form the fatty streaks known as arterial plaque. If the fibrous cap that
keeps all this intact ruptures, a heart attack or stroke can result if the clot seals off the artery further
down the line.
However, this isn’t all that’s fotmd in foam cells. Bacteria is also consistently present within these
structures and I believe they are the primary reason these cells are formed. Chlamydia pneumoniae is a
common cause of pnetunonia worldwide and is often found as a constituent of arterial plaque. This
pathogen belongs to the gram—negative bacteria family. A previous bout of pneumonia is a risk factor
for a heart attack. {Q) Now you know why.
Another bacteria detected in arterial plaque is Srreptococus mutans, the major pathogen responsible for
dental plaque and a leading cause of tooth decay. Q) There is a well—known, long—standing association
between tooth and gum disease, and cardiovascular disease risk, especially in men under 50. (Q
I used to suffer from some serious dental plaque. Flossing or using a Sonicare® toothbrush twice daily
did nothing to curb it. I had to get my teeth cleaned every four months or risk the ire of my dental
hygienist who allotted an hour and a half to chisel away at the stuff. This problem is now gone since I
gave up eating wheat.
Other bacteria found in arterial plaque include Klebsiella pneumoniae, Chijyseomonas and Weillonella
however, up to 50 different types of`bacteria have been discovered in foam cells. Symptoms of a
heart attack also closely mimic an infection. When the plaque ruptures, spilling its bacterial contents
into the arterial bloodstream, it is very common for those afflicted to experience a fever resulting in
chills and sweat.

Where does this bacteria come from? Well, in the case of bacteria from the respiratory tract and mouth,
some enters the bloodstream directly through the gums. But I suspect a good portion is swallowed in
saliva. If it isn’t killed by stomach acid—a very likely possibility in the age of binge drinking, antacids
and proton-pump inhibitors——then it reaches the small intestine where in the presence of depleted
beneficial gut flora populations, it takes up residence. Add in increased intestinal permeability caused
by diet, drugs, alcohol, chronic stress, and the gut dysbiosis itself, and the stage is set for the
inflammatory cascade that eventually results in vascular disease.
This is the most likely reason cigarette smoking and binge drinking are high-risk factors for heart
disease. Cigarette and alcohol are extremely disruptive to the upper respiratory and oral microbiota
which is why those who smoke and drink have 15 times the risk of developing oral cancer. Those who
binge drink and smoke make up 80% of the people who get oral cancer. (Q)
A number of studies have found elevated levels of bacterial pathogens in the mouths of smokers and
heavy drinkers: Streptococci, Prevotella, Véi/lonella, Porphyromonas and Capnocytophaga. You can be
sure these bacteria travel down the throat in saliva, colonize the gut, and enter systemic circulation via
a compromised gut wall.
However, swallowing pathogens isn’t the only way to get small intestinal bacteria overgrowth (SIBO).
Migration of gram-negative bacteria from the colon into the intestine due to impaired motility is the
number—one reason bacteria take up residence in the small bowel. Hence the reason constipation, SIBO,
IBS, IBD, Crohn’s, etc. should be of more than passing interest when it comes to the risk of developing
future cardiovascular disease.
I’ll leave you with another epidemiological study, this one quite large and famous, but again with the
caveat that association never equals causation. While one of its vegan co-authors interpreted the facts to
make it seem that animal protein and saturated fat were the cause of heart disease, Denise Minger’s
masterful review of the original data revealed that of all dietary components studied, wneat inta.ke had
the most statistically significant association with heart disease even after adjusting for numerous
confounding variables. You can read all about that lgerg.
Where Are The Pathogens F ueling Heart Disease Coming From?
I feel a need to clarify exactly what part of the digestive tract these toxins are most likely coming from.
Where these endotoxins cross the gut wall helps give us some idea about what dietary factors are most
likely contributing to the problem. ·
Oral Translocation
Just as any open sore on the skin can allow bacteria, viruses or other harmful foreign substances access
to the bloodstream, so do open sores in the mouth or gums. For this reason periodontal disease is a
potential source of infection that may contribute to the development of cardiovascular disease. As
mentioned in the last post, oral pathogens are commonly found in arterial plaque.
However, while I do believe oral dysbiosis is a source of pathogens, I doubt direct translocation from
the mouth accounts for more than a small fraction under normal circmnstances. Intense immune
responses and the pain they generate at the site of gum and tooth infections are usually agonizing
enough to cause the person to do anything to alleviate the problem. Moreover, the surface area of the
mouth is not very large so potential pathogen exposure to the bloodstream is somewhat limited in
comparison to the intestines.
Oral pathogens are also swallowed in saliva. Combine this with impaired gastric barrier function and
` it’s easy to see how these bacteria can also colonize the intestines. I suspect that oral pathogens
translocating from the small intestine are of bigger concern because of the liver dysftmction that is acommon feature in those diseases we group under metabolic syndrome: diabetes, cardiovascular
r disease, obesity, fatty liver. Bacteria that crosses the gut wall and is not encased in a lipid carrier or
I chylomicron makes its way to the liver first, and it is here that early manifestations of metabolic
E diseases are usually detected.
» Weston A. Price, an early 20th century dentist, traveled across the globe in search of healthy
populations. What he found was that dental health mirrored overall health. None of the healthy
communities Weston A. Price visited had dentists or regularly brushed their teeth. Their dental health
r was a sign of their excellent nutritional status and the absence of dietary factors that would otherwise
l negatively impact oral microbiota and impair nutrient absorption via disordered gut flora.
p To have small gut dysbiosis means being unable to digest food properly and produce the necessary gut
hormones that regulate a whole host of processes not least of which is digestion itself. This is why
nutritional deficiencies are common in those with small intestinal bacterial overgrowth. This
malnutrition, even in the presence of overeating, itself a symptom of malnutrition, will impact all
systems of the body, including the teeth and gums. So I believe that oral dysbiosis, like chronically
elevated cortisol levels or glucose dysfunction or fatty liver, is a symptom of small gut dysbiosis and
the nutritional deficiencies that result from this.
Gut dysbiosis can initiate oral dysbiosis or conversely, oral dysbiosis in the presence of compromised
gastric barrier function, can cause gut dysbiosis; once either develops the one fuels the other in an
endless positive feedback loop. Whether the oral or gut dysbiosis comes first is open to debate.
However, since most of the same dietary factors are involved in both processes our concern should be
focused on eliminating those agents and resolving the disordered flora.
Colonic Translocation
The colon contains the most bacteria of any area in the body. If the colon is perforated for whatever
reason, sepsis can set in threatening life itself. At this point it’s somewhat moot whether the bacteria
flooding the bloodstream are commensals or pathogens because they all represent a potential threat to
survival.
Ironically, many people who undergo a colonoscopy risk precisely this outcome. An estimated 70,000
people are killed or injured yearly when undergoing these procedures. Q)
Apart from perforation, colonic dysbiosis that results in an inflammatory bowel disease causing gut
wall inflammation is another potential source of endotoxemia. What happens in the small intestine, or
to be more precise, what doesn’t happen in the small intestine, often has knock—on effects further down
the gastrointestinal tract. The entry of improperly digested protein, carbohydrate and fat due to small
gut dysbiosis can initiate large intestinal dysbiosis by encouraging the growth of certain pathogenic
bacteria or yeast that ferment these foods thus favoring their growth. Other dietary factors like binge
drinking of alcohol can also cause or exacerbate colon dysbiosis.
Nevertheless, when we’re talking about how diet impacts endotoxemia, we’re really talking about how
it affects the small intestine, the major site of food digestion. The colon or large intestine is not a site of
much absorption apart from water, sodium and some fat-soluble vitamins.
In comparison to the small intestine, the large intestine has a relatively small surface area for the
absorption of endotoxins. Because of the presence of numerous folds and finger—like structures or villi,
the surface area of the small bowel is far greater than the colon so the potential for exposure and
absorption of pathogens is therefore higher, hence the reason for the extensive small intestinal immune
network. Q)
There is another reason the colon is likely not the main source of endotoxin;. Some ofthe bacterial
populations resident in the colon, both beneficial and not, belong to the gram-negative family. One
genus of friendly colonic gut flora, Bacteroides, is of this type. Under normal circumstances, these
gram-negative commensal bacteria cause us no harm because they do not stimulate the same immune
signaling pathways that gram-negative pathogens do. Q)
Dietary Fat, Chylomicrons and Endotoxemia
It appears that fat indeed increases the translocation of inflammatory lipopolysaccharides (LPS) from
the gut into systemic circulation. What needs to be determined is whether all or only some fats do this
and if so how. Let’s begin with what the research shows.
In a study, feeding mice a high-fat diet increased endotoxemia 2.7-fold in comparison to mice fed
regular rodent chow. 72% of energy in the high-fat rodent diet came from a mixture of com oil and
lard. Levels of LPS were consistently higher in these animals. They also became fat and developed
insulin resistance. {_Q
Corn oil is a long—chain, mostly polytmsaturated fat, and lard is a mostly monounsaturated long—chain
fat. Yes, the predominant fat in lard is monotmsaturated oleic acid, the same f`at in olive oil, not
saturated fat.
Also observed were changes in the intestinal microbiota including reduced levels of bifidobacteria.
This is important because bifidobacteria produce short-chain fatty acids that promote a healthy gut wall
thereby decreasing gut permeability Q.) However, in mice fed a diet containing the same composition
of fat but comprising only 40% of energy, the increase in endotoxin levels was a modest 1.4-fold
higher.
In the same study, LPSs were given orally to wild-type mice with either oil or water. Blood levels of
LPSs were elevated in the mice fed the oil mixture again implicating fat ingestion with endotoxemia.
To see if LPS alone was enough to cause the identical symptoms seen in high-fat fed mice, some
animals were fed standard chow and infused continuously with LPS to reach the same levels seen in the
high—fat fed rodents. These mice gained the same amotmt of weight and showed similar levels of
dysregulated glucose control and insulin resistance. Both the high—fat fed and LPS infused mice
experienced increases in inflammation in both muscle and fat tissue.
Finally, the researchers used mice lacking CDI4 immune receptors to see if these mice would develop
obesity and insulin resistance when infused with either LPS or fed the_ same high—fat diet. CDI4 is a
molecule that senses the presence of LPS and initiates an immtme response. These CDl4 knock-out
mice were completely immune to both the LPS infusion and the high-fat feeding. These types of mice
are also naturally hyper—sensitive to insulin when fed a normal diet suggesting that the CDI4 receptor is
involved in insulin sensitivity.
Studies done with mice given antibiotics to kill their gut flora show that they are totally resistant to the
ill effects of a high—fat diet. In these animals, fatty liver and markers of inflammation went down while
insulin sensitivity went up after elimination of gut bacteria. Q) As in the case of both non—alcoholic and
alcoholic fatty liver disease, translocation of gut bacteria is a necessary part of the equation.
These elevated LPS levels have also been observed in human beings. Endotoxemia is 2-fold higher in
BMI-, sex-, and age-matched type 2 diabetics than in non-diabetics. Fasting insulin also significantly
correlates with metabolic endotoxemia even when controlling for sex, age and BMI. gg)
One very small study used twelve “healthy” men as participants. (Q Healthy is in quotes because all l2
men self-identified as occasional smokers. Granted, the researchers were also trying to determine
whether endotoxins from smoking affected systemic LPS levels. Nevertheless, this is a bit of a
confounding variable knowing what we know about smoking’s effect on oral and respiratory flora.
In *·i—·
Another confounder was that they fed these men their fat (LPS enriched butter) on toast. Gluten-grains
have some really negative effects on intestinal pemieability.
What were the results? The researchers noted a significant transient ten-minute increase in plasma
endotoxin levels from baseline after the fatty meal. The highest concentrations were found in the
l “healthy” men who had the high-fat meal and smoked three cigarettes in a four—hour period.
However, the researchers also observed a very rapid clearance of these same bacterial toxins. They also
didn’t see any increase in the cytokine tumor necrosis factor or an increase in C-reactive protein, a
marker for inflammation. However, the authors cautioned that the four-hour duration ofthe study may
( not have given them enough time to witness any increases in inflammatory markers.
Another study showed that ingesting a breakfast containing various types of emulsified (liquid), and
non—emulsified fats resulted in transient increases in plasma LPS with higher levels seen when
l emulsified liquids like olive and safflower oil were eaten in contrast to butter. But again, this study
used French bread as a vehicle for the fat. (Q)
What explains these findings? There are two ways that gut pathogens can cross the gut wall. They can
enter the bloodstream between the cells lining the digestive tract due to increased intestinal
permeability or “leaky gut”; alternatively, they can be incorporated into vehicles that transport fat from
the absorptive cells to systemic circulation. It is this latter route that some researchers believe may
partly account for these findings and it’s what I want to cover now.
Because fats are hydrophobic or “water fearing”, they are insoluble in blood and present a special
problem for digestion. Of the fats present in the standard diet, 95% are triacylglycerols (triglycerides).
This type of fat consists of three fatty acids attached to a glycerol molecule.
Fat digestion begins with the secretion of the enzymes lingual lipase produced by salivary glands in the
‘q mouth and gastric lipase produced in the stomach. These enzymes account for about 10% to 30% of fat
digestion acting primarily on short- and medium-chain fatty acids.
i Apart from their classification as either predominantly saturated, monounsaturated or polyunsaturated,
fats or lipids can also be classified by how many carbon atoms form them. Short—chain fatty acids
contain between four to six such atoms. All short—chain fatty acids, including the highly beneficial ones
~ produced by friendly bifidobacteria in the colon, are saturated.
T Medium—chain fats are between eight and twelve carbon atoms in length. Found in butterfat and
tropical fruit oils like coconut oil, they are rich in antimicrobial substances that inhibit pathogen
growth.
»
T Next come long-chain fatty acids that range in length from fotuteen to twenty-four carbon atoms. These
can be either saturated, monounsaturated or polyunsaturated. Finally, we have very-long-chain fatty
acids that have between twenty—four to thirty carbon atoms.
All fats require a certain amotmt of emulsification in order to be broken down and digested. To
emulsify lipids is a fancy way of saying that larger globules of fat are converted into small droplets like
what happens when you whisk or shake together oil and vinegar to make a vinaigrette. These smaller
fat droplets are called micelles.
Short- and medium-chain fatty acids are partially emulsified by the action of stomach contractions and
from sheer force when they are squirted through the pyloric sphincter into the duodentun. However,
most emulsification of fat, including long-chain fats, occurs in the small intestine as a result of bile
released from the gallbladder. Phase two of fat digestion begins when the pancreas releases lipase to
complete the breakdown of triacylglycerols to diglycerides and finally to fatty acids and
monoglycerides.

I need to interject here that in order for the gallbladder to eject bile and the pancreas to release digestive
enzymes, cholecystokinin or CCK, a gut hormone produced by the L-cells of the small intestine, must
be released first as a signal to do so. Therefore, any dysfunction in the L-cells of the small intestine will
. result in the maldigestion of dietary fat.
As I wrote in this post, opioids from whatever source su presses gut hormone secretion. I would
. P .
imagine gluten-derived adenosine has the same effect. Small intestinal dysbiosis will also impair CCK
release which is why protein and fat malabsorption are so common in those who have small intestinal
bacterial and yeast overgrowth. And a gallbladder that does not contract regularly runs the risk of
forming concentrated and hardened bile, i.e. gallstones.
CCK also has well—known satiating effects, making you feel full when fat and protein are passing
through the first and middle section of the small intestine. Any impairment in its production or release
will also blunt these appetite—suppressing signals.
Once bile and pancreatic enzymes emulsify ingested fat, lipid micelles are sufficiently water soluble to
enter the absorptive cells of the small intestine. Like digested carbohydrates and proteins, short- and
medium—chain fatty acids pass directly Hom the enterocyte into the blood and continue on to the liver.
Longer-chain fatty acids, however, re-form into triacylglycerols within the enterocyte. Together with
phospholipids, cholesterol and proteins, they fonn large particles within the absorptive cell. If there are
lipopolysaccharides in the vicinity, these too hitch a ride on the newly formed lipoprotein vehicle or
chylomicron. Here is a diagram of this process minus the addition of LPSs:
See those protein fragments in the exterior or phospholipid layer? These are composed of both
apolipoproteins and lipopolysaccharide binding protein or LBP. It is the LBP protein that potentially
attaches to lipopolysaccharides and brings them along for the ride, so to speak.
Keep in mind that in a healthy small intestine, there should be negligible amounts of gram—negative
bacteria, certainly none colonizing the gut wall or found in any large ntunber within enterocytes. It’s
the job of friendly small intestinal gut flora to make the gut wall inhospitable to these types of bacterial
pathogens as well as yeast like Candida.
The extensive small intestinal immtme system or GALT complex, should also inactivate most of these
pathogens before they enter enterocytes or cross the gut wall. Nevertheless, even in a healthy digestive
tract, there will always be some gut pathogens that appear in the ltunen so it’s likely that some
translocation of LPS will normally occur. The situation is worse, however, if there is an overgrowth of
gram—negative pathogens due to dysbiosis.
After forming, chylomicrons exit the enterocytes, enter the lymphatic system, travel through the
thoracic duct and are eventually released into systemic circulation. These chylomicrons can continue
entering the bloodstream for up to 14 hours following a high—fat meal. Peak levels of fat in blood
plasma occurs anywhere from 30 minutes to three hours after eating, returning to near normal within
five to six hours. It is chylomicrons that accounts for the milky appearance of blood plasma after a
meal containing fat.
As these chylomicrons access various non—liver tissue sites, an enzyme called lipoprotein lipase is
released causing the triacylglycerols in these lipoproteins to break down where they are then absorbed
by either muscle, including the heart, for use as fuel or conversely stored as fat in adipose tissue in
periods of caloric excess.

V
Once chylomicrons are depleted of triacylglycerols, they return to the liver as a chylomicron remnant
with their load of attached LPSs. Once in the liver, some of their components may be recycled for other
uses while the bound lipopolysaccharides are excreted into bile and feces.
And that is how fat is digested and one way LPS enters systemic circulation.
So yes, long—chain fatty acids and the chylomicrons produced to transport them increase systemic LPS.
But should this alarm you? Not in the least. Why?
It’s absolutely absurd to believe that we don’t have some mechanism to protect us from possible
bacterial translocation when digesting fat. Q) To think otherwise is to believe that dietary fat is to kill
us.
So what would that defense mechanism be? The very vehicles that transport fat and cholesterol through
the blood: lipoproteins.
All carriers of triacylglycerols and cholesterol are part of our innate immune system.
All lipoproteins——chylomicrons, VLDL, IDL, LDL and HDL——bind to and i~n—a-c—t—i—v-a—t-e
lipopolysaccharides. QQ They also protect against gram-positive bacterial pathogens, viruses and
parasites.
And that includes “bad” LDL cholesterol, the lipoprotein that has been so vilified. Do you honestly
believe our livers were designed to produce a substance to kill us?
Take two sets of mice and give each of them a lethal dose of gram-negative E. c0li. Give one set of mice
an infusion of human—derived chylomicrons and VLDL and the survival rate of these mice is 100%. ln
other words, they don’t die from an otherwise deadly dose. lnfuse them with human LDL and HDL and
you get the same result. Q)
Another example, using some LDL receptor deficient mice. Because they have been genetically bred to
lack the LDL receptor, they have unusually high levels of LDL coursing through their little arteries and
veins.
Now pair these LDL—engorged mice against normal wild-type mice. Once again, give both sets of mice
an infusion of gram-negative E. coli. The mice with very high levels of LDL cholesterol will have a
significantly increased survival rate. These LDL mice don’t begin dying off until their endotoxin levels
are eight times higher than their normal litter mates. Their levels of circulating inflammatory cytokines
are also far lower.
Now, with the same set of mice, infect them with Klebsiella pneumoniae, another gram-negative
pathogen that is commonly found in arterial plaque. Again, the LDL mice show increased smvival
rates. After acute infection, only 42% of the mice with higher LDL levels die as opposed to 67% of the
controls.
But what about chylomicrons?
These lipoproteins are particularly potent inhibitors of LPS and have also been found to neutralize and
detoxify gram-positive pathogens. LQ) Remember Streptococus mutans? The oral pathogen that causes
cavities and is often formd in arterial plaque? lt’s a gram-positive pathogen that would be inactivated by
chylomicrons.

% chylomicrons from circulating level
Courtesy: Lipopolysaccharide (LPS)-Binding Protein Mediates LPS Detoxification by Chylomicrons
This chart shows what happens when you incubate E. coli with chylomicrons derived from healthy
human volunteers. The levels of inflammatory cytokines, interleukin 8 represented by circles, and
tumor necrosis factor alpha, represented by squares, are graphed against an increasing concentration of
circulating chylomicrons. What you see here is that the higher the percentage of chylomicrons, the
lower the level of inflammatory cytokines elicited by blood immune cells.
As lmentioned above, all lipoproteins neutralize endotoxins but none, including HDL, holds a candle
to chylomicrons.
Here you see the finger-like projections or villi that make up the absorptive layer. In the bottom-left-
hand corner, you see a close—up of the one-cell thick layer separating the contents of the small intestine
from the blood vessels leading to the liver, and the lymphatic vessels that chylomicrons enter to
transport long—chain lipids to systemic circulation.
Notice the straight line separating each cell or enterocyte. These are tight junctions that rmder normal
conditions prevent pathogens and larger molecules from slipping through.
Here is another view of these junctions:
Absorption of nutrients should always occur through the enterocyte or by transcellular transport. That
is how long-chain fatty acids are absorbed and where they are incorporated into chylomicrons.
Likewise, short- and medium-chain fatty acids should travel across this route as well as amino acids
and simple sugars. Paracellular transport should be limited to water, electrolytes and some trace
nutrients.
Courtesy: Lipopolysaccharide (LPS)-Binding Protein Mediates LPS Detoxification by Chylomicrons
The left bar labeled Blanc, represents LPS-rich blood plasma devoid of lipoproteins. As a result, it
shows the highest concentration of the inflammatory cytokine tumor necrosis factor (TNF). Here you
see that HDL binds some LPS but not much. VLDL and LDL cholesterol come next in inactivating LPS
and reducing levels of TNF. But look at chylomicrons. When it comes to inactivating LPS, blunting the
inflammatory response and escorting them to the liver for elimination from the body, they are truly the
outstanding bacterial scavengers of the body.
This explains why the higher your total cholesterol, the less likely you are to die from an infection.
Please look at the U-shaped blue line on the chart. Those people with total cholesterol between 200 and
240 had the lowest level of death from all causes. Those with cholesterol above these levels
experienced increases in mortality. However, look at the left side of the curve. Those with lower
cholesterol levels also see a jump in all—cause mortality.
Cardiovascular disease, represented by the broken red line, showed a weak correlation with total
cholesterol and was similarly U-shaped. Note that those with total cholesterol levels below 190
experienced “higher” levels of cardiovascular disease than those who had total cholesterol in the 190 to
220 range.
See the green dotted line in the lower—left—hand corner? This tracks deaths from infectious and parasitic
diseases. The lower the total cholesterol, the higher the mortality which makes perfect sense since
cholesterol is part of the immune system. Lower it, and you compromise your defense against both
infections and parasites. It’s also the case that infections and parasites lower total cholesterol which
indicates that cholesterol is a marker for infection.
So does this mean cholesterol has nothing to do with heart disease? Well, let me ask you this. Do
firefighters have anything to do with fire? I certainly have never seen a structure or wild fire without
firefighters present at the scene? So we can say that fires are highly associated with firemen. However,
we don’t jump from this observation to the conclusion that fireman are the cause of fires and that if we
reduced their numbers we would lessen the incidence of destructive conflagrations.
Dysregulated cholesterol (and that includes oxidized LDL), cortisol and glucose levels are all
symptoms of metabolic endotoxemia, not the cause. Statins work because they are anti-inflammatories
and reduce the tendency to form clots. Unfortunately, because they reduce cholesterol and prevent the
synthesis of important substances like CoQ10, they have a number of serious side effects. QQ)
I hope I’ve made clear that chylomicrons are not the likely source of translocated pathogens that appear
in arterial plaque. On the contrary, they protect you from these pathogens by inactivating them and
rapidly removing them from the bloodstream. We need to look elsewhere for an explanation of how
these pathogens are entering systemic circulation. That “elsewhere” is via increased intestinal
permeability spilling contents of the gut lumen into blood flowing to the liver. It is the liver, after all,
that receives the full frontal assault from a “leaky gut”.
Impaired gastric-barrier function, excessive alcohol intake, stress and gluten grains increase intestinal
permeability both directly and by their promotion of bacterial and yeast overgrowth. However, there is
another common dietary component that appears to affect intestinal permeability for the worse:
polyunsaturated vegetable oils.
Dietary Fat, Leaky Gut, Endotoxemia and Heart Disease
Increased intestinal permeability is the most likely source of translocating pathogens.
I once again need to emphasize that once you have intestinal dysbiosis, ANY food you eat will increase
the translocation of bacteria, yeast, larger food molecules, etc. into the bloodstream leading to the liver
and to a smaller extent, systemic circulation. The more often you eat, the more frequently this happens.
Increased intestinal permeability will allow long-chain fatty acids, that would normally only be
incorporated into chylomicrons, access to the blood flowing to the liver also carrying with them
antigens and bacteria that will provoke an immune response. As more fat is now reaching the liver,
more cholesterol will be synthesized to export it. As I said, changes in cholesterol levels are a marker of
endotoxemia, not the cause of it.
Let’s look more closely at the anatomy of the small intestinal gut wall:

Occludin and claudin-1, claudin-2 and claudin—3 are most responsible for maintaining gut barrier
function. Of these two protein classes, claudins are the most important. Mice who are bred to lack
claudin gut protein die within one day of birth.
We know that gluten opens these jtmctions. Q) Plant lectins are also disruptive. Q) Alcohol, especially
bin e drinkin , also com romises intestinal inte ri . 4 Small intestinal d sbiosis and the
3
inflammation that results from such an overgrowth, directly impacts these protein structures for the
worse.
(The immune system uses ROS as an anti—microbial defense. There here we see a direct link between
inflammation and oxidation; inflammation causes white blood cells to gather at a site of injury and then
white blood cells utilise ROS to kill off any microbes). -from another source
All oxidation from gut inflammation has the potential to affect these proteins. Oxidation is a normal
process of cells that use oxygen to produce energy from various substrates, including those cells lining
the intestinal tract. This process is called oxidative phosphorylation, and it would take an entire book to
cover. The gram—negative pathogen, E. coli, is quite adept at growing in an oxidative environment.
Most oxidation within cells will be harmlessly converted to water but not all. Two very harmful
intermediate substances normally produced are superoxide anion and peroxide known collectively as
reactive oxygen species or ROS. These are highly unstable agents. They have the potential to damage
DNA, proteins, fats and intestinal cells, including those producing protective mucus. There are a
number of built-in defenses that cells use to guard themselves against these harmful substances but
suffice it to say that these defenses can be overwhelmed in times of intense free radical production as
part of an immune response.
Anything that increases oxidation in the intestinal tract will also disrupt beneficial bacterial
populations. Especially vulnerable are Lactobacillus species that predominate in the small intestine.
These bacteria do not handle oxidation well, certainly not as well as gram-negative pathogens like E.
coli. Bihdobacteria species in the colon are also negatively affected.
One substance that can be extremely oxidizing is fructose. Fructose forms half ofthe sugar molecule
and can comprise anywhere from 42% to 90% of high—fructose corn syrup. We are well adapted to
handling moderate amotmts of it in its natural form where it comes packaged with fiber, antioxidants,
vitamins and phytochemicals. Strip it of these protective substances during refining and we become far
more prone to its ill effects. In large quantities, fructose produces lots of free radicals in those intestinal
cells that are able to metabolize it because of its ability to rapidly degrade ATP to uric acid.
Fructose, gluten, lectins and alcohol are not the only dietary components that increase oxidative stress
in intestinal cells. Some fats do too.
All fats are combinations of different fatty acids. Canola oil, for example, is 62% monounsaturated fat,
6% saturated fat and 32% polyunsaturated fat. Butter fat is 56% saturated fat, 29% monounsaturated fat
and 32% polyunsaturated fat.
Trans fats, implicated in both heart disease and cancer, are manufactured fats. They are made from
polyunsaturated vegetable oils after the partial addition of hydrogen atoms to empty spots on their
carbon chain. Olive oil and lard can also be subjected to partial hydrogenation to extend shelf life. Any
lard you see that is not refrigerated is partially hydrogenated. Because hydrogenation straightens out
the carbon chain, they have similar physical, although by no means biological, characteristics to natural
animal fats. These are true Frankenfoods and should be avoided at all costs.
Your cells will reflect the type of fat you eat. Lipid peroxidation is the degradation of fats by oxidants
leading to their damage and is not something you want happening to fats that are incorporated into your
cellular structures. Of the fats mentioned, saturated fats are the least susceptible to this process.
Polytmsaturated oils, however, both omega 6 and omega 3, are particularly prone to lipid peroxidation
by virtue of their missing hydrogen atoms. Omega 6 fatty acids are also inflammatory in excess.
While extremely delicate, omega 3 oils reduce inflammatory responses and are good for you as long as
inflammatory stress in the liver is not an issue. Omega 3s subjected to oxidation can be very damaging.

The fastest way to cause alcohol-induced liver injury in an animal model is to feed them fish oil along
with their alcohol.
Oxidation and Fatty Acid Composition
“Although diets that contain SFA [saturated fatty acids] and possibly MUTA [monotmsaturated fatty
acids] may protect the liver against toxic agents, it is unlikely that any public agency would
recommend an increase in intake of animal fats.”
V This quote is from a paper entitled: Dietary saturated and monounsaturated fats protect against acute
acetaminophen hepatoxicity by altering fatty acid composition of liver microsomal membrane in rats.
Well, I’m not a member of the “health authorities” club so I ’ll tell you that in a liver inflamed by
endotoxemia, the last thing you need in your diet are fats that add to the problem and nothing adds to
that damage like polyunsaturated omega 6 vegetable oils.
The protective role of saturated fat in alcohol-induced inflammation of the liver has been a dirty little
secret rarely mentioned lest the public question the whole “saturated fats are bad” meme. In a paper
entitled BeefFat Prevents Alcoholic Liver Disease in the Rat the following graph is found;

Months after starting ethanol
Here you see the results of a six-month rat bender on liver function. The com-oil group had the worst
liver outcomes, followed in the absence of a glucose liquid diet by the lard group (remember, lard is a
predominantly monounsaturated fat). The least affected were the beef tallow group. These results have
been replicated ntunerous times. (Q Q) Qi) (Q) { l0; I could cite more studies but you get the picture.

In the presence of endotoxemia and liver inflammation, saturated fats are protective while
polyunsaturates, especially omega 6 oils, are not.
To bring home this point I want to review an article that was published in May of this year. (LL) To my
knowledge, this is the first paper that links the intake of omega-6 vegetable oils in animals to increased
intestinal permeability.
As in earlier studies of this type, it found that rodents fed ridiculous quantities of alcohol were mostly
protected from the ill effects when fed sattuated fat, in this particular case beef tat and medium-chain
fatty acids. Medium-chain fatty acids are largely found in tropical oils made from coconut and palm.
They have antibacterial and anti-fungal properties making them ideal for those battling small intestinal
bacterial and yeast overgrowth.
Here is a chart detailing the composition of both diets.

Fig. 1. Composition of the experimental Lieber—DeCarli liquid diets. Satu-
rated fat (SF) diet was enriched with medium chain triglyceride (MCT) oil:
beef tallow fat, 82:18 ratio. Unsaturated fat (USF) diet was enriched with
com oil. Soybean oil was used in both diets to provide essential free fatty
acids. The control (SF and USF) diets contained 43% of calories from carbo-
hydrate, 17% from protein, and 40% from fat. SF + EtOH and USF + EtOl—l
diets contained 35% of calories from EtOH to replace the calories from car-
bohydrate. EtOH, ethanol.

White bars represent results before the start of alcohol feeding (first two weeks), black bars represent
results after alcohol feeding (eight weeks). Note that ALT, a test that detects liver damage, is pretty
much the same between the saturated fat (SF) and saturated fat with alcohol or ethanol group
(SF+EtoH). The polyunsaturated com-oil group had slightly better results without alcohol, but this
changed dramatically with its addition. Fat accumulation was also worse in the com-oil group as were
levels of nonesterified free fatty acids (NEPA).
Like I said, this isn’t particularly revelatory. What caught my attention, however, is what happened to
these mice in the two weeks before they were fed alcohol.
By the way, in this study, both the control and alcohol diet had the advantage of not containing
fructose. I say advantage because when I read a rodent study that implicates saturated fat for all evil,
inevitably sucrose, i.e. sugar, is part of the formulation and sucrose is half fructose.
Fructose causes oxidative stress in the intestines and liver. This is why fructose feeding is so effective
at inducing obesity and metabolic syndrome in lab rodents. The fat invariably used in these high—fat
rodent diets is lard, which is typically described as a saturated fat in these papers. This is not correct as
you already know. While monounsaturated fat is more stable than polytmsaturated fat in the presence of
fructose or oxidation, it is more prone to lipid peroxidation than saturated fat. What many of these
studies show is that coupling excess monotmsaturated fat with fructose is not healthy, but neither is
overeating in general.
Returning to our study, the mice fed the corn—oil mixture ate much more during the first week than the
saturated-fat group. This discrepancy narrowed somewhat by the second week. Nevertheless, the corn-
oil group still had higher energy intake during the second week which leads me to believe that they
were hungrier and already suffering from negative changes in the gut.
Once the alcohol part of the trial began, energy intake declined in both groups. I suspect this was due to
increases in the cytokine uunor necrosis factor-alpha which induces wasting syndrome or cachexia. In
the following fluorescence microscopic scans, you can see the different accumulations of liver fat in
both groups represented by the whitish dots:
E
E sr si=+ Eton-1
57 .
:1:
USF USF + EtOH .
The saturated fat group both before and after alcohol constunption showed less fat accumulation in the
liver than the polyunsaturated corn—oil group or USF group. VVhat strikes me is how rapidly fat
accumulated in the unsaturated fatty acid group in the two weeks prior to alcohol feeding compared to
the saturated fat—fed mice.
As I explained here and here, fatty liver and the inflammation that results from it is a direct result of
translocating gut pathogens. This requires increased intestinal permeability which is a direct result of
disrupted intestinal tight junctions. With that in mind, feast your eyes on these charts:

T rr ;i_j;i‘*·* gw ( as
E é ··> é ¤»<· PT . ru l g 0.5 E Q5 g G5 M SF s’°*E’°*” USF “Sf’€‘°”’ E M sr smzron usr usF·Er0H E N 5; sharon usr usnsiou B ,5 g as ,…..T“;……._., is . E P·—-=··-====-—·-·=·=~–=-»-·-·;~j‘ % . E ro F-/_MA‘ ii 1.0 – E 1.¤ E g E E nn i E D5 ns _’ 00 SF SF·EIC·N USF USVLEIOH ;‘ no SF SF•€tOH USF USIWEKOH an 5; $;•E;-gy; U5; u$p.Ey°pg Fig. 6. Erfects or saturated Fa: (SF) and ursazsrared Par (USF) diets on rleum right junction [TJ) protein and pmteemadapter mRNA levels in response to chronic aleohot feedrng. USF dm: sigrthcantly down regulated mRNA kzvels at (A) rtcum TJ proteins and (B] protein adaptors compared mn SF det Ethanol {QOH} suppiemerrted to the USF diet resulted rn further suppression of chess proteins. Intestinal TJ protein mRNA expressicm was assessed by reverse rranscnpuon PCR. The relative mRNA levers were anxyzeci osng 2 “‘ meme:} by nennazng mh res mRNA expressren. Resurts are presented as fold changes over SF grasp ser as 1. Values are mean + SEM, n : B anzmalsr group, ‘;> -< 0 05. t~way ANOVA with Tukeyfs post rect:-est. All of these charts track the level of various tight junction proteins. Higher is most definitely better. In all cases, the saturated fat group had higher levels of these proteins in their iletun than the com—oil group even before the introduction of alcohol. The ileum is that part of the small intestine nearest to the colon and the first to be colonized by migrating colonic gram-negative bacteria in cases of impaired intestinal movement. As a side note, short-chain saturated fatty acids like butyric acid found in dairy products and butyrate, produced by beneficial bifidobacteria, are used by intestinal cells as “food”, nourishing these cells and maintaining intestinal gut wall integrity. The researchers of our mouse study theorized that the down-regulation noted in the corn-oil group was mediated by the proinflammatory effects of omega—6 fatty acids. Omega 6 has known oxidative effects on vascular cells and will activate inflammation in liver Kupffer cells. g 12; 5 13) It is therefore not a stretch to believe they do the same to cells lining the digestive tract. Apart from their negative effect on tight junction proteins, the pro—inflammatory effects of these fats will also negatively impact mucus secreting intestinal cells and beneficial bacterial populations. In fact, polyunsaturated omega 6 fatty acids are the main fatty acids found in arterial plaque. They comprise over 50% of the fatty acids fotmd here, with monounsaturated fat making up 30% and only twenty percent composed by supposedly “artery clogging” saturated fat. ( 143 The more omega 6 found in arterial plaque, the more likely it is to rupture and lead to either a heart attack or stroke. ( 15) To sum up, does fat have anything to do with endotoxemia and heart disease? Yes it does. Any fat in the presence of gut wall dysfunction, along with protein and carbohydrate, will cause translocation of gut pathogens. The majority of these pathogens will end up in the liver creating oxidative damage and disease. A small portion will bypass the liver entirely and directly enter the bloodstream. In more advanced cases of “leaky gut” and subsequent hepatic damage, these pathogens will also escape the liver and enter systemic circulation. Cholesterol will try to neutralize these substances and repair thedamage they cause in arteries, but along with other responding immune cells, fonn atheromas and fibrous caps. If unstable, these complexes can rupture producing a heart attack or stroke. In populations where gut dysbiosis and endotoxemia are rampant, encouraging people to substitute highly reactive and inflammatory omega 6 polyunsaturated fats for saturated fat is nothing short of dietary madness and a denial of the basics of fatty acid structure and biochemistry. T`he cause of heart disease is metabolic endotoxemia. Binge drinking, excess consumption of sugar, trans fats, overeating, omega 6 oils, tooth decay, respiratory infections, gluten, stress, aging, poor anti- oxidant status, cigarette smoking, etc. are all risk factors for cardiovascular disease because they can all negatively impact gut wall integrity and beneficial bacterial populations. Correcting dysbiosis through changes in diet and resolving bacterial and yeast infections while replenishing and maintaining beneficial gut flora populations is the only hope you have for preventing this potentially deadly disease. Cholesterol, Leaky Gut, Errdotoxemia and Heart Disease Cholesterol is an alcohol but not the same type of alcohol you drink. That kind has two carbon, one oxygen and six hydrogen atoms. In contrast, the cholesterol molecule is composed of 27 carbon, one oxygen and 46 hydrogen atoms. That’s a lot of molecule so it’s termed a high-molecular weight alcohol. Technically, it’s a sterol which is a subgroup of steroids. Cholesterol is fat soluble like fatty acids and triglycerides (triacylglycerols) but unlike the latter two, is not used by the body for energy. In food, the levels between fat and cholesterol are vastly different. Cholesterol is measured in milligram quantities whereas fats are eaten in gram amounts. A three ounce serving of salmon, for example, would contain anywhere from three to ten grams of fat and about thirty to seventy milligrams of cholesterol. Cholesterol is essential to life and without it you would not exist. All cells in the body have it and can produce it. Cholesterol is the building block for steroid and sex hormones, bile acids, and vitamin D synthesis when your skin is exposed to sunlight. It builds and maintains cellular membranes and moderates their fluidity. Within the cell, it has functions important for intracellular transport, cell signaling and nerve conduction. And as I mentioned here, cholesterol is an extremely important part of your immune system. _ Contrary to what you may have been told, it’s impossible to meet your daily cholesterol needs by diet alone. To make up the difference between what your body needs and what you take in through diet, your liver and other organs synthesize it. If you eat very little of it, your body produces more, and if you have a cholesterol-rich diet, your body produces less, which is why dietary changes are, with some exceptions that I’ll get to shortly, typically useless for affecting cholesterol concentrations inthe blood. lll Qi). Associations between total cholesterol and heart—disease risk are U—shaped as I noted in part three of this series: While this graph charts cholesterol and death rates in men, it is equally indicative of cholesterol’s effects on women. To reiterate, people with total cholesterol levels between 200 and 240 have the lowest rates of death from all causes. Those with total cholesterol levels between 190 and 220 have the lowest incidence of cardiovascular disease but note the sharp increase in death from infections and heart disease the lower your levels of cholesterol go. For now, I want to focus on the rising upward slope of this cholesterol-cardiovascular-disease curve. How could gut dysbiosis and the translocation of gut pathogens or endotoxemia raise cholesterol levels? There are several mechanisms I can think of although there are no doubt others. – A First, endotoxemia increases the production of cortisol, the stress hormone as described hge. Cortisol V 4 A r‘c‘i Eiirequires cholesterol for its production, so an increase in its adrenal output will require more production it of cholesterol. Cortisol levels are associated with increased levels of LDL. Q) Cortisol increases » intestinal permeability, which adds to increased gut pathogen translocation, further raising cortisol levels. A second reason LDL cholesterol may go up is because a quantity of long-chain fatty acids that would normally be incorporated into chylomicrons and enter the lymphatic system, may instead leach into the portal vein where they end up in the liver and are incorporated into VLDL lipoproteins. As roughly half of these particles will turn into LDL cholesterol, this will cause an increase in cholesterol concentrations. This assumes, however, that lipoproteins are capable of being manufactured by the liver, an assumption that is not always true as you’ll read later in this post. A third reason is that endotoxemia-induced inflammation appears to down—regulate the enzyme lipoprotein lipase. As l explained in my post on chylomicrons, as lipid—rich lipoproteins circulate throughout the body, this enzyme breaks down the triglycerides they contain so they can be absorbed into various tissues throughout the body. If lipoprotein lipase is suppressed, triglyceride levels rise and HDL falls. fg) » A fourth reason cholesterol may increase is to repair vascular damage. In its role as repair substance, it will be produced in larger quantities to heal whatever damage is being done. A fifth reason cholesterol may rise is in response to infection: bacterial, viral and parasitic. As part of our immune system, an increase in infection will cause the liver to produce more cholesterol to counter this. Lipopolysaccharides from gram—negative bacteria, for example, are inherently dangerous, and you can expect the liver to produce more cholesterol to neutralize this threat. The fireman coming to put out the fire, so to speak. Q) LQ) But again, there is an exception to this that I’ll cover shortly. A sixth reason is that gut dysbiosis in the ileum or fnal section of the small intestine can interfere with the production of a protein necessary for HDL cholesterol formation. By inhibiting the secretion of a gut hormone called PY! production of HDL is negatively impacted. Lower levels of HDL increase levels of circulating triglycerides. A seventh reason that gut dysbiosis and endotoxemia raises cholesterol is by causing fatty liver. Fatty liver impairs this organ’s ability to take up LDL from circulation increasing LDL concentrations in the 6* blood. , i A final reason, and one that underlies all causes of cholesterol dysregulation, is an increase in inflammation. Atherosclerosis is consistently associated with higher levels of ttunor necrosis factor-a (TNF-a), interleukin 6 (IL-6), and C-reactive protein. TNF-a and lL—6 are inflammatory cytokines and C-reactive protein is a marker for inflammation. In persons with this pattem, LDL and triglyceride levels are elevated in relation to HDL. Q) TNF-a, and especially IL-6, are also associated with low- thyroid function or hypothyroidism which itself is a risk factor for heart disease, not to mention obesity. Q5) The increase in levels of LDL cholesterol and triglycerides coupled with decreased levels of HDL are a sign of bacterial translocation from the gut. Cholesterol is not the cause of this problem, it’s merely responding to the endotoxemia. lf you have high levels of HDL cholesterol (over 40 to 50 milligrams per deciliter or mg/dl for men, 50-60 mg/dl for women) and low triglyceride levels (under 150 mg/dl), l don’t believe elevated total cholesterol is of any concern. In fact, this pattern shows appropriate uptake of fat and cholesterol from both chylomicrons and LDL lipoproteins and HDL transport back to the liver, suggesting proper cholesterol handling and a healthy immune system But how do we reconcile what I just described with the left side of the slope that also sees an association between increasing rates of cardiovascular disease, but this time due to lower levels of total cholesterol? I believe the left-side of this slope would be steeper than it is were it not for one major reason. Many of those who would develop heart disease were they to live long enough instead die of numerous other causes first; a fact illustrated by the steeply curved blue line that tracks death from all causes as cholesterol levels decline. Q J One of the reasons heart disease was rare before the 20th century was because death from infections was the ntunber-one killer of people in the developed world before the age of sanitation, rising living standards, vaccines and antibiotics. If you die young, you’ll never grow old enough to have a heart attack and be counted in the statistics. Many who argue that heart disease rates in certain parts of the underdeveloped world are low due to their low—anima1 protein or saturated-fat diets usually fail to mention the abysmal life expectancy rates that kill many of these people well before heart disease has a chance to do the same. Heart disease is typically a disease of old age. Before resolving this seeming contradiction, I want to review an old (1965) study. F amously known as the Rose Corn Oil trial, it was one of the first studies that tried using a reduced saturated—fat—intervention diet to lower the incidence of heart disease in the treated group(s). Q) It was based on the assumption that Ancel Kevs was right and saturated fat was the cause of heart disease launching the entire lipid-cholesterol—heart disease industry era that we are all still living with today. What I like about this study is that it was a randomized, controlled trial unlike the confounder-prone crappy population studies that are always touted by the anti-saturated-fat and lower—cholesterol—is— always-good—for—you camp. Unfortunately, due to its length, it was not a live-in study. In the study intro, the authors remarked on the lower cardiovascular-disease rates in olive—oil consuming nations like Italy and Greece, so they wanted to see if it was protective against heart disease. They were also curious to see if polyunsaturated vegetable oils offered similar protection. Participants were randomized to three groups. A control group whose members were given no advice to change eating behavior, and two other intervention groups that I’ll get to in a minute. The trial was expected to last three years. However, by the end of the second year, only half of the original participants were arormd, either because they had died, had another incapacitating heart attack or just stopped showing up. For that reason, only results from the first two years of the study were published. Criteria to be admitted to the trial included 1) evidence of having had a heart attack or having angina, 2) being under the age of seventy, 3) absence of heart failure or other disease that would threaten life within two years and 4) absence of personal factors that would interfere with study participation. As the control group was not instructed to change anything, they went about their “artery clogging”, saturated—fat ways eating sausage and mash, Shepard’s Pie and black pudding (it was a British study). The other two groups got the “heart—healthy” nutritional advice to avoid fried foods, fatty meats, sausages, pastry, ice-cream, cheese, cake and to restrict milk, eggs and butter. In other words, both intervention groups were advised to restrict their constunption of saturated fat. Sound familiar? Apart from being instructed to limit these foods, one group was told to consume 80 grams of olive oil daily while the other was instructed to consume 80 grams of polyunsaturated corn oil per day. That’s about 3 ounces. Diarrhea was a common complaint along with distaste and nausea. What did the diet and oils do to total cholesterol levels in these two groups? TABLE 1V.——Changes in Serum—ch0lester0l Le-vels _a¢ Different Periods of the Trial, With Their Standard Errors and Significance Le-uels Control Olive Oil Com Oil Period —·—··—··‘_””” —‘j-“‘—”””` “”*“””_°°““””`_ (Months) Mean and S.E. P Mean and S.E. P Mean and S.E. P (mg./100 ml.) (mg./100 ml.) (mg.]’100 ml.) 0-6 , . +4-4 (1 7-2) > 0-5 + 3-5 (1 9-2) > 0-7 — 25-0 (1 8-8) < 0-01 6-12 .. +0-3 (1 9-2) > 0-8 + 12-0 (1 17-5) > 0-4 -30-8 (1 10-5) < 0-01 12-18 .. — 7-9 (1 9-4) > 0-4 + 4-0 (1 20-2) > 0-6 – 30-3 (1 9-9) < 0-01 18-24 .. -2-8 (1 12-1) > 0-8 — 0-9 (1 10-2) > 0-8 – 19-9 (1 13-5) <0-2
The control, or saturated-fat group, showed pretty consistent results throughout the two-year period
which is remarkable given all the sugar and wheat-laden garbage they were no doubt eating along with
their animal fats, all probably washed down with quite a bit of beer at the local pub with cigarette in
hand.
The olive-oil group was all over the lot. First up, then down, but nonetheless, relatively consistent over
the two years. However, look at the corn-oil group. Their cholesterol levels went down and stayed
there. The negative 19.9 figure recorded in the last six months in this group was apparently an
aberration because according to the researchers, levels fell again during the third year of the study.
We’ve found a dietary substance that consistently lowers cholesterol! Time to slap that bought-and—
paid for American Heart Association “Heart Healthy” seal on all those inviting amber-colored bottles
lining the grocer’s shelf.
But wait! What’s this? Two participants in both “heart—healthy” oil groups developed glycosuria. And
what is that? From Taber’s Medical Dictionary we learn:
“The presence of a reducing sugar found during routine urinalysis is suggestive but not diagnostic of
diabetes mellitus. It is found when the blood glucose level exceeds the renal threshold (about 170 mg/dl
of blood). The fasting level of blood glucose is normally between 70 and 99 mg/ dl of blood.”
Now one of the two people so afflicted entered the trial with mild diabetes, but oil made it worse. lt’s
not clear which oil group this patient was in, however. Oil was stopped, and the glycosuria went away
but restarted once oil was added back to the diet. ·
And what about cardiac events? Well, at two years, the group that was the least likely to have a cardiac
episode (75% to be exact) was the I’m—g0ing-1*0-eat-anything-]-want-with—l0ts—0fsatu1·atedfat· group.
Only 57% of the “heart healthy” olive-oil group remained free of cardiac disease. And what of the low-
cholesterol group? The corn-oil group fared worst of all with a 25% increase in heart attacks and death
in contrast to the control group.
Now to be fair, compliance with this distasteful oil regimen and diet declined with the researchers
estimating that by year two, both groups were probably only taking 60% of the recommended oil dose.
Nevertheless, that cholesterol levels remained so low in the com-oil group suggests compliance was
enough to keep levels depressed throughout the study.
In typical British tmderstatement the authors stated: “It is concluded that under the circumstances of
this trial corn oil cannot be recommended as a treatment of ischaemic heart disease. It is most unlikely
to be beneficial, and it is possibly harrnfi1l.”
Analysis of subsequent trials purportedly showing cardiovascular benefit from consuming omega—6
vegetable oils found these studies to be unreliable because they failed to distinguish between omega-3
and omega-6 polyrmsaturated—fat intake. { 10] V
Why did polytmsaturated omega-6 corn oil do this and why would heart events go up even though j
cholesterol levels went down. . .way down?
If my last post is any clue, it’s because these fats increase gut dysbiosis, intestinal permeability and
translocation of gut pathogens to the liver. This in turn increases inflammatory immune responses in
that organ:
“Acute and chronic inflammation cause hypocholesterolemia [low cholesterol levels] in humans and
nonhtunan primates. Many of the effects of inflammation on lipoprotein metabolism appear to be
mediated by cytokines [inflammatory proteins]. Injection of interleukin-2, colony stimulating factor, or
interferon results in hypocholesterolemia in humans, whereas tumor necrosis factor-a ( l N F—a) and
interleukin (IL-6) cause a rapid fall in plasma cholesterol as well as the concentrations of
apolipoprotein (apo) A~I and ap0B in nonhuman primates.” ( ll [
Translation: inflammation in the liver lowers total cholesterol. The more severe the inflammation, the
lower your cholesterol goes, including LDL cholesterol. With its negative eifects on tight junctions in
the small intestine and oxidation in the liver, you now know why the polyunsaturated omega-6 oil
group had the outcomes they did and why focusing only on high cholesterol is a potentially deadly
mistake.
But, didn’t you say that inflammation caused by endotoxemia raises cholesterol? Yes, I did. The
solution to this riddle comes down to the level of gut pathogen translocation. In a liver that is
responding to chronic levels of gut bacteria, but protected somewhat by saturated fat, LDL cholesterol »
and triglycerides will rise and HDL fall for the reasons I explained above. .
However, in a liver under a lot of oxidative stress brought about by ingesting lots of polyunsaturated
omega-6 oils, not to mention gluten, refined fructose, and alcohol, coupled with reducea intake of liver-
protecting saturated and omega-3 fatty acids, total cholesterol production of both HDL and LDL will go
down while triglycerides go up.

This is a graphic of lipoproteins, the vehicles that transport cholesterol and fat throughout the
bloodstream. Do you see the protein segment attached to the shell and colored purple? This is an
essential component of all lipoproteins. These proteins come in classes labeled A, B, C, D, E, and H
with variations within some groups. Apolipoprotein B or apo-B proteins are found in chylomicrons
(apo—B—48) and VLDL, LDL and LDL cholesterol (apoB—l00). Apolipoprotein A or apo-A is found in
chylomicrons and HDL. VVhat is important to take from all of this is that you cannot assemble
cholesterol-transporting lipoproteins without them:
“The effects of cytokines on lipoprotein metabolism are complex, and the mechanisms by which
cytokines cause hypocholesterolemia [low cholesterol] have not been studied extensively. However, at
least two changes in lipoprotein metabolism appear to be important in the development of acquired
hypocholesterolemia from inflammation in primate species. First, the metabolism of low-density
lipoprotein (LDL) and high—density lipoprotein (HDL) particles is altered by inflammation;
concentrations of both particles fall rapidly after injection of lipopolysaccharide and cytokines. Data
from Schectman et al suggest that inflammation causes a decrease in LDL production rates, as injection
of interferon into normocholesterolemic [normal levels of cholesterol] humans reduced the LDL-apoB
production rate but did not change the fractional catabolic rate. Second, injection of lipopolysaccharide
and cytokines into nonhuman primates results in a significant reduction in the cholesterol ester content
of HDL and LDL that is preceded by a rapid fall in the plasma concentration of lecithin: cholesterol
acyltransferase (LCAT), suggesting that acute inflammation may result in lower production of
cholesterol esters in plasma.” (Q)
Translation: very low total cholesterol is not a sign of health, but of acute inflammation.
When the production of these proteins go down, fat that the liver produces from diet will largely stay
there where it will tend to accumulate:
“Thus, it appears that cytokines may increase lipogenesis [fat production] in Hep G2 ‘liver] cells but
reduce secretion of cholesterol due to the inhibition of the secretion of apolipoproteins.” (LL)
Translation: inflammation increases the production of fat in the liver but prevents its export because
yotu· poor liver can’t produce adequate levels of these needed proteins to assemble the vehicles that
would otherwise cart the fat away.
The reason you’ve never heard of this happening in rodent studies is this: “ln human and nonhuman
primates inflammatory stimuli as well as individual cytokines consistently cause hypocholesterolemia
[low cholesterol], whereas the acute effect in rodents of inflammation and cytokines is either an
increase or no change in cholesterol levels.” (ll)
Translation: in humans cholesterol production in response to acute inflammation reacts differently to
what happens in rodents making any results from these animal studies next to useless for learning how
inflammation affects cholesterol levels in us. However, rodent studies are of huge value in keeping the
saturated—fat and cholesterol—kills—you hypothesis alive and well.
So the solution to this puzzle comes down to this: chronic, low—level translocation of gut pathogens
caused by disturbed gut flora and increased intestinal permeability raises both LDL and triglyceride
levels but lowers HDL levels. Acute endotoxemia, however, lowers not only HDL levels, but LDL and
total cholesterol levels. Neither is ideal, but I’d rather have the former than the latter because at least I
would still have a functioning immune system.
Confinnation for the cho1esterol—lowering effects of acute infection is evident in septicemia or blood
poisoning. (gg) Not even statins or “heart healthy” polyunsaturated vegetable oils are as effective at
lowering total cholesterol. Blood poisoning will decrease total cholesterol, including HDL and LDL
cholesterol while simultaneously increasing triglyceride levels.

Here we see the results of a study that tracked 54 patients who developed sepsis during their hospital
stay. White dots represent those who survived their infection and black dots those who didn’t. ln those
that survived, total cholesterol levels increased, as did HDL, LDL (represented by elevations in
apoprotein B) and albumin. They also experienced decreases in triglyceride levels. Those that died
didn’t. Next time someone tries to convince you that cholesterol is bad, be sure to point this out to
them.
Similar results are seen in those afflicted with cancer (Q;) and persons who experience a heart attack
gl;. This latter effect should come as no surprise to those who have read this series from the
beginning. Once the fibrous cap in the artery ruptures, it spills its load of bacterial toxins into the
bloodstream lowering serum cholesterol levels as in sepsis. Q5)
Here’s a quote you won’t often hear from doctors. It’s from the Honolulu Heart Program study that
followed 3,572 Japanese American Men for 20 years:
“Our data accord with previous findings of increased mortality in elderly people with low serum
cholesterol, and show that long—term persistence of low cholesterol concentration actually increases
risk of death. Thus, the earlier that patients start to have lower cholesterol concentrations, the greater
the risk of death.” QQ
So is cholesterol testing worth the trouble?
Let’s follow two patients in their 60s who visit the same doctor. Patient A arrives complaining of
gastrointestinal symptoms that include bloating, cramps, and constipation with alternating diarrhea.
This patient is clinically obese and testing reveals they are borderline diabetic.
After a series of tests that do not include screening for small intestinal bacterial overgrowth, the patient
is told they have irritable bowel syndrome (IBS). Translation: “we don t know what is causing your
problem but so as not to appear stupid we ’lI tell you you have [BS so you ’ll have something to tell
your fiends and famihfi
In addition to dysregulated glucose control, cholesterol tests show high LDL, triglycerides over 200
mg/dl and HDL hovering in the 20 to 30 mg/dL range. The doctor writes out a prescription for a statin,
hands it to the patient, advises said patient to lose weight, cut back on their saturated—fat intake,
increase their consumption of “healthy” whole—gluten-grains, and rushes out the examining-room door
to see their next victim patient.
Later that day, patient B arrives also complaining of the same GI issues; But this patient is not obese.
Test results come back, and once again our patient is diagnosed with IBS and told to watch their stress
levels which is a polite way of implying that the problem is all in their head. Liver tests come back
slightly elevated but nothing to concem our clinician. Thyroid ftmction, however, is very low and the
patient tells the doctor they feel cold all the time and have low energy. The physician schedules a
referral to an endocrinologist.
Cholesterol results, however, are stellar, the doctor exclaims! Total levels are well below 200 and some
of the lowest they have seen. The patient, still miserable about their unresolved IBS, nonetheless perks
up when hearing this bit of “good” news and shares with the doctor how they credit their “heart—
healthy” low—saturated fat, high—polyunsaturated omega-6 and whole—gluten—grain diet for these
“fantastic” results. The doctor grins from ear to ear congratulating our patient on how well they are
doing and encourages him or her to keep up the excellent work!
Two patients, both with raging gut dysbiosis and translocation of gut pathogens to the liver and
systemic circulation, but entirely different cholesterol readings. If doctors were trained to interpret low
cholesterol results with equal alarm, I would say cholesterol testing is a valuable part of the diagnosticarsenal when complemented with routine testing for inflammatory cytokines and other indicators of
endotoxemia. But we all know that’s not how these tests are actually used.
A week later our physician finds out that patient B suffered a heart attack and was admitted to the local
hospital where the patient is also battling a severe case of pneumonia. The doctor, a bit perplexed,
chalks this up as another example of the cholesterol “paradox”. Nonetheless, our upholder of the
Hippocratic oath has no time for reflection because he or she needs to pack their bags to attend an all-
expenses-paid medical conference in Hawaii sponsored, coincidentally enough, by a manufacturer of
statin drugs.
Conclusion
I started this series noting that the holiday season is the most heart-attack prone time of the year. The
reason for that should be clear. This season is hardest on beneficial gut flora populations and the
integrity of the gut wall. Excess alcohol, gluten, refined fructose, polytmsaturated omega 6 vegetable
oils—all of these dietary agents are drunk or eaten to excess over the holidays. There isn’t a
commercially made fast- or processed-food “delight” that isn’t loaded with industrial omega—6 fats,
gluten and refined fructose. Wash it all down with copious quantities of alcohol, add a pinch or two of
stress along with a simmering case of small intestinal bacterial and yeast overgrowth, and your gut wall
hasn’t got a chance.
The next stop for translocating gut pathogens is the liver, and it’s only as healthy as the gut. If it’s
simultaneously battling a case of viral hepatitis or fat accumulation or fending off a long-standing case
of gut dysbiosis, don’t be shocked to discover it’s as incapable of handling what you’re throwing at it
as your gut flora and intestinal wall.
Maybe, your gut dysbiosis will “only” cause you to gain some stubborn-to—lose weight, mess with your
sleep, increase anxiety or depression or mood swings, exacerbate an existing autoimmune disorder,
depress your defenses against catching the cold or flu, and make your intestines spasm. Or, you may
not live to see the new year.
Bacterial Bioiilms and Cardiovascular Disease
I consider metabolic syndrome (insulin resistance, hypertension, cardiovascular disease, etc.) as
fundamentally caused by translocating gut bacteria to the liver and systemic circulation. This explains
what initiates what I’ve termed “The lnflammatogg-Cortisol Ballet” and the metabolic consequences
that flow from that. When it comes to heart disease and stroke, I’ve written that they can’t be explained
simply by referring to what happens to changes in concentrations of lipoproteins, be they LDL or HDL.
{ While there is clearly an association between dyslipidemia and arterial disease, focusing solely on these
markers is not likely to get you very far in unraveling the processes underlying plaque fonnation and
rupture.
On June 10th, I briefly highlighted a scientihc paper concerning a study that confirmed the presence of
bacterial pathogens in arterial plaque. (I) While this isn’t the first study to find evidence of bacteria in
plaque, it is the first to fmd these pathogens living in biofilms.
A biofihn is any grouping of bacteria adhering to a surface, and protected by formation of what is
called an extracellular polymeric substance. This substance is also popularly referred to as slime.
Pathogens living in biofilms are much harder to kill because of this slimy protective cover. Many
pathogens that would normally succumb to immune cells like neutrophils and macrophages are better
able to evade these defenses when part of a biofilm. Q) Q) (Q)
In this study, samples of diseased carotid arteries were obtained from Hfteen patients, all of whomexhibited advanced arteriosclerosis. The samples were subjected t0 bacterial analysis.
All samples were found to contain genetic material from a number of bacterial species. Five out of the
fifteen samples were subjected to further genetic analysis to determine the unique bacterial composition
contained within their plaque.
Each of these five samples was found to contain anywhere from 10 to 18 different bacterial pathogens
living in the biofilm. Eight bacterial species were common to all five arterial samples, while the rest
were unique to each patient.
ln a previous paper, this research group identified one particular pathogen—Pseudomonas aeruginosa
(R aeruginosa)—as a common colonizing bacteria in many diseased arterial samples. To see if this was
the case here, all samples were analyzed for the presence of this gram-negative pathogen. Five of the
fifteen carotid samples tested positive for this particular one, and one tested positive for another strain
of Pseudomonas.
Further analysis of five sub-samples confirmed that these bacteria were grouped together in
biofilmslocated in various locations of the artery wall.

In the lower left-hand corner, we see a cross—section of an artery displaying an atheromatous plaque
held in place by a fibrous cap. Contrary to the popular belief that fat and cholesterol somehow plaster
themselves to the internal arterial wall or tunica intema, we clearly see that plaque accumulates from
below the arterial wall.
The background area in green is a flourescence scan of patient number one’s carotid artery. The first
biofilm, labeled Ll, was found next to the internal elastic lamina, and the second, labeled L2, was
located within the tunica externa.
Patient number two’s sample showed a single biofilm located next to the internal elastic lamina just
below the fibrous cap. Patient three also had one bacterial biofilm, but theirs was located in the tunica
intema and showed signs of previous rupture.
Patient four showed an extensive bacterial colony within the tunica interna. And patient five had a
biofilm residing next to the intemal elastic lamina. Of all the bacterial biofilms detected, 76.5% were
located either near the internal elastic lamina or the tunica intema and fibrous cap.
Now before I continue, this discovery of biofihris in arterial plaque dovetails with what we know of
cardiovascular disease as an inherently inflammatory process. Cholesterol and the lipoproteins that
transport it, have a role in innate immtmity. All lipoproteins—chylomicrons, VLDL, IDL, LDL and
HDL——bind to and i-n—a—c—t-i-v-a-t-e lipopolysaccharides. They also protect against gram—positive
bacterial pathogens, viruses and parasites.
And that includes “bad” LDL cholesterol, the lipoprotein that has been so vilified. Do you honestly
believe that our livers were designed to produce a substance to kill us?
Take two sets of mice and give each of them a lethal dose of gram—negative E. coli. Give one set of mice
an infusion of human-derived chylomicrons and VLDL and the survival rate of these m’ce is 100%. ln
other words, they don’t die from an otherwise deadly dose. lnfuse them with htnnan LDL and HDL and
you get the same result.
Another example, using some LDL receptor deficient mice. Because they have been genetically bred to
lack the LDL receptor, they have unusually high levels of LDL coursing through their little arteries and
veins.
Now pair these LDL—engorged mice against normal wild-type mice. Once again, give both sets of mice
an infusion of gram-negative E. coli. The mice with very high levels of LDL cholesterol will have a
significantly increased survival rate. These LDL mice don’t begin dying off until their endotoxin levels
are eight times higher than their normal litter mates. Their levels of circulating inflammatory cytokines
are also far lower.
Now, with the same set of mice, infect them with Klebsiella pneumoniae, another gram-negative
pathogen that is commonly found in arterial plaque. Again, the LDL mice show increased survival
rates. After acute infection, only 42% ofthe mice with higher LDL levels die as opposed to 67% of the
controls?
So what this study suggests is that cholesterol’s involvement with cardiovascular disease is the same as
the immune cells also found residing in plaque, namely as an innate immune response to bacterial
infiltration of the arterial wall. Whatever oxidation of LDL cholesterol is found in plaque is likely the
normal outcome of being subjected to the reactive oxygen and nitrogen species generated by immune
cells in an attempt to destroy these bacterial colonies.
But where are these bacteria coming from? The most likely answer is a digestive tract incapable of
keeping them confined to the oral and/or intestinal cavity. That would explain why periodontal and
inflammatory bowel diseases are highly associated with increased risk of cardiovascular disease. Q) {Q
For what I consider one of the best explanations of how pathogens cause development of arterial
plaque, I refer you to this paper by doctors Uffe Ravnskov and Kilmer S. McCully. Their hypothesis is
certainly a credible elucidation of how immtme responses to these pathogens initiate this process.
Returning to the research paper under review, these scientists did not just stop at cataloging the number
and location of arterial biofilms. They sought to test another hypothesis about how acute stress may
weaken and rupture the fibrous cap that contains this mixture of bacteria, oxidized cholesterol, lipids,
and immune cells.
This part of the paper is admittedly the most speculative in that the following experiments were done in
vitro or in the laboratory. What’s true for a test tube experiment doesn’t necessarily translate to real-
world biological processes.
In order to suffer a stroke or heart attack, more is needed than the buildup of arterial plaque. While
plaque does narrow arterial passageways, a blockage of that artery requires that a plaque formation
rupture and form a clot or thrombus. It is this clot that prevents the flow of blood and oxygen needed
by the brain or heart causing damage and possibly death should the blockage not be cleared in a timely
manner.
It has long been known that stress is often a precipitating factor for cardiovascular events. So too
sudden physical exertion and emotional upset. The question, however, is how these states are connected
to the rupture of plaque, and what role, if any, bacteria may play in this chain of events.
To answer this question, these researchers subjected biofilms of R aeruginosa to two substances to
determine if this would cause a dispersal of bacteria that could conceivably undermine the integrity of a
plaque formation containing them.
The first of these substances was free iron. Iron, in its free or tmbound state, can be utilized by a
number of bacteria to grow.
In this experiment, they found that the addition of free iron to the culture medium did indeed cause the
release of bacteria from biofilms after about 20 minutes. However, there was no evidence that bacterial
populations grew in this time period leading to speculation that the slime containing these pathogens
was somehow undermined. Nonetheless, Hee iron is not how this element is typically stored or
transported through our bodies so its real-world relevance is doubtful, which explains the rationale for
the next experiment.
In this second experiment, biofilms were now subjected to norepinephrine and the bound fonn of iron,
transferrin. Norepinephrine is one of the catecholamines released during the stress response, along with
cortisol. It shares this category with epinephrine (aka adrenaline) and dopamine.
Epinephrine and norepinephrine are part of the fight-or-flight response, and like cortisol release from
the adrenals, are regulated by the hypothalamic—pituitary-adrenal gHPAl axis. This is the same axis
activated by bacterial translocation through the gut wall during acute episodes of leaky gut.
Addition of norepinephrine in concentrations typically seen during a stress response caused an increase
in free iron concentrations that in turn caused a significant release of bacteria from their biofilm. Now,
whenever bacteria escape from within a biofilm, they must produce degradative enzymes to break
down the extracellular polymeric substance or slime that otherwise encases them, and it appears that
free iron contributes to this chain of events.
These researchers hypothesize that these enzymes are not only capable of degrading biofilm slime, they
may also be capable of destabilizing the fibrous cap. As they point out:
“Biofilm dispersion by this microorganism was also shown here to be induclble by the addition of
norepinephrine to transferrln-containing culture medium. Thus, under laboratory conditions, an invitro spike in hormone concentration was shown to induce biofilm dispersion. lt is unclear at this
time whether a biofilm dispersion response is inducible in viva. For instance. sequestration of
biofilm deposits within atheromas may have a mitigating effect on the ability of norepinephrine to
induce iron release in the vicinity of the infecting bacteria. Furthermore, the association of ‘
degradative enzyme release during the biofilm dispersion response with collateral tissue damage
is speculative on our part. We have no direct evidence that this occurs in vivo; however, we believe
that the potential for additional damage to surrounding tissues due to bacterial enzyme release
may be an additional significant factor contributing to thrombogenesis [clot formation].”
Moreover, they point to other non-bacterial factors that may contribute to disruption of the fibrous cap,
such as inflammatory cytokines and C-reactive protein. Another factor is composition of the lipids that
l are contained in plaque. Of these, polyunsaturated omega—6 fatty acids (omega 6 PUFAs) have been
associated with plaque rupture given their propensity to readily oxidize and form pro-inflammatory
lipid peroxidation byproducts. Q;) QQ;) QQ Nevertheless, this hypothesis may offer another clue to the
puzzle as to how acute stress precipitates a cardiovascular event separate and apart from transitory
increases in blood pressure and constriction of arteries.
If the source of these pathogens is the digestive tract, then it becomes imperative to prevent their
translocation, which cannot be accomplished without the active assistance of beneficial oral and gut
flora that line the digestive cavity. As beneficial gut flora is also necessary for maintaining a healthy
immune response, their reduction or absence makes it more likely that these pathogens will escape
immune destruction prior to forming arterial biofilms. And once biohlms do form, clearing these
pathogens becomes much more difficult.
Controlling blood sugar levels is also vitally important as chronically elevated blood glucose is
associated with immune suppression and increased risk of infection. This likely explains the higher
incidence of heart disease in this population.
However, as l’ve noted elsewhere, pre- and type 2 diabetes is itself a reaction to tran locating gut
bacteria that in turn causes inflammation in the liver and increases cortisol generation in that organ. It is
this increase in intracellular hepatic cortisol generation via up-regulation of the enzyme 11B-
hydroxysteroid dehydrogenase type l that likely causes a liver to become deaf to the insulin secreted by
an overworked pancreas. QQ) Once this occurs, runaway hepatic glucose production is the result. QQ)
This increase in intracellular cortisol concentrations has an anti-inflammatory effect. But, anti-
inflammatory is another way of saying immune suppressing. This chronic activation of the cortisol-
cortisone shunt by a leaky gut always results in suppressing the very system that could eradicate these
pathogens from systemic circulation and arterial plaque.
This study adds to a growing body of evidence that cardiovascular diseases are primarily driven by the
interaction between pathogens, the immune response to these agents, genetic predisposition, and the
regulatory systems (HPA-axis and cortisol-cortisone shunt) that drive catecholamine responses and
determine extracellular and intracellular cortisol concentrations.
It explains why practices like binge drinking are highly associated with heart attack and stroke risk.
This mode of imbibing alcohol increases oral dysbiosis, compromises gastric-barrier function,
promotes disturbances to gut flora populations, increases intestinal permeability, contributes to liver
damage, activates the cortisol-cortisone shunt, acutely stimulates the HPA—axis, and causes immune
suppression. In other words, alcohol on its own is more than capable of rapidly promoting arterial
disease when abused.
However, alcohol is far from the only drug that would be expected to increase dysbiosis and elevate the
risk of cardiovascular disease. Acid—suppressing drugs, antibiotics, non-steroidal anti-inflammatories
(NSAIDs), glucocorticoids, and opioid—based analgesics can all contribute to development of dysbiosis.

Acid suppressors because they compromise gastric—barrier function, antibiotics by the collateral
damage done to beneficial bacteria, NSAIDs by causing increased intestinal permeability,
glucocorticoids by suppressing immune function, and opioids by depressing intestinal peristalsis and
thereby contributing to the onset of small intestinal fungal and bacterial overgrowth.