Ray Peat, PhD on Endotoxin

Also see:
Bowel Toxins Accelerate Aging
Ray Peat, PhD on the Benefits of the Raw Carrot
Protective Cascara Sagrada and Emodin
Fermentable Carbohydrates, Anxiety, Aggression
Protective Bamboo Shoots
Endotoxin-lipoprotein Hypothesis
Endotoxin: Poisoning from the Inside Out
Protection from Endotoxin
How does estrogen enhance endotoxin toxicity? Let me count the ways.
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Alcohol Consumption – Estrogen and Progesterone In Women
Autoimmunity and Intestinal Flora
Hypothyroidism, Intestinal Bacterial Overgrowth, & Lactose Intolerance
Estrogen, Endotoxin, and Alcohol-Induced Liver Injury
Protective “Essential Fatty Acid Deficiency”
PUFA and Liver Toxicity; Protection by Saturated Fats
Can Endurance Sports Really Cause Harm? The Lipopolysaccharides of Endotoxemia and Their Effect on the Heart

“The maladaptive sequence, starting from stress or hypothyroidism, would typically involve increased absorption of endotoxin, leading to interference with mitochondrial respiration, a shift to fat oxidation, inflammation, and the increase of a wide range of stress hormones. Each of these happens to interfere with the production of progesterone, leading to increased LH.”

“The liver is the major source of the acute phase proteins, and it is constantly burdened by toxins absorbed from the bowel; disinfection of the bowel is known to accelerate recovery from stress.”

“It takes a few days for the intestine to adjust to raw carrot, but the indigestible fiber is very protective for the intestine. Boiled bamboo shoots, which are also mostly indigestible, have a similar effect. These fibers prevent the reabsorption of estrogen in the intestine, and can shift the balance away from cortisol and estrogen, toward progesterone and thyroid, in just a few days of regular use. Oatmeal and potatoes do provide fiber, but they are good food for bacteria, and bacterial endotoxin is usually the basic problem causing hormone imbalance, by being a chronic burden for the liver, keeping it from storing enough sugar to process thyroid and the other hormones effectively.”

“The mitochondria are responsible for the efficient production of energy needed for the functioning of complex organisms, and especially for nerves. The enzyme in the mitochondria that reacts directly with oxygen, and that is often rate limiting, is cytochrome oxidase.

This enzyme is dependent upon the thyroid hormone and is inhibited by nitric oxide, carbon monoxide, estrogen, polyunsaturated fatty acids, serotonin, excess or free iron, ionizing radiation, and many toxins, including bacterial endotoxin. Red light, which passes easily through the tissues, reactivates the enzyme, which slowly loses its function during darkness.

Estrogen impairs the mitochondria in multiple ways, including blocking the function of cytochrome oxidase, decreasing the activity of ATP synthase, increasing heme oxygenase which produces carbon monoxide and free iron, damaging mitochondrial DNA, and shifting metabolism from glucose oxidation to fat oxidation, especially by inhibiting pyruvate dehyrogenase complex. These changes including the loss of cytochrome oxidase, are seen in the Alzheimer’s brain. The fact that this kind of energy impairment can be produced by estrogen doesn’t imply that estrogen is the cause, since many other things can cause similar effects–radiation, aluminum, endotoxin, for example.”

“When estrogen overlaps with endotoxin (as it tends to do), multiple organ failure is the result.”

“Hyperventilation is present in hypothyroidism, and is driven by adrenalin, lactate, and free fatty acids. Free fatty acids and lactate impair glucose use, and promote edema, especially in the lungs. Edema in the lungs limits oxygen absorption. Swelling of the brain, resulting from increased vascular permeability and the entry of free fatty acids, reduces its circulation and oxygenation; lactic acidemia causes swelling of glial cells. Swelling of the endothelium increases vascular resistance by making the channel narrower, eventually affecting all organs. Cells of the immune system release tumor necrosis factor and other inflammatory cytokines, and the bowel becomes more permeable, allowing endotoxin and even bacteria to enter the blood. Endotoxin impairs mitochondria, increases estrogen levels, causes Kupffer cells in the liver to produce more tumor necrosis factor, etc. Despite its name, tumor necrosis factor stimulates the growth and metastasis of some types of cancer. Dilution of the body fluids, which occurs in hypothyroidsim, hyperestrogenism, etc., stimulates tumor growth.”

“The saturated fats, in themselves, seem to have no “signalling” functions, and when they are naturally modified by our desaturating enzymes, the substances produced behave very differently from the plant-derived “eicosanoids.” As far as their effects have been observed, it seems that they are adaptive, rather than dysadaptive. All of the factors that affect the brain of a fetus should be examined in relation to the aging brain. Besides estrogen and fats, I am thinking of oxygen and carbon dioxide, glucose, iron and calcium, cholesterol, progesterone, pregnenolone, DHEA, the endorphins, GABA, thyroid, and vitamin A. An additional factor, endotoxin poisoning, eventually tends to intervene during stress and aging, exacerbating the trend begun under the influence of the other factors.”

“Endotoxin: Antimitochondrial action, causes elevation of estrogen. It synergizes with unsaturated fats, and naloxone opposes some of its toxic effects.”

“A “deficiency” of polyunsaturated fatty acids leads to altered rates of cellular regeneration and differentiation, a larger brain at birth, improved function of the immune system, decreased inflammation, decreased mortality from endotoxin poisoining, lower susceptibility to lipid peroxidation, increased basal metabolic rate and respiration, increased thyroid function, later puberty and decreases other signs of estrogen dominance. When dietary PUFA are not available, the body produces a small amount of unsaturated fatty acid (Mead acids), but these do not activate cell systems in the same way that plant-derived PUFAs do, and they are the precursors for an entirely different group of prostaglandins.”

“The absence of cancer on a diet lacking unsaturated fats, the increased rate of metabolism, decreased free radical production, resistance to stress and poisoning by iron, alcohol, endotoxin, alloxan and streptozotocin, etc., improvement of brain structure and function, decreased susceptibility to blood clots, and lack of obesity and age pigment on a diet using coconut oil rather than unsaturated fats, indicates that something very simple can be done to reduce the suffering from the major degenerative diseases, and that it is very likely acting by reducing the aging process itself at its physiological core.”

“In the bowel, the capillary malfunction increases the absorption of endotoxin, which intensifies the systemic energy problem. (Polyunsaturated oils, especially fish oil, damage the bowel capillaries, allowing more endotoxin to be absorbed.)”

“The amyloids and lipoproteins are powerfully responsive to bacterial endotoxin, LPS, and their structural feature that binds it, the “pleated sheet” structure, appears to also be what allows the amyloids to form amorphous deposits and fibrils under some circumstances. Our innate immune system is perfectly competent for handling our normal stress induced exposures to bacterial endotoxin, but as we accumulate the unstable fats, each exposure to endotoxin creates additional inflammatory stress by liberating stored fats. The brain has a very high concentration of complex fats, and is highly susceptible to the effects of lipid peroxidative stress, which become progressively worse as the unstable fats accumulate during aging.”

“By some tests, the “prion” resembles the LPS endotoxin. One of the interesting developments of the prion theory is that a particular structure that appears when the prion becomes toxic, the “beta pleated sheet,” is also a feature of most of the normal proteins that can form amyloid, and that this structure is directly related to binding and eliminating the bacterial LPS. If the prion theory is correct about the conversion of a normal protein into the pleated sheet, it isn’t necessarily correct about the incurability of the condition. The innate immune system should be able to inactivate the prion just as it does the bacterial endotoxin, if we remove the conditions that cause the innate immune reaction to amplify the inflammation beyond control.”

“We are all subject to a variable degree of inflammatory stimulation from the endotoxin absorbed from the intestine, but a healthy liver normally prevents it from reaching the general circulation, and produces a variety of protective factors. The HDL lipoprotein is one of these, which protects against inflammation by binding bacterial endotoxins that have reached the bloodstream. (Things that increase absorption of endotoxin–exercise, estrogen, ethanol–cause HDL to rise.) Chylomicrons and VLDL also absorb, bind, and help to eliminate endotoxins. All sorts of stress and malnutrition increase the tendency of endotoxin to leak into the bloodstream. Thyroid hormone, by increasing the turnover of cholesterol and its conversion into the protective steroids, is a major factor in keeping the inflammatory processes under control.”

“Endotoxin formed in the bowel can block respiration and cause hormone imbalances contributing to instability of the nerves, so it is helpful to optimize bowel flora, for example with a carrot salad; a dressing of vinegar, coconut oil and olive oil, carried into the intestine by the carrot fiber, suppresses bacterial growth while stimulating healing of the wall of the intestine. The carrot salad improves the ratio of progesterone to estrogen and cortisol, and so is as appropriate for epilepsy as for premenstrual syndrome, insomnia, or arthritis.”

“TNF is produced by endotoxin, and estrogen increases the amount of endotoxin in the blood. Even without endotoxin, though, estrogen can stimulate the production of TNF. Lactic acid and unsaturated fats and hypoxia can stimulate increased formation of TNF. Estrogen increases production of nitric oxide systemically, and nitric oxide can stimulate TNF formation. How does TNF work, to produce tissue damage and wasting? It causes cells to take up too much calcium, which makes them hypermetabolic before it kills them. It increases formation of nitric oxide and carbon monoxide, blocking respiration. TNF can cause a 19.5 fold increased in the enzyme which produces carbon monoxide (Rizzardini, et al., 1993), which blocks respiration.”

“The relatively few studies of fish oil and linoleic acid that compare them with palmitic acid or coconut oil have produced some very important results. For example, pigs exposed to endotoxin developed severe lung problems (resembling “shock lung”) when they had been on a diet with either fish oil or Intralipid (which is mostly linoleic acid, used for intravenous feeding in hospitals), but not after palmitic acid (Wolfe, et al., 2002).”

“Carrageenan enters even the intact, uninflamed gut, and damages both chemical defenses and immunological defenses. When it has produced inflammatory bowel damage, the amount absorbed will be greater, as will the absorption of bacterial endotoxin. Carrageenan and endotoxin synergize in many ways, including their effects on nitric oxide, prostaglandins, toxic free radicals, and the defensive enzyme systems.

The continuing efficient production of energy is a basic aspect of metabolic defense, and this is interrupted by carrageenan and endotoxin. The energy failure becomes part of a vicious circle, in which permeability of the intestine is increased by the very factors that it should exclude.”

“On a typical diet, tissues progressively accumulate linoleic acid, and this alters the structure of mitochondrial cardiolipin, which governs the response of the mitochondrial enzymes to the thyroid hormone. This process is especially evident in the female liver. In the “autoimmune” diseases, such as lupus, there are typically antibodies to cardiolipin, as if the body were trying to reject its own tissues, which have been altered by the storage of linoleic acid. The altered mitochondrial function, which is involved in so many symptoms, can become part of a vicious circle, with endotoxin and estrogen having central roles, once the stage has been set by the combination of diet, stress, and toxins.”

“The premenstrual estrogen-dominance usually leads progressively to higher prolactin and lower thyroid function. Estrogen is closely associated with endotoxinemia, and with histamine and nitric oxide formation, and with the whole range of inflammatory and “autoimmune” diseases. Anything that irritates the bowel, leading to increased endotoxin absorption, contributes to the same cluster of metabolic consequences.”

“Incidental stresses, such as strenuous exercise combined with fasting (e.g., running or working before eating breakfast) not only directly trigger the production of lactate and ammonia, they also are likely to increase the absorption of bacterial endotoxin from the intestine. Endotoxin is a ubiquitous and chronic stressor. It increases lactate and nitric oxide, poisoning mitochondrial respiration, precipitating the secretion of the adaptive stress hormones, which don’t always fully repair the cellular damage.”

“The toxic mechanism of bacterial endotoxin (lipopolysaccharide) involves inappropriate stimulation (Wang and White, 1999) of cells, followed by inflammation and mitochondrial inhibition. The stimulation seems to be a direct “biophysical” action on cells, causing them to take up water (Minutoli, et al., 2008), which is especially interesting, since estrogen’s immediate excitatory effect causes cells to take up water.

Hypoosmolarity itself is excitatory and anabolic. It stimulates lipolysis and fat oxidation (Keller, et al. 2003), and osmotic swelling stimulates glycolysis and inhibits mitochondrial respiration (Levko, et al., 2000). Endotoxin causes hyponatremia (Tyler, et al., 1994), and a hypertonic salt solution is protective, lactate solutions are harmful. Other stresses and inflammations also cause hyponatremia.

One of the effects of endotoxin that leads to prolonged cellular excitation is its inhibition of the glucuronidation system (Bánhegyi, et al., 1995), 1995), since this inhibition allows excitatory estrogen to accumulate.

In women and rats, antibiotics were found to cause blood levels of estrogen and cortisol to decrease, while progesterone increased. This effect apparently resulted from the liver’s increased ability to inactivate estrogen and to maintain blood sugar when the endotoxin stress was decreased.

Now that hog farmers’ use of antibiotics to stimulate growth has been discouraged, they have sought vegetables that have a natural antibiotic effect, reducing the formation and absorption of the intestinal toxins. The human diet can be similarly adjusted, to minimize the production and absorption of the bacterial toxins.”

“Bacteria thrive on starches that aren’t quickly digested, and the bacteria convert the energy into bulk, and stimulate the intestine. (But at the same time, they are making the toxins that affect the hormones.)”

“Since endotoxemia can produce aerobic glycolysis in an otherwise healthy person (Bundgaard, et al., 2003), a minimally “Warburgian” approach– i.e,, a merely reasonable approach–would involve minimizing the absorption of endotoxin. Inhibiting bacterial growth, while optimizing intestinal resistance, would have no harmful side effects. Preventing excessive sympathetic nervous activity and maintaining the intestine’s energy production can be achieved by optimizing hormones and nutrition. Something as simple as a grated carrot with salt and vinegar can produce major changes in bowel health, reducing endotoxin absorption, and restoring constructive hormonal functions.”

“Chronic constipation, and anxiety which decreases blood circulation in the intestine, can increase the liver’s exposure to endotoxin. Endotoxin (like intense physical activity) causes the estrogen concentration of the blood to rise. Diets that speed intestinal peristalsis might be expected to postpone menopause. Penicillin treatment, probably by lowering endotoxin production, is known to decrease estrogen and cortisone, while increasing progesterone. The same effect can be achieved by eating raw carrots (especially with coconut oil/olive oil dressing) every day, to reduce the amount of bacterial toxins absorbed, and to help in the excretion of estrogen. Finally, long hours of daylight are known to increase progesterone production, and long hours of darkness are stressful. Annually, our total hours of day and night are the same regardless of latitude, but different ways of living, levels of artificial illumination, etc., have a strong influence on our hormones. In some animal experiments, prolonged exposure to light has delayed some aspects of aging.”

“Besides being an ecologically favorable source of calcium, protein, sugar, and fat, the composition of milk causes it to be digested efficiently, supporting the growth of bacteria that are relatively safe for the intestine and liver, and reducing the absorption of endotoxin.”

“Animals that lack the unsaturated fatty acids have a higher metabolic rate and ability to use glucose, converting it to CO2 more readily, have a greater resistance to toxins (Harris, et al., 1990; even cobra venom: Morganroth, et al., 1989), including endotoxin (Li, et al., 1990)– preventing excessive vascular leakage–and to immunological damage (Takahashi, et al., 1992), and to trauma, and their neuromuscular response is accelerated while fast twitch muscles are less easily fatigued (Ayre and Hulber, 1996).”

“During pregnancy, the reduced blood volume doesn’t adequately nourish and oxygenate the growing fetus, and the reduced circulation to the kidneys causes them to release a signal substance (renin) that causes the blood to circulate faster, under greater pressure. A low salt diet is just one of the things that can reduce kidney circulation and stimulate renin production. Bacterial endotoxin, and other things that cause excessive capillary permeability, edema, or shock-like symptoms, will activate renin secretion.”

“Endotoxin, produced by bacteria, mainly in the intestine, disrupts energy production, and promotes maladaptive inflammation. The wide spectrum of benefit that iodide has, especially in diseases with an inflammatory component, suggests first that it protects tissue by blocking free radical damage, but it also suggests the possibility that it might specifically protect against endotoxin.”

“Serotonin, an important mediator of stress, shock, and inflammation, is a vasoconstrictor that impairs circulation in a great variety of circumstances.

Stress impairs metabolism, and serotonin suppresses mitochondrial energy production.

Stress and shock tend to increase our absorption of bacterial endotoxin from the intestine, and and endotoxin causes the release of serotonin from platelets in the blood.”

“A very important form of prenatal stress occurs in toxemia and preeclampsia, in which estrogen is dominant, and endotoxin and serotonin create a stress reaction with hypertension and impaired blood circulation to the uterus and placenta.”

“Therapies that have been successful in treating schizophrenia include penicillin, sleep therapy, hyperbaric oxygen, carbon dioxide therapy, thyroid, acetazolamide, lithium and vitamins. These all make fundamental contributions to the restoration of biological energy. Antibiotics, for example, lower endotoxin formation in the intestine, protect against the induction by endotoxin of serotonin, histamine, estrogen, and cortisol. Acetazolamide causes the tissues to retain carbon dioxide, and increased carbon dioxide acidifies cells, preventing serotonin secretion.”

“When animals have been “deprived” of the EFA during gestation and nursing, and then given a standard diet, they develop larger bones, with a thicker cortex and more trabecular bone, both of which would suggest a lower level of stress. Many types of inflammation and stress are significantly reduced in “EFA deficient” animals. Inflammation caused by the injection of carrageenan is decreased, partly because of the absence of prostaglandins in these animals. The absence of the EFA protects against colitis and nephritis. The kidneys are more effective in several ways in the deficient animals.

Shock, caused by the injection of endotoxin, which is 100% lethal to normally fed animals, is only 24% lethal to the deficient animals.”

“Another process with potentially deadly results that increase with aging and stress, is the passage of bacteria from the intestines into the blood stream.”

“Aging and stress increase some of the inflammatory mediators, tending to reduce the barrier function of the bowel, letting larger amounts of bacterial toxins enter the bloodstream, interfering with energy metabolism, creating inflammatory vicious circles of increasing leakiness and inflammation.”

“The gerontologist, V.V. Frolkis, recently found that mice lived 43% longer than animals on the standard diet when they periodically had activated charcoal added to their food. This is the clearest evidence I have seen that “bowel toxins” make a major contribution to the aging process.”

“Bacterial endotoxin inhibits mitochondrial respiration, and this respiration is needed for the intramitochondrial conversion of cholesterol into pregnenolone. With aging, pregnenolone and its derivatives, progesterone and DHEA, decline sharply. The brain, the organ with the highest concentration of those stabilizing substances, has many systems for adapting to their decreasing concentration, but the immune system is probably less able to compensate for those aging changes.”

“In the last century, it was observed that digitoxin (a natural steroid derivative) lowered the fever caused by enteritis. This is probably another example of a catatoxic function, a protective function common to many steroids, and probably worked by way of stabilizing the detoxifying enzymes and preventing the absorption of endotoxin. Endotoxin is known to destabilize and inactivate the bowel’s detoxifying enzymes, just as an overdose of cortisol does.”

“Bacterial toxins, whether produced in the intestine or in the manufacture of food supplements, pass through the wall of the intestine in larger amounts in stress, malnutrition, and old age. Endotoxin suppresses mitochondrial respiration, and tends to produce a shock-physiology similar to that produced by endogenous hormones. I have mentioned before that I think endotoxin can be involved in the premenstrual syndrome, and I think it might even be involved in some breast syndromes.”

“In aging, stress, and malnutrition, the barrier function of the intestine is weakened.”

“Two features of mitochondrial damage in severe stress (regardless of whether endotoxin is involved) are a depletion of the antioxidant reserves, and loss of the ability to convert cholesterol into the protective steroid hormones. Mitochondrial damage is more likely in hypothyroidism, as I have discussed previously; thyroxin inhibits lipid peroxidation, end it tends to be inversely related to adrenalin, preventing or minimizing “catecholamine toxicity,” for example. Beans and lentils happen to be powerful anti-thyroid agents, so it isn’t surprising to see indications of decreased aerobic capacity, resulting from decreased peak oxygen consumption in association with the chronic fatigue syndrome (CFS), if that syndrome is caused by chronic exposure to dietary legumes.”

“One aspect of taxol research might advance our understanding of the body’s defenses against cancer. It happens that taxol, like bacterial endotoxin, stimulates macrophages to secrete tumor necrosis factor (TNF). This knowledge might lead to an insight into the nature of the process that controls TNF, and how that process fits into nonnal immunity. Promoting the body’s natural immunity, combined with reducing our exposure to cancer-causing factors, should have higher priority in the health sciences, but the power of the drug industry focuses attention on the idea of medically killing cancer cells.”

“Endotoxin or other material absorbed from intestinal bacteria contributes to a variety of autoimmune problems, including thyroiditis (Penhale and Young, 1988). Combining an indigestible fiber, such as raw carrot, with mild germicides, such as vinegar and coconut oil, can improve the hormonal environment, while reducing the immunological burden.”

“Estrogen and PUFA create insulin resistance, and the resulting state of “diabetes” and stress de-energizes tissues, with the mitochondria that are damaged by unsaturated fatty acids, nitric oxide, tumor necrosis factor (TNT), serotonin, etc., failing to meet the tissues’ energy needs. Stress, endotoxinemia, and increased estrogen tend to activate TNF, which has a role in brain degenerative diseases and osteoporosis and multiple organ failure.”

“Systemic metabolic problems make local problems worse, and if a local injury is serious, it can cause the liver to produce stress-related proteins called “acute phase proteins,” including fibrinogen and serum amyloids A and P, C-reactive protein, and other inflammation-related proteins. These proteins are a primitive sort of immune system, that· can directly bind to some harmful substances. Endotoxin absorbed from bowel bacteria is probably the commonest reason for increased production of these proteins. The acute phase proteins contribute to the development of tumors in various ways. For example fibrinogen degradation products are pro-inflammatory. Although these are called acute phase proteins, they sometimes might better be called chronic inflammation proteins, since they are associated with diabetes, cancer, and heart disease.”

“The stress response is self-sustaining on several levels. For example, stress increases the absorption of bacterial endotoxin from the intestine, which increases the estrogen level and synergizes with biliverdin and cortisol.”

“Estrogen is now known to increase with athletic stress, trauma, sickness, endotoxin poisoning, etc., and to be an essential factor in prostate cancer, as well as all other cancers, so it doesn’t seem to be such a big step to go from “stress hormone” to “age hormone.” Estrogen is beginning to lose its false identity as the “female hormone,” which was always just a promotional concept of the pharmaceutical industry. Hundreds of false claims have been made about estrogen’s “youth promoting” effects, but they always turn out to be the opposite of what is claimed. For example, “estrogen increases the collagen content of skin,” but in fact collagen accumulation is characteristic of aging, radiation injury, and-many other types of damage. ”Estrogen makes the skin plumper,” but it is by causing water retention; bloating might stretch wrinkly skin until it is smooth, or even tight, but a swollen old face is, if anything, biologically older than a lean and creased face. (I have discussed many other such advertising ploys in my books, e.g., From PMS to Menopause: Hormones in Context.)”

“One of the factors promoting excess cortisol production is intestinal irritation, causing absorption of endotoxin and serotonin. Fermentable fibers (including pectins and fructooligosaccharides) support the formation of bacterial toxins, and can cause animals to become anxious and aggressive. Fed to horses, some types of fiber increase the amount of serotonin circulating in the blood. Grains, beans, and other seeds contain fermentable fibers that can promote intestinal irritation. The liver has several ways to detoxify endotoxin and serotonin, but these can fail as a result of poor nutrition and hypothyroidism.”

“Besides the direct effects of endotoxin and fatty acids, endotoxin’s activation of prostaglandins and nitric oxide contribute to the metabolic shift toward inflammation and away from efficient oxidation of glucose.”

“Just friction, or scratching or stretching the intestine is enough to cause it to release serotonin into the bloodstream. Serotonin increases the permeability of the intestine and blood vessels, and so is likely to be a major cause of the absorption of endotoxin (and other harmful material) during intestinal irritation or stress. The biological meaning of serotonin might be very different without endotoxin, but that hasn’t been investigated.

Bacterial endotoxin increases serotonin release from the intestine, and increases its synthesis in the brain (Nolan, et al., 2000) and liver (Endo, 1983). It also stimulates its release from platelets, and reduces the lungs’ ability to destroy it. The formation of serotonin in the intestine is also stimulated by the lactate, propionate and butyrate that are formed by bacteria fermenting fiber and starch, but these bacteria also produce endotoxin. The inflammation-producing effects of lactate, serotonin, and endotoxin are overlapping, additive, and sometimes synergistic, along with histamine, nitric oxide, bradykinin, and the cytokines.

There have been some studies showing that bacterial fermentation in the intestine can cause many symptoms, including behavioral changes.

For example, a diet of soy protein increases aggression in monkeys (Simon, et al., 2004) and chickens (McKeegan, et al., 2001).

When various fermentable carbohydrates were fed to rats, they became anxious and agressive, and these changes in behavior corresponded to the fermentation of these materials by bacteria in the lower intestine, with the production of lactic acid (Hanstock, et al., 2003, 2004).”

“Defensive aggression is probably a response intermediate between fearful giving up and confident achievement. When a rat is restrained, held down on its back, it quickly develops ulcers, but if it has a stick to bite, it is very resistant to the formation of the ulcers. The ability to do something with a defensive meaning prevents the excessive production of serotonin and its consequences, such as increased production of cortisol and other stress hormones, and disturbance of cirulation and energy production. Endotoxin and prostaglandins activate these same systems, and progesterone and aspirin are among the protective factors that can oppose those effects.”

“Chronically elevated cortisol is commonly seen in depressed people, but giving a supplement of cortisol is effective in relieving depression. Both cortisol and the pituitary corticotropic hormone that stimulates its production, ACTH, have some antidepressant effects, and they inhibit the hypothalamic corticotropin release hormone, CRH. CRH is more directly associated with depression than cortisol is, and it by itself activates many inflammatory processes, including the release of histamine, cytokines, and nitric oxide. CRH is promoted in the hypothalamus (and in many other tissues) by inflammation, endotoxin, serotonin, interleukins, and prostaglandins, but also by the perception of unavoidable difficulties.

Besides cortisol, progesterone and androgens are internal factors that decrease the activity of CRH. Estrogen and hypothyroidism increase its activity.”

“The excessive stimulation of a cell increases its internal alkalinity, causing it to take up more water. The mediators of inflammation, such as CRH, serotonin, and endotoxin cause cell swelling and increased alkalinity. CRH and endotoxin can increase the susceptibility to seizures, but they can also block the ability of cells to respond to normal stimulation.”

“If the internal and external causes of stress converge, additively, on the cell’s internal communication and integration system, then the basic resistance of the organism to stress can be increased by any of the factors which oppose the signals of stress.

Carbon dioxide, progesterone, and thyroid act on many of the factors that interfere with our ability to handle stress constructively. A diet that reduces fermentation and endotoxin, with an abundance of calcium–fruit, milk, and cheese, for example–can help to shift the balance away from lactic acid, estrogen, and serotonin, toward carbon dioxide, progesterone, and thyroid.”

“One nearly ubiquitous source of inappropriate excitation and energy depletion is the endotoxin, bacterial lipopolysaccharides absorbed from the intestine (Wang and White, 1999). That this ubiquitous toxin has a role in rosacea is suggested by the observation that intestinal stimulation, to speed transit through the bowel, immediately relieved symptoms (Kendall, 2002). Increased cortisol (Simon, et al., 1998) and sepsis (Levy, 2007) interfere with mitochondrial energy production.”

“Lactate, glutamate, ammonium, nitric oxide, quinolinate, estrogen, histamine, aminolevulinate, porphyrin, ultraviolet light, polyunsaturated fatty acids and endotoxin contribute to e.xcitatory and excitotoxic processes, vasodilation, angioneogenesis, and fibrosis.

Carbon dioxide, glycine, GABA, saturated fatty acids (for example, Nanji, et al., 1997), vitamin K, coenzyme Q10, niacinamide, magnesium, red light, thyroid hormone, progesterone, testosterone, and pregnenolone are factors that can be increased to protect against inappropriate cellular excitation.”

“Some of the benefit from antibiotics probably results from the reduced endotoxin stress when intestinal bacteria are suppressed. However, antibiotics can kill the intestinal bacteria that produce vitamin K, so it’s important to include that in the diet when antibiotics are used.

Some fibers, such as raw carrots, that are effective for lowering endotoxin absorption also contain natural antibiotics, so regular use of carrots should be balanced by occasional supplementation with vitamin K, or by occasionally eating liver or broccoli.”

“Polyunsaturated fatty acids, derived from foods, have a special role in the immune system, intensifying the effects of stress (cholesterol newsletter, September, 2005) in killing lymphocytes, and blocking the proliferative response of thymic cells (Rotondo, et aI., 1994). They tend to shift immune functions from cellular immunity to humoral (antibody) immunity, and this pattern predisposes to autoimmunity. They are probably directly toxic to the liver (Ritskes-Hoitinga, 1998). DHA increases the leakiness of the bowel, allowing more endotoxin to enter the circulation (RoigPerez, et al., 2004).”

“The rate of cholesterol production, and the amount in circulation, tend to be inversely related to systemic inflammation. All of the types of lipoprotein absorb, bind, and help to eliminate endotoxin, for example. Carbon dioxide and the major steroids stabilize cells against excessive stimulation, and protect the cell structure.

Bacteria and plants produce a variety of lipids that serve some purposes analogous to our cholesterol and phospholipids. Some of the common intestinal bacteria produce a molecule containing amino sugars and fatty acids (lipopolysaccharide, LPS), that’s called endotoxin. The “endo” root distinguishes it from the “exotoxins” secreted by some bacteria, because the endotoxin is a structural part of the bacterium, that protects the bacterium against some of the exotoxins produced by other microorganisms. Normally, our intestine and liver destroy most of the LPS endotoxin before it reaches the general circulation. The bile acids, a major end product of cholesterol, have a detergent action in the intestine that usually keeps endotoxin in solution, away from the absorptive surfaces of the intestine. If the flow of bile is obstructed, endotoxin is allowed to enter the system (Bertok, 2004). Estrogen can inhibit the flow of bile (Stieger, et aI., 2000). A mucus lining is part of the protective barrier, but the microscopic integrity of the intestinal cells themselves finally regulates the passage of materials into the blood and lymphatic vessels.

The barrier function of the intestine is weakened by poisons, malnutrition, and the reduced circulation that can result from stress. Estrogens, such as oral contraceptives or Premarin, can cause colitis by shutting off the blood supply (Gurbuz, et aI., 1994; Deana and Dean, 1995).

When our cells are exposed to LPS, they produce many of the same reactions that they would produce in response to our endogenous phospholipids. The major proteins that interact with cholesterol contain lipophilic regions called beta sheets, in which a relatively flat surface is formed by parallel strands of the protein. LPS contains a group of fatty acids bound together by the polysaccharide, that strongly binds to these proteins.

The alarm reaction produced either by damage of some of our own tissue or by the entrance of LPS into the circulation can, under ideal circumstances, lead to a series of protective and defensive reactions, that resolve the problem. The production of steroids is increased, and, early in life, the liberation of fatty acids itself can contribute to the antiinflammatory processes that restore the barrier function and energy production. But when the endogenous omega-9 fatty acids have been thoroughly displaced by dietary omega-6 and omega -3 fatty acids, the systemic release of fatty acids becomes an amplifier of the stress state initiated by injury or other stress. The liver, for example, decreases its detoxification of estrogen in the presence of polyunsaturated fatty acids.

In the ovary and uterus, the healthy alternation of excitation and quiescence usually continues for many years, and in rodents it often ends in a state of “persistent estrus,” in which the excitatory state can’t be terminated in the usual way, by the production of progesterone. In humans, menopause is analogous, because the excitatory FSH hormone from the pituitary becomes excessive, with the ovary continuing to produce estrogen but failing to produce progesterone, sometimes with the pituitary failing to shift from FSH to LH. In rodents, it’s recognized that persistent estrus is caused by chronically elevated estrogen, but in humans there has been tremendous resistance to the recognition of estrogen’s central role in menopause and senescence. An excess of the basic promoter of inflammation, serotonin, which is closely associated with estrogen’s influence, can have similar effects on the reproductive cycle (Cooper, et al., 1986). The industry has devoted the necessary funding to making the easily manipulated medical culture, and the public, believe the opposite, i.e., that reproductive aging is mainly caused by estrogen deficiency.

The liver, besides its important role in keeping endotoxin from reaching the circulation, normally “destroys” all of the estrogen that reaches it, that is, it makes it water soluble so that it will be excreted in the urine or bile, rather than being retained by cells. But in malnutrition, hypothyroidism, or stress, the liver allows estrogen to pass through without being completely inactivated. M.S. Biskind and G.R. Biskind (1941, 1946) showed that the B vitamins were crucial for estrogen elimination, and others around the same time demonstrated that toxins, protein deficiency, hypothyroidism, and even hyperestrogenism itself tended to reduce the liver’s ability to detoxify estrogen. Endotoxin’s inhibition of this detoxifying system (Banhegyi, et al., 1995) is just one of the ways that it increases estrogen systemically. Estrogen, which was named for a gadfly, is excitatory in all of its biological actions (including nervous excitation and cellular proliferation), and in most tissues this excitatory action has been shown to cause oxidation damage. Many different toxic changes have been produced in the liver by estrogen, but lipid peroxidation can be clearly demonstrated in the liver as an early reaction to subcutaneous estrogen injection (Gene, et al., 1999).

Endotoxin and estrogen interact in many interesting and potentially deadly ways. Both of them activate many of the same alarm systems, including phospholipases, nitric oxide synthase, tumor necrosis factor (TNF), interleukins (including IL-6, according to Bengtsson, et aI., 2004), and the enzymes that form prostaglandins from polyunsaturated fatty acids. Estrogen makes the toxic-mediator-producing cells in the liver (Kupffer cells) hypersensitive to LPS–15 times more sensitive than normal (Ikejima, et al., 1998). One way estrogen increases the toxicity of endotoxin is probably by making the intestine more permeable (Enomoto, et al., 1999). The acute phase reaction, a process in which the liver decreases its production of albumin and increases the production of serum amyloids, lipoproteins, and fibrinogen, is promoted by both estrogen and endotoxin. Estrogen (like endotoxin) activates nuclear factor kappa-B (Shyamala and Guiot, 1992; Hamilton, et al., 2003), which activates cells to produce TNF, nitric oxide, prostaglandins, and interleukins. A long series of observations have indicated that estrogen’s main effects begin with redox changes in the mitochondria, and recent evidence (Felty and Roy, 2005) shows that oxidative free radicals produced in the mitochondria by estrogen induce NF kappa-B. Old age is associated with increased activity of NF kappa-B.”

“The amount of injury needed to increase the endotoxin in the blood can be fairly minor. Two thirds of people having a colonoscopy had a significant increase in endotoxin in their blood, and intense exercise or anxiety will increase it. Endotoxin activates the enzyme that synthesizes estrogen while it decreases the formation of androgen (Christeff, et aI., 1992), and this undoubtedly is partly responsible for the large increases in estrogen in both men and women caused by trauma, sickness or excessive fatigue.

The positive interactions among estrogen and endotoxin and NF kappa-B, and their negative interactions with progesterone and testosterone, tend to “stabilize” the inflammatory condition. In a young person, good food, sunlight, and a high altitude can often overcome severe and progressive inflammatory conditions. In an older person, whose tissues contain larger amounts of polyunsaturated fats and their breakdown products, it takes more environmental support to get out of the inflammatory pattern.”

“The liver’s important role in regulating endotoxin and estrogen, and the cascade of inflammatory mediators that can be released as a result of a depression of the liver’s function, makes it important to keep the liver in mind, even when the immediate problem seems to be in the brain, the lungs, kidneys, pancreas, blood vessels, heart, eyes, prostate, ovaries, muscles, or any other organ.”

“The effects of endotoxin and estrogen on cells are additive, for example in causing vascular leakiness (e.g., Tollan, et al., 1992), even in the brain (Oztas and Kaya, 1998). Dementia, respiratory distress/shock lung, and all of the classical inflammatory conditions, are promoted by the simple process of making capillaries excessively permeable. But the cellular changes that make capillaries leaky, also affect other cells, changing their antigenicity, leading to “autoimmune” processes (Sekigawa, et aI., 2004).”

“Stress activates the endorphin system (partly by increased histamine, according to Kjaer, et aI., 1993), and these intrinsic hormones, like morphine and the other opiates, are pro-inflammatory. Both estrogen and endotoxin activate the endorphin system. Excessive exposure to estrogen destroys many of the betaendorphin nerves in the hypothalamus, resulting in an adaptive hypersensitivity, that maintains a chronic activation of the endorphin sensitive tissues, suppressing progesterone production (Desjardins, 1995).”

“The saturated fatty acids found in coconut oil inhibit the formation of histamine (Mimura, et al., 1980), as does glucose (Kaneko, et al., 1997), and prevent leakiness of the intestine, protecting the liver from endotoxin (Kono, et al., 2003). Progesterone and testosterone protect against histamine, while estrogen increases its formation and actions. Benadryl (diphenhydramine) protects the liver and other organs from various toxins, and from the toxic effects of histamine.”

“One of the roles of fat in the food is to stimulate the secretion of bile by the gall bladder. Besides that important function, saturated fats have a variety of protective, antiinflammatory effects, including the reduction of endotoxemia and lipid peroxidation (Nanji, et al., 1997). “Coconut oil completely abolished the responses to endotoxin” (Wan and Grimble, 1987).

Appetizing foods stimulate the digestive secretions, but it’s important to avoid foods that
directly trigger an inflammatory reaction, or that are indigestible and as a result support harmful bacterial growth. Cellulose can accelerate transit through the intestine and lower estrogen systemically (partly by simply preventing the reabsorption of estrogen that has been secreted by the bile), but the lignans found in many seeds and grains tend to promote inflammation. Raw carrots, for example, lower estrogen, while flax meal can increase it.

Constipation or diarrhea, or their alternation, usually develops when there is inflammation in the bowel. A laxative can sometimes reduce the inflammation, but it’s important to identify the foods that contribute to the problem. A salad of shredded carrot, with oil and vinegar dressing, has a germicidal action, and is stimulating to the digestive processes. Most salad vegetables, though, are likely to produce intestinal irritation, directly or as a result of bacterial decomposition.

One or a few of the anti-inflammatory measures can often make a tremendous difference, but for serious chronic problems, it’s best to use as many safe techniques as possible, including periodic breathing in a paper bag to increase carbon dioxide retention, and taking niacinamide to inhibit lipolysis, until the signs of inflammation begin to subside. Eventually, the goal should be to become “deficient” in the “essential fatty acids,” since experiments have shown that such animals are extremely resistant to endotoxin poisoning (Li, et al., 1990).”

“Other things that protect against excessive polyamines are procaine and other local anesthetics (Yuspa, et al., 1980), magnesium, niacin, vitamin A, aspirin, and, in some circumstances, caffeine. Since endotoxin stimulates the formation of polyamines, a diet that doesn’t initate the intestine is important. Tryptophan and methionine contribute to the formation of polyamines, so gelatin, which lacks those amino acids and is soothing to the intestine, should be a regular part of the diet.”

“Besides the systemic toxic effects of dietary polyunsaturated fats, those fats appear to be a major factor in making tissues susceptible to damage from immunological reactions, since the tissues of rats that are deficient in the “essential fatty acids” are not damaged by antibodies that would seriously injure or kill “normal” tissues. (Takahashi, et al., 1992; Schreiner, et al., 1988). These animals are also resistant to many toxins, including endotoxin.”

“Mechnikov was right in seeing bacterial toxins from the intestine as a cause of aging, and he was on the right track in trying to introduce a more beneficial bacterial ecology into the intestine by using sour milk. The lactobacilli do have some protective effects, but the lactic acid that they produce turns out to function as an alarm signal, which accelerates the same aging processes that the other bacterial endotoxins produce.”

“The recent renewal of interest in inflammation as a basic cause of chronic and degenerative disease, is a first step toward an integral therapeutic system, even though the systemic restorative processes are still being neglected.

Bacterial endotoxins are probably the central problem, but polyunsaturated fats, heavy metals, and extraneous hormones interact with them, extending their toxic actions.

Reducing the toxic factors, relative to the restorative factors, should be the aim, rather than looking for another drug.”

“To put their claims into context, it’s helpful to look at a variety of experiments
involving treatment with niacinamide. It protects nerves, vascular cells, insulin producing cells in the pancreas, and a variety of other types of cell from cell death produced by lack of oxygen, excitotoxicity, endotoxin, and a variety of stressors and toxins. (Niacinamide acts in many ways as a negation of resveratrol; for example, resveratrol interferes with the ability of the beta cells to secrete insulin [Szkudelski, 2007]).

Niacinamide protects mitochondrial respiration from many of the age-related factors that can damage mitochondria and decrease energy production. Lipopolysaccharide, the bacterial endotoxin, increases the production of the free radical nitric oxide, leading to the secretion of inflammatory mediators and the suppression of energy production by the mitochondria. These effects are blocked by niacinamide (Fukuzawa, et al., 1997). Calorie restriction also protects mitochondrial respiration, in yeasts (Lin, et al., 2002) and rats (Broderick, et al., 2002).”

“In the presence of bacterial endotoxin, respiratory energy production fails in the cells lining the intestine. Nitric oxide is probably the main mediator of this effect.”

“Some leakage from the lumen of the intestine or the lumen of a blood vessel can occur between cells, but it is often claimed that the “paracellular” route accounts for all leakage. (Anthraquinones may inhibit paracellular leakage [Karbach & Wanitschke, 1984].) When a cell is inflamed or overstimulated or fatigued, its cytoplasmic contents leak out. In that state, its barrier function is weakened, and external material can leak in. This was demonstrated long ago by Nasonov, but the “membrane” doctrine is incompatible with the facts, so the paracellular route is claimed to explain leakage. Since the cells that form the barrier begin to form regulatory substances such as nitric oxide when they are exposed to endotoxin, it is clear that major metabolic and energetic changes coincide in the cell with the observed leakiness. Permeability varies with the nature of the substance, its oil and water solubility, and the direction of its movement, arguing clearly that it isn’t a matter of mere holes between cells.

Besides endotoxin, estrogen, vibrational injury, radiation, aging, cold, and hypoosmolarity, increase NO synthesis and release, and increase cellular permeabilities throughout the body.

Estrogen excess (relative to progesterone and androgens), as in pregnancy, stress, and aging, reduces intestinal motility, probably by increasing nitric oxide production. The anthraquinones inhibit the formation of nitric oxide, which is constantly being promoted by endotoxin.”

“Many types of evidence indicate that environmental PUFA and prostaglandins produced from the “essential” fatty acids are required for inflammation to progress to degeneration. The n-9 polyunsaturated tatty acids (the kind we can make make from saturated fat or sugar) seems to be positively protective against inflammation. For example, rats fed a diet with 2% hydrogenated coconut oil for two weeks had lower levels of IL-6 and C-reactive protein than when a small amount of arachidonic acid and docosahexaenoic acid (DHA) were added. Mead acid (20:3n9) was lower in the group with the PUFA supplement, and the inflammatory reaction to endotoxin was greater in the supplemented group (Ling, et aI., 2012).

Many of the things that can he achieved by vaccination and treatment with safe anti-inflammatories such as aspirin could be done better by long-term changes of diet, and by taking into account the interactions of the hormones, especially progesterone, estrogen, and thyroid, with nutrients and stressors. But much more than than is needed: The nature of the relationships between environmental factors and the body’s reactions has to be clarified, so that the processes of healing and regeneration can more closely resemble the prenatal condition, possibly even continuing in adulthood the “pedomorphic” process, realizing human potentials that haven’t previously been seen.”

“We are susceptible to many things that interfere with energy production-the substitution of iron for copper in the respiratory enzyme, the absorption of endotoxin, the accumulation of PUFA, a deficiency of thyroid hormone, the formation of increased amounts of nitric oxide, serotonin, and histamine, etc. Different environments will condition the way the defensive mechanisms of inflammation are produced.”

“Endotoxin absorbed from the intestine is one of the ubiquitous stresses that tends to cause free radical damage. Fructose, probably more than glucose, is protective against damage from endotoxin.”

“Excitotoxins (including endotoxin) increase the formation of ncuroprostanes and isoprostanes (from n-3 and n-6 PDFA) (Milatovic, et al., 2005), and acrolein and other fragments, which inhibit the use of glucose and oxygen. DHA and EPA produce acrolein and HHE, which react with lysine groups in proteins, and modify nucleic acids, changing the bases in DNA.”

“Bacterial endotoxin causes some of the same effects as adrenalin. When stress reduces circulation to the bowel, causing injury to the barrier function of the intestinal cells, endotoxin can enter the blood, contributing to a shock state, with further impairment of circulation. In old age and in “winter sickness,” something like a chronic borderline state of shock can develop. Intravenous glucose has been used successfully to bring patients out of septic shock. The tonic effects of intravenous local anesthetics are, I think, largely the result of their ability to open the arterioles. Magnesium and vitamin A also have some ability to normalize blood vessel tone, and can help to maintain the barrier function of the bowel.”

“Penicillin has been found to relieve PMS, but the mechanism by which it increases progesterone and decreases estrogen and cortisone isn’t clear, and probably involves endotoxin and the liver.”

“Since progesterone tends to promote its own synthesis, it shouldn’t be necessary to keep using it, unless the ovaries have been removed, or the thyroid or cholesterol level is very low, or aging has damaged their ability to convert cholesterol to progesterone. While an excess of carotene can inhibit progesterone synthesis, a carrot salad (grated carrots, vinegar, coconut oil, and salt) can often help to normalize progesterone, apparently by protecting against intestinal absorption of bacterial endotoxin, and by helping to reduce the reabsorption of estrogen which has been excreted in the bile.

The beneficial hormonal effects that have been seen during antibiotic therapy (raising progesterone while lowering cortisol and estrogen) can be achieved safely with the carrot salad in most cases, without the possible toxic effects of the antibiotics.”

“Once we accept Warburg’s thesis, that damaged respiration is the prime cause of cancer, the therapeutic use of thyroid in cancer seems obvious. Aging and estrogen-dominance are other states in which cells seem to be relatively insensitive to thyroid hormones. (Unsaturated fats are involved in resistance to thyroid, and promote the incidence of cancer in a variety of ways.) If the liver is a main site of T4’s conversion to T3, cancer patients may require very large doses of thyroid hormone, or else direct use of T3 (possibly in large doses), since the liver is so likely to be inefficient. Incidentally, thyroid’s ability to improve digestion and peristalsis is important for liver function; endotoxin absorbed from the intestine can be a serious burden to the liver, and it is known to cause a large increase in the blood estrogen level.”