Endotoxin (lipopolysaccharide, LPS) is a structural piece of the outer wall of Gram-negative bacteria. In the bowel it is normal cargo. Trouble starts when enough of it crosses the barrier into blood. Innate immune receptors, mainly TLR4, fire. Cytokines rise. Inflammation becomes systemic.

Endotoxin (Lipopolysaccharide, LPS)
General structure of lipopolysaccharide: O-antigen, core oligosaccharide, and lipid A
General structure of lipopolysaccharide: O-antigen, core oligosaccharide, and lipid A
Formula Variable (glycolipid macromolecule, no fixed formula)
Class
Administration Not administered; endogenous bacterial cell-wall component
Solubility Amphipathic: lipid A anchors in membrane, polysaccharide chain is water-soluble
Legal status
Brand names
Bioavailability
Recommended dose
Upper limit
LD50
Ray's verdict Generally hurts
"I'm inclined to think that even cancer is largely an endotoxin problem."

In this framework chronic endotoxemia is not a side issue. It is a main driver of stress pathology: weaker thyroid and mitochondrial respiration, higher estrogen and cortisol, leaky vessels and aging tissue.[1][2]

Peat considered chronic endotoxin exposure a major driver of cancer as well as heart disease, not just acute sepsis:

"I'm inclined to think that even cancer is largely an endotoxin problem. Chronic year after year of bad food irritating the intestine, causing increased histamine and serotonin and estrogen, but a constant stream of endotoxin flowing through the system, shaking up chromosomes, creating inflammation, fatiguing the repair systems. Finally, when the repair systems are down to a certain extent, the cancers that are constantly popping up stop being removed. And so if you don't die of acute sepsis, then heart disease and cancer, I think, are the result of chronic exposure to the endotoxin."

— Ray Peat[3]

The cascade

[edit]

Stress and hypothyroidism slow and loosen the gut. More LPS crosses. The liver sees it first; when the liver is already burdened, clearance fails and spillover spreads. TLR4 activation raises nitric oxide, free radicals, and cytokines. Mitochondrial respiration falls. Fuel shifts toward fat oxidation. Stress hormones climb. Progesterone synthesis falls. LH rises.[1]

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.

— Ray Peat[4]

PUFA in membranes amplify the same LPS signal. A given endotoxin load does more inflammatory damage when polyunsaturated fats are high. See PUFA, Tissue leakiness, Randle cycle.

In healthy volunteers, a low dose of intravenous endotoxin weakened the forearm arteries' endothelium-dependent widening, and high-dose vitamin C brought it back.[5]

Gut as reservoir

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The bowel holds the supply. Slow transit, fermentable starch overload, and barrier leak raise absorption. Raw carrot salad is the classic practical fiber that binds and clears without feeding the same putrefactive load. Good thyroid speeds transit and tightens energy at the barrier. Saturated fat and glycogen support the liver that must detoxify what arrives.

Antibiotics and some tetracyclines appear in inflammatory and septic patterns partly through anti-inflammatory actions beyond pure killing. They are tools with costs, not daily food. See Carrot, Thyroid, Liver.

For Ray Peat, germ-free animals are direct evidence that gut bacteria, not food itself, drive much of this damage:

Germ-free animals eat about 20% or 30% more calories than ordinary germ-bearing mice, but they are leaner and don't suffer from anxiety. This means the bacteria are producing something that poisons your metabolism.

— Ray Peat[6]

Peer-reviewed work supports each part of this. Germ-free rodents outlive conventionally colonized controls.[7][8] Despite eating more, germ-free mice stay leaner and resist diet-induced obesity, excreting a large share of the surplus calories rather than storing them as fat.[9][10][11] The protection isn't universal: on a lard-based high-fat diet rather than a sugar-rich Western diet, germ-free mice gained as much fat as conventional controls, showing that diet composition, not just the presence of bacteria, determines the outcome.[12] Germ-free mice also show reduced anxiety-like behavior and altered stress-hormone signaling compared to conventionally raised mice.[13][14]

Foods and antimicrobials that reduce the load

[edit]

Eating raw carrots daily, ideally with a coconut or olive oil dressing, cuts the bacterial toxins absorbed and helps excrete estrogen.[15] Endotoxin constantly promotes nitric oxide formation, and estrogen excess slows intestinal motility, probably through more nitric oxide; anthraquinones such as cascara inhibit that nitric oxide formation.[16]

Dietary cocoa lowered metabolic endotoxemia about 40% and improved gut barrier markers in high-fat-fed mice; dark chocolate also lowered permeability markers after hard training in elite football players. See Chocolate.[17][18]

Daily pomegranate extract (900 mg ellagitannin-rich PE for 5 to 35 days before surgery) lowered plasma lipopolysaccharide-binding protein (LBP), a metabolic endotoxemia marker, in newly diagnosed colorectal cancer patients in a time-dependent RCT.[19]

Beyond carrot salad, Ray Peat's short list of foods and disinfectants that lower bacterial putrefaction and endotoxin production in the gut, without the broader collateral damage of general-purpose antibiotics: bamboo shoots, well-cooked white button mushrooms (which are also anti-aromatase and anti-nitric oxide), activated charcoal, and flowers of sulfur.

"PUFA (e.g., fish oil) worsens absorption, inflammation, and toxicity; saturated fats like coconut oil protect against it. Avoid starches/oats/potatoes that feed bacteria; favor raw carrots, bamboo shoots, milk, fructose, fruit/cheese to suppress growth, reduce serotonin/estrogen, boost metabolism/thyroid, and enhance longevity/stress resistance. Niacinamide aids protection."

— Ray Peat

"The intestine is a potential source of reabsorbed estrogen, and a daily raw carrot (grated or shredded, with a little olive oil, vinegar, salt) helps to lower excess estrogen (and endotoxin produced by bacteria)."

— Ray Peat

"Considering the longevity and stress-resistance of germ-free animals, choosing foods (such as raw carrots or cooked bamboo shoots or cooked mushrooms) which accelerate peristalsis and speed transit through the bowel, seems like a convenient approach to increasing longevity."

— Ray Peat[20]

In extreme, short-term cases low-dose Penicillin or Minocycline have also been used to suppress the endotoxin-producing gut flora directly, generally paired with a raw carrot and limited to a few days.

Diet composition also determines whether a single meal itself becomes an endotoxin source. In a controlled trial, a 900-kcal high-fat, high-carbohydrate meal raised plasma endotoxin and TLR4 expression within hours when washed down with water or glucose, but not when the same meal was paired with 300 kcal (about 2.5 cups) of orange juice instead.[21]

Detoxing PUFA

[edit]

PUFA can be cleared without lipolysis through glucuronidation, where glucuronic acid is conjugated to PUFA in the liver and the resulting compound is excreted via the intestine or bladder. A well-functioning liver, less burdened by endotoxin, supports this route.

Protective set

[edit]

What lowers absorption and what raises clearance form one set, not a shopping list of unrelated tips. Keep transit moving. Lower seed oils. Support thyroid and progesterone. Use aspirin when inflammatory and prostaglandin load is high. Keep oxidation oriented to glucose and CO2 rather than chronic free-fat burning. Progesterone mixed with endotoxin before injection reduced hypotension and improved survival in cats. Progesterone may bind or inactivate LPS.[22] Dietary glycine (5% of diet) completely prevented mortality from intravenous LPS in rats (0% died vs. 50% of controls), reduced liver necrosis and TNF-alpha, and blocked LPS-induced calcium overload in Kupffer cells.[23]

Hard exercise raises endotoxin too. In healthy volunteers, a short bout of maximal aerobic exercise raised blood endotoxin, and 1,000 mg of vitamin C taken beforehand prevented the rise.[24]

The opposite set is familiar: cold, underfeeding, polyunsaturated oils, stagnant bowel, low thyroid, unopposed estrogen. Each step feeds the next.

House dust

[edit]

Endotoxin also collects in household dust, and its level tracks cleaning, crowding and pets. In an observational survey of 405 randomly chosen homes in two German cities, living-room dust held about two-thirds more endotoxin where carpets were rarely vacuumed and almost double where a cat lived. Season, room temperature and indoor humidity made no difference, and home levels were far below those measured in farm workplaces. In that study, high dust endotoxin served as a marker of poor household hygiene.[25]

Dampness and visible mold went with somewhat more endotoxin in house dust in an observational study of Boston homes and in a US national survey.[26][27] In the same national survey, drier indoor air went with higher endotoxin in bedrooms (cross-sectional survey).[27]

More endotoxin in bedroom dust goes with more asthma in adults. In the US national survey, adults whose bedroom floor and bedding dust held more endotoxin more often had diagnosed asthma, recent asthma symptoms and wheeze; the link did not appear in children (cross-sectional survey).[28] A later and larger national survey linked higher home endotoxin to wheeze whether or not people had allergies.[29] Among rural children in Germany, Austria and Switzerland, more endotoxin in mattress dust went with less hay fever and allergic asthma (cross-sectional study).[30]

TLR5 and asthma

[edit]

Bacterial flagellin (a TLR5 ligand, structurally distinct from the LPS/TLR4 axis but part of the same innate-immune pattern-recognition family) in house dust extracts primed strong allergic airway responses in mice, TLR5 was required for that priming, and people with asthma carried more flagellin-specific antibodies.[31]

Behavioral and social effects

[edit]

Endotoxin exposure produces measurable "sickness behavior" across species independent of any active pathogen, which supports treating chronic endotoxemia as a direct behavioral and mood variable, not just a metabolic one.

In 20 healthy men, a low intravenous endotoxin dose raised anxiety and depressed mood and impaired verbal and nonverbal memory compared with saline, and the changes tracked the rise in cytokines.[32]

A systematic review and meta-analysis covering schizophrenia, bipolar disorder, and major depression found markers of gut dysbiosis and leaky gut, including elevated antibodies to bacterial LPS, across all three diagnoses.[33]

In women, experimentally administered LPS reduced empathy for other people's psychological pain relative to placebo. Low-grade inflammation may reduce social/emotional responsiveness as an energy-conserving strategy.[34] In mice, LPS increases active defensive behavior shortly after injection but potentiates "behavioral despair" (immobility in the forced-swim test) roughly a day later.[35] Systemic LPS also blunts hedonic response directly: injected endotoxin significantly reduced saccharin preference in fluid-deprived rats, a standard anhedonia measure and one of the earliest demonstrations that endotoxin alone produces a depressive-like episode.[36] Wild vampire bats given LPS produce fewer contact calls and spend less time with roostmates, a same-species analog of social withdrawal.[37] Mice with a chronic cerebellar inflammatory condition show an exaggerated loss of social exploration after LPS or IL-1β compared to normal mice, indicating pre-existing inflammation sensitizes the behavioral response to a given endotoxin dose.[38]

Two interventions reverse these effects in animal studies: vitamin E (alpha-tocopherol) blocked LPS-induced loss of social behavior in mice, though only at a low LPS dose, not a high one[39]; and COX-2 inhibitors (celecoxib, etoricoxib) reversed LPS-induced depressive- and anxious-like behavior in mice. Prostaglandins, as well as cytokines, help drive the mood effects of endotoxin.[40] See Aspirin.

Endotoxin and male hormones

[edit]

In a placebo-controlled trial, one small intravenous dose of endotoxin lowered testosterone in healthy young men by about 30% within hours, with no change in the pituitary hormones LH and FSH; levels were back to normal the next day.[41] In mice, a single high dose inflamed the testes, turned down the genes for the junction proteins that seal off developing sperm, and shed immature sperm cells into the ducts.[42] See Testosterone and Fertility.

Endotoxin and spontaneous abortion

[edit]

Lipopolysaccharide (LPS) administered to pregnant mice caused fetal abortion correlating with a sharp rise in serum nitric oxide (NO), not with the pro-inflammatory cytokines usually blamed (TNF-alpha, IFN-gamma, IL-4 were unchanged; only IL-10 fell). Blocking NO synthase with aminoguanidine rescued the pregnancies and normalized spleen weight and serum NO, isolating NO, downstream of endotoxin exposure, as the actual mechanism of the fetal loss.[43]

Estrogen and Kupffer cell sensitivity

[edit]

Rats given estrogen 24 hours before a sublethal LPS dose all died, while controls survived; their Kupffer cells made about twice the TNF-alpha and nitrite and needed 15-fold less LPS to raise intracellular calcium.[44]

Endotoxin and insulin resistance

[edit]

In healthy young adults, one intravenous dose of endotoxin cut insulin sensitivity by about a third within a day, while the pancreas kept releasing insulin normally. The same dose gave every volunteer a short fever. In their fat tissue, endotoxin set off inflammation and lowered IRS-1, the docking protein that carries the insulin signal into the cell (experimental challenge, before and after, without a placebo group).[45]

In mice, four weeks on a high-fat diet raised blood endotoxin two- to threefold. Infusing endotoxin under the skin to that same level for four weeks raised fasting glucose and insulin and added as much weight as the high-fat diet. Insulin resistance appeared in the liver only, while whole-body insulin sensitivity held. Mice lacking CD14, a receptor partner that helps cells detect endotoxin, resisted most of these changes.[46]

Stress, even emotional stress, decreases the barrier function of the intestine, allowing bacterial endotoxin to be absorbed. Endotoxin activates a variety of enzymes, including those that liberate free fatty acids from the tissues. ... This immediate direct effect of endotoxin, the lipolytic increase of free fatty acids in the circulation, blocks insulin-stimulated glucose uptake.

— Ray Peat[47]

Endotoxin and fat-cell dysfunction

[edit]

Bacterial endotoxin fragments entering the bloodstream from the gut directly impair fat-cell metabolic activity and reduce their ability to convert to metabolically active brown-like fat, with the effect worsening as weight increases. In human fat cells, endotoxin cut mitochondrial dynamics and biogenesis and lowered brown-in-white (BRITE) markers, and circulating endotoxin tracked lower brown-fat gene expression in adipose tissue.[48]

Neurosteroid suppression of TLR4

[edit]

Pregnenolone promotes ubiquitination and degradation of the TLR2/4 adaptor TIRAP (and TLR2) in macrophages and microglia, reducing TLR2/4-driven TNFα and interleukin-6.[49] Allopregnanolone (3α,5α-THP) and pregnenolone (0.5–1.0 μM) each cut LPS-driven TLR4 signaling by about 80% in RAW264.7 macrophages, likely by blocking TLR4/MD-2 interaction; in alcohol-preferring rat VTA, allopregnanolone (15 mg/kg IP) lowered TRAF6, CRF, and MCP-1 and reduced TLR4 binding to GABA-A α2 and MyD88.[50]

Sepsis

[edit]

Sepsis is life-threatening organ dysfunction from infection and host response; endotoxin and free fatty acids drive much of the secondary damage. When stress is very intense, as in trauma or sepsis, liberating free fatty acids becomes dangerously counter-productive: cells take up water and calcium, leak ATP and enzymes, and can slide into a systemic inflammatory state often leading to death.[51] Hospital treatment is mandatory; background metabolic health changes risk and recovery. See Shock, Fever, Iron, Harm reduction.

Mold

[edit]

Mold and water-damaged buildings load some people with irritation and mycotoxin exposure. Fix the building. Detox product stacks are secondary.

Mycotoxins and the gut

[edit]

Mycotoxins are poisons made by molds. The gut takes the first hit from those in food, and most of the gut evidence comes from animals and cell cultures.

Ochratoxin A (OTA) comes from Aspergillus and Penicillium molds and turns up in coffee and many other foods.[52] In a laboratory model of the human colon, a chain of linked vessels holding human gut bacteria (an in vitro study), one week of OTA wiped out Lactobacillus reuteri, and the loss was "specific, but lasting".[53] Short-chain fatty acids, the fats colon cells burn for fuel (butyrate among them), fell in the same model, while bifidobacteria changed only slightly.[54] In live rats given OTA by mouth for four weeks (a rat study), Lactobacillus rose instead, and the doses were thousands of times higher per kilo of body weight than people typically eat.[55][52]

Trichothecenes come from two unrelated sources. Fusarium molds on wheat, maize and other cereals make deoxynivalenol (DON), a trichothecene common in grain foods.[56] Stachybotrys chartarum, the "black mold" of water-damaged buildings, makes larger macrocyclic trichothecenes that are mostly breathed in, and their role in building-related illness is still unproven.[57] Nearly all the gut findings come from DON in food and feed, so they say little about indoor black mold.[56]

In piglets fed DON-contaminated feed for five weeks (a pig study), the villi, the finger-like folds that absorb food, became shorter and fused, and the gut lining had fewer goblet cells, the cells that make protective mucus.[58] In human and pig gut-cell cultures, DON lowered claudins, the tight-junction proteins that seal the gaps between lining cells, and let more material leak through; piglets eating DON showed the same claudin drop.[59] In a human gut-cell line (a cell study), DON cut the activity of SGLT1, the main glucose-absorbing pump, by about half.[60] In people, DON is known mainly from outbreaks of vomiting and diarrhea after eating badly contaminated grain.[56]

The DON doses in these studies mostly sit close to real contamination levels, and average intake in European infants and children already exceeds the tolerable daily intake.[56][61]

Milk carries far less ochratoxin than the blood it is made from.

The cells of the mammary gland, in receiving substances from the blood, are selective in what they accept, allowing nutrients and protective substances to be concentrated, and reducing the concentration of many toxins that the blood has absorbed from the intestine. For example, the fungal toxin found in wheat and bread, ochratoxin, is reduced by 75-80% between the blood and the milk.

— Ray Peat[62]

Mycotoxins and the brain

[edit]

Several common grain mycotoxins can reach the brain, and most of the evidence comes from animals and cell cultures.[63]

In mice, a family of newer Fusarium toxins found in cereals (ring-shaped peptides) crossed into the brain quickly and barely left again.[64] In a cell model of the blood-brain barrier, the two most common of these toxins also passed through easily, and support cells from the brain died more readily than the barrier cells themselves.[65]

T-2 toxin, a trichothecene from Fusarium on oats, barley and wheat, built up inside human astrocytes, the support cells of the brain, and triggered their self-destruction at low doses within hours (a cell study).[66]

Children with autism had more ochratoxin A in urine and blood than unrelated healthy children in a small Italian case-control study.[67] The study measured exposure at one time and cannot show that the toxin caused the autism.

Mycotoxins in tobacco

[edit]

Cured tobacco can carry the same molds found on stored grain. In 40 Egyptian cigarette tobaccos, Aspergillus and Penicillium species were the most common fungi, and a few samples carried aflatoxins, zearalenone or T-2 toxin.[68] Snuff sold in Nigerian markets carried toxin-producing Aspergillus and aflatoxins B1 and B2.[69] In US smokeless tobacco, aflatoxin B1 turned up mostly in dry snuff and chewing tobacco, at levels far below the food limit, and not in moist snuff.[70]

Burning seems to destroy aflatoxin. In smoking-machine tests, cigarettes deliberately spiked with aflatoxin B1 gave no detectable aflatoxin in the smoke, and in one study the toxin stayed in the filter.[71][72][68] Good-grade and moldy American leaf tested negative for aflatoxin B1 in 1967.[71] Snuff and chewing tobacco skip the burning step, so mold control in curing and storage matters most there.

Practice

[edit]

Remediate environment. Support gut and liver energy. See Detox, Liver, Endotoxin, Harm reduction.

Tissue leakiness

[edit]

Tissue leakiness is barrier failure. Blood, cells, and organs lose clean separation. Energy falls. Vessel walls and cell surfaces open too wide. Protein and fat leave the blood. Water and solutes enter cells. Gut toxins enter the bloodstream. Aging is generalized leakiness.

Supports for barriers: thyroid, progesterone, gelatin/glycine, saturated fats, aspirin, vitamin E, CO₂.

Cellular energy metabolism is the basis for maintaining the barrier functions. Energy depletion causes the endothelial cells lining blood vessels to become excessively permeable.

— Ray Peat[73]

Endothelial cells line blood vessels.

The prevention of inappropriate leakiness can protect against the degenerative processes, and against aging itself, which is, among other things, a state of generalized leakiness.

— Ray Peat[74]

Full essay: Library:Leakiness, aging, and cancer / [raypeat.com](https://raypeat.com/articles/articles/leakiness.shtml).

Barriers and energy

[edit]

A thin fibrin layer lines vessels. Fibrin is a clotting protein that also filters and repairs. Energy fails; fibrin and other molecules appear where they should not. Light scatters in the eye (flare). Albumin (a blood protein) appears in urine under stress.[75] Escaped fibrin drives inflammation, scar (fibrosis), and tumor support.[75]

A. P. Nasonov (reviewed by Troshin) tired cells and watched dyes enter. Energy returned; dyes left. Long excitation shifts sodium and calcium balance.[75] Heavy-metal stain stops at the surface of a live energetic cell. Starve oxygen or hit with radiation; stain floods the whole cell. Energy organizes the barrier.[75]

Hormones, PUFA, gut toxins

[edit]

High estrogen plus mild stress (hard effort, bad sleep) lets gut toxins (and bacteria) into blood. Systemic inflammation follows. Polyunsaturated fats in tissues widen vessel leak and amplify stress signals.[76]

In the hormonal environment dominated by estrogen, mild stresses such as exertion, or even restless sleep, allow toxins (and sometimes bacteria) from the intestine to enter the bloodstream, triggering a complex chain of events that create a systemic inflammatory state.

— Ray Peat[77]

Estrogen opens capillaries and pulls water into cells at once. Progesterone rises after a short estrogen pulse and closes that window. Chronic estrogen keeps tissues open.[75] In baboon endometrium, a serum estradiol rise to about 500 pg/mL widened microvessel tight-junction cleft width from 5.03 nm to 7.27 nm within 6 hours and raised endothelial cell proliferation from 2.9% to 21.4%, mediated by VEGF.[78] Low thyroid leaks enzymes from cells. Thyroid support, progesterone, and testosterone rank as natural antiestrogens that tighten vessels.[79]

Carbon dioxide and supports

[edit]

Over-breathing dumps CO₂. Platelets and vessel cells lose structure. Same pattern as low energy. Yandell Henderson: oxygen without CO₂ sense injures lungs. Old dialysis fluid used acetate or lactate in place of bicarbonate and raised organ permeability.[80]

Antioxidants, thyroid hormone, progesterone, and antiinflammatory agents, including glycine or gelatin, niacin, and saturated fats, can prevent, and in many cases reverse, these degenerative inflammatory processes.

— Ray Peat[81]

Glycine and proline (main amino acids in gelatin) protect liver and raise albumin. Saturated fat reverses liver scar in cited models. Thyroid fights estrogen-driven heart scar. Progesterone and pregnenolone are antifibrotic steroids. Aspirin and vitamin E slow estrogen-driven fibrin turnover.[79] Lower gut endotoxin load (bacterial wall toxin) speeds recovery. See Endotoxin.[79]

In rats kept on alcohol with fish oil, switching the fat to palm oil or medium-chain triglycerides for 2 weeks reversed liver inflammation and scarring while the alcohol continued, with less gut endotoxin in the blood.[82]

See also

[edit]

References

[edit]
  1. ↑ 1.0 1.1 Ray Peat, "Ray Peat on Endotoxin," functionalps.com.
  2. ↑ Ray Peat, "Leakiness, aging, and cancer," raypeat.com.
  3. ↑ Philosophy and Physiology: Metabolism and Consciousness, Deep Politics with Ray Peat and Georgi Dinkov, Generative Energy Podcast #19 (2020), 35:27
  4. ↑ Ray Peat, PhD on Endotoxin
  5. ↑ Pleiner J et al. 2002. "High doses of vitamin C reverse Escherichia coli endotoxin-induced hyporeactivity to acetylcholine in the human forearm." Circulation 106(12):1460-4. Randomized double-blind crossover, n=8; E. coli LPS 20 IU/kg IV cut acetylcholine forearm blood flow response 30% (P<0.05), nitroglycerin response unchanged; intra-arterial vitamin C 24 mg/min restored it to baseline. doi:10.1161/01.cir.0000030184.70207.ff. PMID 12234948.
  6. ↑ Ray Peat, "Ask Your Herb Doctor: You Are What You Eat", KMUD
  7. ↑ Gordon HA, Bruckner-Kardoss E, Wostmann BS. "Aging in germ-free mice: life tables and lesions observed at natural death," J Gerontol. 1966;21(3):380-387.
  8. ↑ Tazume S, et al. "Effects of germfree status and food restriction on longevity and growth of mice," Exp Anim. 1991;40(4):517-522. PMID 1748169.
  9. ↑ Wostmann BS, et al. "Dietary intake, energy metabolism, and excretory losses of adult male germfree Wistar rats," Lab Anim Sci. 1983;33(1):46-50.
  10. ↑ Bäckhed F, Manchester JK, Semenkovich CF, Gordon JI. "Mechanisms underlying the resistance to diet-induced obesity in germ-free mice," Proc Natl Acad Sci USA. 2007;104(3):979-984.
  11. ↑ Rabot S, et al. "Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism," FASEB J. 2010;24(12):4948-4959. PMID 20724524.
  12. ↑ Fleissner CK, et al. "Absence of intestinal microbiota does not protect mice from diet-induced obesity," Br J Nutr. 2010;104(6):919-929. PMID 20441670.
  13. ↑ Diaz Heijtz R, et al. "Normal gut microbiota modulates brain development and behavior," Proc Natl Acad Sci USA. 2011;108(7):3047-3052.
  14. ↑ Neufeld KM, et al. "Reduced anxiety-like behavior and central neurochemical change in germ-free mice," Neurogastroenterol Motil. 2011;23(3):255-264,e119. PMID 21054680.
  15. ↑ Ray Peat, "Menopause and its causes," raypeat.com.
  16. ↑ Ray Peat, "Cascara, energy, cancer and the FDA's laxative abuse," raypeat.com.
  17. ↑ Gu Y, et al. "Dietary cocoa reduces metabolic endotoxemia and adipose tissue inflammation in high-fat fed mice," J Nutr Biochem. 2014;25(4):439-445. PMID 24561154.
  18. ↑ Nocella C, et al. "Dark Chocolate Intake Positively Modulates Gut Permeability in Elite Football Athletes: A Randomized Controlled Study," Nutrients. 2023;15(19). PMID 37836487.
  19. ↑ González-Sarrías A, et al. "Consumption of pomegranate decreases plasma lipopolysaccharide-binding protein levels, a marker of metabolic endotoxemia, in patients with newly diagnosed colorectal cancer: a randomized controlled clinical trial," Food Funct. 2018;9(5):2617-2622. doi:10.1039/c8fo00264a. PMID 29770393.
  20. ↑ Bowel toxins accelerate aging, functionalps.com
  21. ↑ Ghanim H, Sia CL, Upadhyay M, Korzeniewski K, Viswanathan P, Abuaysheh S, Mohanty P, Dandona P, "Orange juice neutralizes the proinflammatory effect of a high-fat, high-carbohydrate meal and prevents endotoxin increase and Toll-like receptor expression," Am J Clin Nutr. 2010;91(4):940-9. PMID 20200256.
  22. ↑ Silk MR. "The effect of progesterone on cats administered endotoxin," J Surg Res. 1967;7(1):35-40. PMID 4959441.
  23. ↑ Ikejima K, Iimuro Y, Forman DT, Thurman RG. "A diet containing glycine improves survival in endotoxin shock in the rat," Am J Physiol. 1996;271(1 Pt 1):G97-103. PMID 8760112.
  24. ↑ Ashton T et al. 2003. "Exercise-induced endotoxemia: the effect of ascorbic acid supplementation." Free Radic Biol Med. doi:10.1016/s0891-5849(03)00309-5 Small human study, healthy volunteers; plasma LPS rose after maximal acute aerobic exercise (p < 0.01); 1000 mg oral ascorbic acid abolished the rise in LPS and nitrite but raised the ascorbate free radical.
  25. ↑ Bischof W, Koch A, Gehring U, Fahlbusch B, Wichmann HE, Heinrich J; INGA Study Group. "Predictors of high endotoxin concentrations in the settled dust of German homes," Indoor Air. 2002;12(1):2-9. doi:10.1034/j.1600-0668.2002.120102.x. PMID 11951708.
  26. ↑ Sordillo JE, Alwis UK, Hoffman E, Gold DR, Milton DK. "Home characteristics as predictors of bacterial and fungal microbial biomarkers in house dust," Environ Health Perspect. 2011;119(2):189-195. doi:10.1289/ehp.1002004. PMID 20965804.
  27. ↑ 27.0 27.1 Thorne PS, Cohn RD, Mav D, Arbes SJ, Zeldin DC. "Predictors of endotoxin levels in U.S. housing," Environ Health Perspect. 2009;117(5):763-771. doi:10.1289/ehp.11759. PMID 19479019.
  28. ↑ Thorne PS, Kulhánková K, Yin M, Cohn R, Arbes SJ Jr, Zeldin DC. "Endotoxin exposure is a risk factor for asthma: the national survey of endotoxin in United States housing," Am J Respir Crit Care Med. 2005;172(11):1371-1377. doi:10.1164/rccm.200505-758OC. PMID 16141442.
  29. ↑ Thorne PS, Mendy A, Metwali N, et al. "Endotoxin Exposure: Predictors and Prevalence of Associated Asthma Outcomes in the United States," Am J Respir Crit Care Med. 2015;192(11):1287-1297. doi:10.1164/rccm.201502-0251OC. PMID 26258643.
  30. ↑ Braun-Fahrländer C, Riedler J, Herz U, et al. "Environmental exposure to endotoxin and its relation to asthma in school-age children," N Engl J Med. 2002;347(12):869-877. doi:10.1056/NEJMoa020057. PMID 12239255.
  31. ↑ Wilson RH, Maruoka S, Whitehead GS, et al. "The Toll-like receptor 5 ligand flagellin promotes asthma by priming allergic responses to indoor allergens," Nat Med. 2012;18(11):1705-1710. doi:10.1038/nm.2920. PMID 23064463.
  32. ↑ Reichenberg A et al. 2001. "Cytokine-associated emotional and cognitive disturbances in humans." Arch Gen Psychiatry 58(5):445-452. PMID 11343523. Double-blind crossover, Salmonella abortus equi endotoxin 0.8 ng/kg IV vs saline; anxiety effect size 0.55, depressed mood 0.66; TNF-α, IL-6, IL-1ra and cortisol rose.
  33. ↑ Safadi JM, Quinton AMG, Lennox BR, Burnet PWJ, Minichino A. "Gut dysbiosis in severe mental illness and chronic fatigue: a novel trans-diagnostic construct? A systematic review and meta-analysis," Mol Psychiatry. 2022;27(1):141-153. PMID 33558650.
  34. ↑ Flasbeck V, Dersch N, Engler H, Schedlowski M, Brüne M. "Acute experimental inflammation in healthy women attenuates empathy for psychological pain," Brain Behav Immun. 2024. PMID 38548183.
  35. ↑ Renault J, Aubert A. "Immunity and emotions: lipopolysaccharide increases defensive behaviours and potentiates despair in mice," Brain Behav Immun. 2006;20(6):517-26.
  36. ↑ Yirmiya R. "Endotoxin produces a depressive-like episode in rats," Brain Res. 1996 Mar 4;711(1-2):163-74. PMID 8680860.
  37. ↑ Stockmaier S, et al. "Immune-challenged vampire bats produce fewer contact calls," Biol Lett. 2020. PMID 32673543.
  38. ↑ Bluthé RM, et al. "Hypersensitivity of lurcher mutant mice to the depressing effects of lipopolysaccharide and interleukin-1 on behaviour," NeuroReport. 1997. PMID 9175096.
  39. ↑ Berg BM, Godbout JP, Kelley KW, Johnson RW. "Alpha-tocopherol attenuates lipopolysaccharide-induced sickness behavior in mice," Brain Behav Immun. 2004;18(2):149-157. PMID 14759592.
  40. ↑ da Silva DMA, et al. "Cyclooxygenase-2 inhibitors alleviated depressive and anxious-like behaviors in mice exposed to lipopolysaccharide: Involvement of oxidative stress and neuroinflammation," Pharmacol Biochem Behav. 2024. PMID 38679081.
  41. ↑ Tremellen K, McPhee N, Pearce K, Benson S, Schedlowski M, Engler H. "Endotoxin-initiated inflammation reduces testosterone production in men of reproductive age," Am J Physiol Endocrinol Metab. 2018;314(3):E206-E213. doi:10.1152/ajpendo.00279.2017. PMID 29183872. PMCID PMC5899218. Randomized placebo-controlled endotoxin challenge (0.8 ng/kg IV, 17 vs 16 healthy lean men aged 18-40) plus an observational study of 75 fertility-clinic men.
  42. ↑ Shen P, Ji S, Li X, Yang Q, Xu B, Wong CKC, Wang L, Li L. "LPS-Induced Systemic Inflammation Caused mPOA-FSH/LH Disturbance and Impaired Testicular Function," Front Endocrinol (Lausanne). 2022;13:886085. doi:10.3389/fendo.2022.886085. PMID 35813649. PMCID PMC9259990. Mouse study (single 4 mg/kg intraperitoneal dose, tissues taken at 48 h).
  43. ↑ Athanassakis I, et al. "Inhibition of nitric oxide production rescues LPS-induced fetal abortion in mice," Nitric Oxide. 1999. PMID 10442853.
  44. ↑ Ikejima K, Enomoto N, Iimuro Y, et al. "Estrogen increases sensitivity of hepatic Kupffer cells to endotoxin," Am J Physiol. 1998;274(4):G669-676. doi:10.1152/ajpgi.1998.274.4.G669. PMID 9575848.
  45. ↑ Mehta NN, McGillicuddy FC, Anderson PD, Hinkle CC, Shah R, Pruscino L, Tabita-Martinez J, Sellers KF, Rickels MR, Reilly MP. "Experimental endotoxemia induces adipose inflammation and insulin resistance in humans," Diabetes. 2010;59(1):172-181. doi:10.2337/db09-0367. PMID 19794059. PMCID PMC2797919. Experimental endotoxemia in 20 healthy adults (50% men, mean age about 27), 3 ng/kg intravenous bolus, measurements before and after with no placebo arm. Insulin sensitivity index (FSIGT Si) fell 35%, from 3.17 ± 1.66 to 2.06 ± 0.73 ×10−4 μU·ml−1·min−1 at 24 h (P < 0.005); no change in beta-cell function (AIRg, HOMA-B). Adipose IRS-1 suppressed, SOCS1 and SOCS3 induced. Peak free fatty acids correlated inversely with Si (r = −0.81). Transient febrile illness in all subjects.
  46. ↑ Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmée E, Cousin B, Sulpice T, Chamontin B, Ferrières J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. "Metabolic endotoxemia initiates obesity and insulin resistance," Diabetes. 2007;56(7):1761-1772. doi:10.2337/db06-1491. PMID 17456850. Mouse study. A 4-week high-fat diet raised plasma LPS two to three times; 4-week continuous subcutaneous LPS infusion matched that level and increased fasting glycemia, insulinemia and whole-body, liver and adipose weight gain to a similar extent as high-fat feeding; "liver, but not whole-body, insulin resistance was detected in LPS-infused mice"; CD14 mutant mice resisted most features.
  47. ↑ Ray Peat, "Protecting and restoring nerves", p. 3(Ray Peat's Newsletter, March 2014)
  48. ↑ Omran F, Murphy AM, Younis AZ, et al., Christian M. "The impact of metabolic endotoxaemia on the browning process in human adipocytes," BMC Med. 2023;21:154. doi:10.1186/s12916-023-02857-z. PMID 37076885.
  49. ↑ Murugan S, Jakka P, Namani S, Mujumdar V, Radhakrishnan G. "The neurosteroid pregnenolone promotes degradation of key proteins in the innate immune signaling to suppress inflammation," J Biol Chem. 2019;294(12):4596-4607. PMID 30647133. doi:10.1074/jbc.RA118.005543.
  50. ↑ Balan I, Beattie MC, O'Buckley TK, Aurelian L, Morrow AL. "Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-one Inhibits Toll-like-4 Receptor Activation and Pro-inflammatory Signaling in Macrophages and Brain," Sci Rep. 2019;9:1220. PMID 30718548.
  51. ↑ Ray Peat, "Fats: Functions and Malfunctions." "When stress is very intense, as in trauma or sepsis, the reaction of liberating fatty acids can become dangerously counter-productive, producing the state of shock. In shock, the liberation of free fatty acids interferes with the use of glucose for energy and causes cells to take up water and calcium... and to leak ATP, enzymes, and other cell contents, in something like a systemic inflammatory state often leading to death."
  52. ↑ 52.0 52.1 EFSA Panel on Contaminants in the Food Chain (CONTAM), Schrenk D, Bodin L, et al. "Risk assessment of ochratoxin A in food," EFSA J. 2020;18(5):e06113. doi:10.2903/j.efsa.2020.6113. PMID 37649524. Risk assessment.
  53. ↑ Ouethrani M, Van de Wiele T, Verbeke E, Bruneau A, Carvalho M, Rabot S, Camel V. "Metabolic fate of ochratoxin A as a coffee contaminant in a dynamic simulator of the human colon," Food Chem. 2013;141(4):3291-3300. doi:10.1016/j.foodchem.2013.05.157. PMID 23993484. In vitro gut-simulator study.
  54. ↑ Liew WP, Mohd-Redzwan S. "Mycotoxin: Its Impact on Gut Health and Microbiota," Front Cell Infect Microbiol. 2018;8:60. doi:10.3389/fcimb.2018.00060. PMID 29535978. Review.
  55. ↑ Guo M, Huang K, Chen S, Qi X, He X, Cheng WH, Luo Y, Xia K, Xu W. "Combination of metagenomics and culture-based methods to study the interaction between ochratoxin A and gut microbiota," Toxicol Sci. 2014;141(1):314-323. doi:10.1093/toxsci/kfu128. PMID 24973096. Rat study.
  56. ↑ 56.0 56.1 56.2 56.3 Pinton P, Oswald IP. "Effect of deoxynivalenol and other Type B trichothecenes on the intestine: a review," Toxins (Basel). 2014;6(5):1615-1643. doi:10.3390/toxins6051615. PMID 24859243. Review.
  57. ↑ Pestka JJ, Yike I, Dearborn DG, Ward MD, Harkema JR. "Stachybotrys chartarum, trichothecene mycotoxins, and damp building-related illness: new insights into a public health enigma," Toxicol Sci. 2008;104(1):4-26. doi:10.1093/toxsci/kfm284. PMID 18007011. Review.
  58. ↑ Bracarense AP, Lucioli J, Grenier B, Drociunas Pacheco G, Moll WD, Schatzmayr G, Oswald IP. "Chronic ingestion of deoxynivalenol and fumonisin, alone or in interaction, induces morphological and immunological changes in the intestine of piglets," Br J Nutr. 2012;107(12):1776-1786. doi:10.1017/S0007114511004946. PMID 21936967. Pig feeding study.
  59. ↑ Pinton P, Nougayrède JP, Del Rio JC, Moreno C, Marin DE, Ferrier L, Bracarense AP, Kolf-Clauw M, Oswald IP. "The food contaminant deoxynivalenol, decreases intestinal barrier permeability and reduces claudin expression," Toxicol Appl Pharmacol. 2009;237(1):41-48. doi:10.1016/j.taap.2009.03.003. PMID 19289138. Cell, tissue and pig study.
  60. ↑ Maresca M, Mahfoud R, Garmy N, Fantini J. "The mycotoxin deoxynivalenol affects nutrient absorption in human intestinal epithelial cells," J Nutr. 2002;132(9):2723-2731. doi:10.1093/jn/132.9.2723. PMID 12221236. Cell study.
  61. ↑ EFSA Panel on Contaminants in the Food Chain (CONTAM), Knutsen HK, Alexander J, et al. "Risks to human and animal health related to the presence of deoxynivalenol and its acetylated and modified forms in food and feed," EFSA J. 2017;15(9):e04718. doi:10.2903/j.efsa.2017.4718. PMID 32625635. Risk assessment.
  62. ↑ Adaptogenic Milk, Ray Peat Newsletter, September 2017
  63. ↑ Kuć-Szymanek A, Kubik-Machura D, Kościelecka K, Męcik-Kronenberg T, Radko L. "Neurotoxicological Effects of Some Mycotoxins on Humans Health and Methods of Neuroprotection," Toxins (Basel). 2025;17(1):24. doi: 10.3390/toxins17010024. Review.
  64. ↑ Taevernier L, Bracke N, Veryser L, Wynendaele E, Gevaert B, Peremans K, De Spiegeleer B. "Blood-brain barrier transport kinetics of the cyclic depsipeptide mycotoxins beauvericin and enniatins," Toxicol Lett. 2016;258:175-184. doi: 10.1016/j.toxlet.2016.06.1741. PMID 27349679. Mouse study of beauvericin and enniatins; influx constant K1 11 to 53 µL/(g·min); about 95% reached brain tissue rather than the capillary wall; efflux under 0.005/min.
  65. ↑ Krug I, Behrens M, Esselen M, Humpf HU. "Transport of enniatin B and enniatin B1 across the blood-brain barrier and hints for neurotoxic effects in cerebral cells," PLoS One. 2018;13(5):e0197406. doi: 10.1371/journal.pone.0197406. PMID 29768483. Cell study of enniatin B and B1; astrocytoma IC50 8.9 µM (ENN B) and 4.4 µM (ENN B1); only enniatin B raised caspase-3.
  66. ↑ Weidner M, Lenczyk M, Schwerdt G, Gekle M, Humpf HU. "Neurotoxic potential and cellular uptake of T-2 toxin in human astrocytes in primary culture," Chem Res Toxicol. 2013;26(3):347-355. doi: 10.1021/tx3004664. PMID 23363530. Primary human astrocyte culture; apoptosis by caspase-3 activation and annexin V; cells converted T-2 to HT-2 toxin.
  67. ↑ De Santis B, Brera C, Mezzelani A, et al. "Role of mycotoxins in the pathobiology of autism: A first evidence," Nutr Neurosci. 2019;22(2):132-144. doi: 10.1080/1028415X.2017.1357793. PMID 28795659. Case-control study; 52 autistic children vs 58 controls (31 siblings, 27 unrelated); OTA urine p=0.0002, serum p=0.0017 vs unrelated controls; gliotoxin and zearalenone also measured.
  68. ↑ 68.0 68.1 El-Maghraby OM, El-Maraghy SS. "Mycoflora and natural occurrence of mycotoxins in tobacco from cigarettes in Egypt," Zentralbl Mikrobiol. 1993;148(4):253-264. doi:10.1016/s0232-4393(11)80101-0. PMID 8368025. 40 cigarette tobacco samples; 42 fungal species, commonest Aspergillus flavus, A. fumigatus, A. niger, Penicillium; toxin in 4 of 40: aflatoxins B1+B2 in 2 (15.5 and 20.7 µg/kg), zearalenone 1, T-2 toxin 1; cigarettes spiked with 10-50 µg aflatoxin gave non-toxic smoke extracts with no mycotoxin detected, aflatoxin found in the filter.
  69. ↑ Ugwuanyi CC, et al. "Aspergillus species and aflatoxin contamination of tobacco snuff samples sold in some parts of southeastern Nigeria," Mycotoxin Res. 2025. doi:10.1007/s12550-025-00590-5. PMID 40332655. Snuff from 30 vendors in six markets; 42 Aspergillus isolates (A. niger 57%, A. fumigatus 31%, A. flavus 12%); aflatoxins B1 and B2 detected by TLC, G1 and G2 absent.
  70. ↑ Zitomer N, Rybak ME, Li Z, Walters MJ, Holman MR. "Determination of Aflatoxin B1 in Smokeless Tobacco Products by Use of UHPLC-MS/MS," J Agric Food Chem. 2015;63(41):9131-9138. doi:10.1021/acs.jafc.5b02622. PMID 26452144. 32 US smokeless products; aflatoxin B1 from below 0.007 ppb (LOD) to 0.271 ppb dry mass; detected mostly in dry snuff and chew, moist snuff all below LOD; FDA food/feed limit 20 ppb.
  71. ↑ 71.0 71.1 Tso TC, Sorokin T. "Examination of Aflatoxin B1 in Leaf Tobacco and in Cigarette Smoke Condensate," Beiträge zur Tabakforschung. 1967;4(1):18-20. doi:10.2478/cttr-2013-0162. Seven good-grade flue-cured, Burley and Maryland leaf samples and four moldy flue-cured samples; aflatoxin B1 not detected (TLC, detection limit 0.3 ppb); 0.5 µg aflatoxin B1 added per cigarette (about 500 ppb) not recovered in smoke condensate.
  72. ↑ Kaminski EJ, Lazanas JC, Wolfson LL, Fancher OE, Calandra JC. "Fate of Aflatoxins in Cigarette Tobacco," Beiträge zur Tabakforschung. 1970;5(4). doi:10.2478/cttr-2013-0235. Commercial non-filter cigarettes spiked with crystalline aflatoxin B1 and machine-smoked; no aflatoxin in butts, particulate phase, gaseous phase or ash in six experiments (TLC and spectrophotofluorometry, limit 0.01 µg); aflatoxin B1 decomposes at about 264 °C.
  73. ↑ Leakiness, aging, and cancer, Ray Peat newsletter
  74. ↑ Leakiness, aging, and cancer, Ray Peat newsletter
  75. ↑ 75.0 75.1 75.2 75.3 75.4 Ray Peat, "Leakiness, aging, and cancer," raypeat.com.
  76. ↑ Ray Peat, "Leakiness, aging, and cancer," raypeat.com.
  77. ↑ Leakiness, aging, and cancer, Ray Peat newsletter
  78. ↑ Aberdeen GW, et al. "Vascular endothelial growth factor mediates the estrogen-induced breakdown of tight junctions between and increase in proliferation of microvessel endothelial cells in the baboon endometrium." Endocrinology. 2008;149(12):6076-6083.
  79. ↑ 79.0 79.1 79.2 Ray Peat, "Leakiness, aging, and cancer," raypeat.com.
  80. ↑ Ray Peat, "Leakiness, aging, and cancer," raypeat.com.
  81. ↑ Leakiness, aging, and cancer, Ray Peat newsletter
  82. ↑ Nanji AA, Jokelainen K, Tipoe GL, Rahemtulla A, Dannenberg AJ. "Dietary saturated fatty acids reverse inflammatory and fibrotic changes in rat liver despite continued ethanol administration." J Pharmacol Exp Ther. 2001;299(2):638-644. Rat study, 6 male Wistar rats per group. PMID 11602676.