Lipopolysaccharide compositionLipopolysaccharides, also called endotoxins, are structural components of bacteria that are released in the intestine and safeguarded against by an optimal physiology and the integrity of the intestinal barrier, but unhealthy lifestyles, bad eating habits, genetic predispositions, or infections can increase endotoxin concentration to intolerable levels, or make us more sensitive to “normal” levels, for example when the intestine is permeable, allowing endotoxin into the bloodstream (Mokkala, et al., 2017). The point at which endotoxin is so high that it kills is what we know as sepsis, or septic shock. Anything below that may cause chronic conditions that indicate a subclinical “poisoning” of the bloodstream by endotoxin and the mediators that increase it.

endotoxin process mediatorsTo get a picture of what endotoxin is doing, picture an acute fever or virus with the “sickness behavior” characterized by depression, brain fog and possibly delirium, reduced sociability, weakness, fatigue, palor, and pain. This is mediated by endotoxin in the blood stream because the infectious bacteria is stimulating the immune system to cause inflammation. The more obscure understanding of endotoxin is as a constant contributor to inflammation and thus degenerative processes that lead to the chronic, long-term, and terminal illnesses of an almost universal variety. Looking at the factors that increase or decrease our vulnerability to endotoxin gives us the power to steer our health and longevity in a positive direction.

Progesterone treatment significantly blunts the inflammatory cytotoxicity (cell-killing) consequences of endotoxin (Garcia-Ruiz, et al., 2015). In cats, progesterone protects against the blood pressure-deranging effects of endotoxin and prolongs their survival (Silk, 1967). Endotoxin raises prostaglandins and cortisol, and decreases progesterone, contributing to the chances of terminated pregnancy. Specifically, endotoxin leads to the release of prostaglandin PGF2 alpha which inappropriately and prematurely contracts the uterine smooth muscle which depletes plasma progesterone, which terminates pregnancies (Giri, et al., 1990; Al-dughaym and Homeida, 2010). Here it becomes evident that endotoxin is antithetical to progesterone (the “gestation hormone”), and in that sense antithetical to life.

The dangerous circulatory effects of endotoxin are intensified by the serotonin family: tryptophan → 5-hydroxytryptamine (5-HTP) → serotonin. Anti-serotonin medications are commonly used to treat nausea, but they can have powerful, even life-saving properties in the context of endotoxemia and endotoxin-induced cardiovascular crises. Endotoxic shock can induce respiratory failure, but the injection of the antiserotonin drug cyproheptadine prevents the respiratory failure from occurring even under the presence of endotoxin (Almgvist, et al., 1984).

Endotoxin administration spikes blood sugar (hyperglycemia) with a reactive plummet (reactive hypoglycemia), and with enough endotoxin, that hypoglycemic plummet can be fatal. When mice are poisoned with endotoxin and then given tryptophan, they die more often than with endotoxin alone. The antiserotonin drug cyproheptadine was shown to decrease the death rate and protect against the hypoglycemia (Moon, 1971).

An interesting and paradoxical exception is when endotoxin induces compensatory mechanisms in the body that improve symptom states. For example, a gold standard in medical research for making people or animals quickly and severely depressed is to inject them with endotoxin (Yirmiya, 1996). A crucial mechanism of how the serotonin-reuptake inhibitors (SSRIs) work is by activating inflammatory cytokines, which leads to a compensatory, “defensive” increase in the protein p11, which improves mood and behavior; the serotonin is actually harmful, it’s what the body does to regulate this induced endotoxin-serotonin bombardment that relieves depression.

pnas SSRIs NSAIDS p11
NSAIDs like aspirin, acetaminophen, or ibuprofen have been shown to interfere with the antidepressant effect of SSRIs because they’re disrupting that initial inflammation (Warner-Schmidt, et al., 2011).

Excessive intense exercise, like ultra-marathons, can poison the blood enough to cause endotoxic shock (Gill, et al., 2015), but reasonable and regular exercise increases our clearance of, and defenses against, endotoxin. Exercise increases the steroid hormone DHEA, which increases Kupffer liver cells, which are the prime detoxifiers of endotoxin through the liver (Komine, et al., 2017). A sedentary lifestyle seems to coincide with or increase general inflammation and endotoxin circulation (Lira, et al., 2010).

Rat mothers who regularly exercised during pregnancy gave birth to offspring who experienced significantly less inflammation from endotoxin injection: the mother’s exercise genetically primed those newborn rats to have less mRNA expression of endotoxin-inflammation (Yamada, et al., 2018)

Higher mRNA expression of the TLR4 receptor, which regulates endotoxin release, predicts a lower survival rate in cancer (Zhao, et al., 2019) Higher concentrations of plasma endotoxin and inflammation predict a higher the risk is of colon tumors (Kang, et al., 2013), and endotoxin directly supports metastasis of (colon) cancer cells (Hsu, et al., 2011).

The neuroinflammation from endotoxin causes cognitive impairment that we could call “brain fog” at subclinical severity, but at clinical severity becomes neurodegenerative, as in dementia, multiple sclerosis, or Parkinson’s Disease (Wang and White, 1999; Tufek, et al., 2011).

Autism and schizophrenia involve an incongruence between the self and the environment, and the self’s ability to discern its own emotional state from that of other individuals: not a lack of empathy, but a deranged emotional discernment ability (Stroth, et al., 2019). Endotoxin is already known to contribute to the pathophysiology of autism (Emanuele, et al., 2010), and it’s been found that endotoxin decreases test subjects’ ability to understand the emotional state of other people when looking into their eyes. There is an unfortunate positive feedback loop here, since psychosocial stress and social disconnection both activate further inflammation (Moieni, et al., 2015).

Intermittent fasting (IF) protects the brain from endotoxin by not only suppressing inflammation but also directly enhancing neuronal function. IF allows neurons to resist inflammatory insults with less damage and prevents endotoxin from stopping neurogenesis (growth of new brain cells) in the hippocampus. Like the exercising rat mothers, IF reduces the mRNA expression that encodes for endotoxin release (Vasconcelos, et al., 2014). IF is one of the best practices for intestinal health and maintenance because it repairs the intestinal barrier, restructures the microbiome to reduce pathogens, reduces autoimmunity, and allows for cellular waste to be removed (Catterson, et al., 2018). All of these processes are important for our tolerance and reaction to endotoxin, determining if we will experience severe symptoms from it or be able to process it safely.

Factors and Compounds that Reduce and Protect from Endotoxin

 

Works Cited

Balan, Irina, et al. “Endogenous Neurosteroid (3α,5α)3-Hydroxypregnan-20-One Inhibits Toll-like-4 Receptor Activation and Pro-Inflammatory Signaling in Macrophages and Brain.” Scientific Reports, vol. 9, no. 1, 2019, doi:10.1038/s41598-018-37409-6.

Bruck, Rafael, et al. “Glycine Modulates Cytokine Secretion, Inhibits Hepatic Damage and Improves Survival in a Model of Endotoxemia in Mice.” Liver International, vol. 23, no. 4, 2003, pp. 276–282., doi:10.1034/j.1600-0676.2003.00839.x.

Cai, Yu, et al. “Curcumin Protects Against Intestinal Origin Endotoxemia in Rat Liver Cirrhosis by Targeting PCSK9.” Journal of Food Science, vol. 82, no. 3, 2017, pp. 772–780., doi:10.1111/1750-3841.13647.

Catterson, James H., et al. “Short-Term, Intermittent Fasting Induces Long-Lasting Gut Health and TOR-Independent Lifespan Extension.” Current Biology, vol. 28, no. 11, 2018, doi:10.1016/j.cub.2018.04.015.

Chu, Ming, et al. “Role of Berberine in Anti-Bacterial as a High-Affinity LPS Antagonist Binding to TLR4/MD-2 Receptor.” BMC Complementary and Alternative Medicine, vol. 14, no. 1, 2014, doi:10.1186/1472-6882-14-89.

Emanuele, Enzo, et al. “Low-Grade Endotoxemia in Patients with Severe Autism.” Neuroscience Letters, vol. 471, no. 3, 2010, pp. 162–165., doi:10.1016/j.neulet.2010.01.033.

Garcia-Ruíz, G., et al. “In Vitro Progesterone Modulation on Bacterial Endotoxin-Induced Production of IL-1β, TNFα, IL-6, IL-8, IL-10, MIP-1α, and MMP-9 in Pre-Labor Human Term Placenta.” Reproductive Biology and Endocrinology, vol. 13, no. 1, 2015, doi:10.1186/s12958-015-0111-3.

Ghosh, Siddhartha S., et al. “Curcumin-Mediated Regulation of Intestinal Barrier Function: The Mechanism Underlying Its Beneficial Effects.” Tissue Barriers, vol. 6, no. 1, 2018, doi:10.1080/21688370.2018.1425085.

Ghosh, Siddhartha S., et al. “Curcumin-Mediated Regulation of Intestinal Barrier Function: The Mechanism Underlying Its Beneficial Effects.” Tissue Barriers, vol. 6, no. 1, 2018, doi:10.1080/21688370.2018.1425085.

Gill, S., et al. “The Impact of a 24-h Ultra-Marathon on Circulatory Endotoxin and Cytokine Profile.” International Journal of Sports Medicine, vol. 36, no. 08, 2015, pp. 688–695., doi:10.1055/s-0034-1398535.

Giri, Shri N., et al. “Effects of Endotoxin Infusion on Circulating Levels of Eicosanoids, Progesterone, Cortisol, Glucose and Lactic Acid, and Abortion in Pregnant Cows.” Veterinary Microbiology, vol. 21, no. 3, 1990, pp. 211–231., doi:10.1016/0378-1135(90)90033-r.

He, Yan, et al. “Berberine Exerts a Protective Effect on Gut-Vascular Barrier via the Modulation of the Wnt/Beta-Catenin Signaling Pathway During Sepsis.” Cellular Physiology and Biochemistry, vol. 49, no. 4, 2018, pp. 1342–1351., doi:10.1159/000493412.

Hsu, Rich Y.c., et al. “LPS-Induced TLR4 Signaling in Human Colorectal Cancer Cells Increases β1 Integrin-Mediated Cell Adhesion and Liver Metastasis.” Cancer Research, vol. 71, no. 5, 2011, pp. 1989–1998., doi:10.1158/0008-5472.can-10-2833.

Kang, Melissa, et al. “Association of Plasma Endotoxin, Inflammatory Cytokines and Risk of Colorectal Adenomas.” BMC Cancer, vol. 13, no. 1, 2013, doi:10.1186/1471-2407-13-91.

Komine, Shoichi, et al. “Exercise Training Enhances in Vivo Clearance of Endotoxin and Attenuates Inflammatory Responses by Potentiating Kupffer Cell Phagocytosis.” Scientific Reports, vol. 7, no. 1, 2017, doi:10.1038/s41598-017-12358-8.

Kox, M., et al. “Voluntary Activation of the Sympathetic Nervous System and Attenuation of the Innate Immune Response in Humans.” Proceedings of the National Academy of Sciences, vol. 111, no. 20, 2014, pp. 7379–7384., doi:10.1073/pnas.1322174111.

Kox, Matthijs, et al. “The Influence of Concentration/Meditation on Autonomic Nervous System Activity and the Innate Immune Response.” Psychosomatic Medicine, vol. 74, no. 5, 2012, pp. 489–494., doi:10.1097/psy.0b013e3182583c6d.

Kumari, Asha, et al. “Curcumin Inhibits Lipopolysaccharide (LPS)-Induced Endotoxemia and Airway Inflammation through Modulation of Sequential Release of Inflammatory Mediators (TNF-α and TGF-β1) in Murine Model.” Inflammopharmacology, vol. 25, no. 3, 2017, pp. 329–341., doi:10.1007/s10787-017-0334-3.

Li, Fei, et al. “Neutral Sulfate Berberine Modulates Cytokine Secretion and Increases Survival in Endotoxemic Mice.” Acta Pharmacologica Sinica, vol. 27, no. 9, 2006, pp. 1199–1205., doi:10.1111/j.1745-7254.2006.00368.x.

Li, Hong-Mei, et al. “Berberine Protects against Lipopolysaccharide-Induced Intestinal Injury in Mice via Alpha 2 Adrenoceptor-Independent Mechanisms.” Acta Pharmacologica Sinica, vol. 32, no. 11, 2011, pp. 1364–1372., doi:10.1038/aps.2011.102.

Lira, Fabio S, et al. “Endotoxin Levels Correlate Positively with a Sedentary Lifestyle and Negatively with Highly Trained Subjects.” Lipids in Health and Disease, vol. 9, no. 1, 2010, p. 82., doi:10.1186/1476-511x-9-82.

Lucki, Irwin. “Faculty of 1000 Evaluation for Antidepressant Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) Are Attenuated by Antiinflammatory Drugs in Mice and Humans.” F1000 – Post-Publication Peer Review of the Biomedical Literature, 2011, doi:10.3410/f.10348956.11164054.

Middendorp, Henriët Van, et al. “The Role of Outcome Expectancies for a Training Program Consisting of Meditation, Breathing Exercises, and Cold Exposure on the Response to Endotoxin Administration: a Proof-of-Principle Study.” Clinical Rheumatology, vol. 35, no. 4, 2015, pp. 1081–1085., doi:10.1007/s10067-015-3009-8.

Moieni, Mona, et al. “Inflammation Impairs Social Cognitive Processing: A Randomized Controlled Trial of Endotoxin.” Brain, Behavior, and Immunity, vol. 48, 2015, pp. 132–138., doi:10.1016/j.bbi.2015.03.002.

Moieni, Mona, et al. “Trait Sensitivity to Social Disconnection Enhances pro-Inflammatory Responses to a Randomized Controlled Trial of Endotoxin.” Psychoneuroendocrinology, vol. 62, 2015, pp. 336–342., doi:10.1016/j.psyneuen.2015.08.020.

Mokkala, Kati, et al. “Increased Intestinal Permeability, Measured by Serum Zonulin, Is Associated with Metabolic Risk Markers in Overweight Pregnant Women.” Metabolism, vol. 69, 2017, pp. 43–50., doi:10.1016/j.metabol.2016.12.015.

Molteni, Monica, et al. “Natural Products with Toll-Like Receptor 4 Antagonist Activity.” International Journal of Inflammation, vol. 2018, 2018, pp. 1–9., doi:10.1155/2018/2859135.

Murugan, Subathra, et al. “The Neurosteroid Pregnenolone Promotes Degradation of Key Proteins in the Innate Immune Signaling to Suppress Inflammation.” Journal of Biological Chemistry, vol. 294, no. 12, 2019, pp. 4596–4607., doi:10.1074/jbc.ra118.005543.

“Ray Peat, PhD on Endotoxin.” Ray Peat, PhD on Endotoxin – Functional Performance Systems (FPS), www.functionalps.com/blog/2012/11/29/ray-peat-phd-on-endotoxin/.

Silk, Mark R. “The Effect of Progesterone on Cats Administered Endotoxin.” Journal of Surgical Research, vol. 7, no. 1, 1967, pp. 35–40., doi:10.1016/0022-4804(67)90007-8.

Stroth, Sanna, et al. “Empathy in Females With Autism Spectrum Disorder.” Frontiers in Psychiatry, vol. 10, 2019, doi:10.3389/fpsyt.2019.00428.

Tore, Pio Alfredo Di, et al. “Autism Spectrum as an Empathy Disorder.” Autism-Open Access, vol. 07, no. 01, 2017, doi:10.4172/2165-7890.1000198.

Tritz, Gerald J., and Kcom. “THE BACTERIA.” Dr. Tritz: Bacteria, http://www.atsu.edu/faculty/chamberlain/Website/Lects/Bacteria.htm.

Tufekci, Kemal Ugur, et al. “The Endotoxin-Induced Neuroinflammation Model of Parkinson’s Disease.” Parkinson’s Disease, vol. 2011, 2011, pp. 1–25., doi:10.4061/2011/487450.

Vasconcelos, Andrea R, et al. “Intermittent Fasting Attenuates Lipopolysaccharide-Induced Neuroinflammation and Memory Impairment.” Journal of Neuroinflammation, vol. 11, no. 1, 2014, p. 85., doi:10.1186/1742-2094-11-85.

Wang, Yushan S., and Thomas D. White. “The Bacterial Endotoxin Lipopolysaccharide Causes Rapid Inappropriate Excitation in Rat Cortex.” Journal of Neurochemistry, vol. 72, no. 2, 1999, pp. 652–660., doi:10.1046/j.1471-4159.1999.0720652.x.

Warner-Schmidt, J. L., et al. “Antidepressant Effects of Selective Serotonin Reuptake Inhibitors (SSRIs) Are Attenuated by Antiinflammatory Drugs in Mice and Humans.” Proceedings of the National Academy of Sciences, vol. 108, no. 22, 2011, pp. 9262–9267., doi:10.1073/pnas.1104836108.

Xu, Fa Liang, et al. “Glycine Attenuates Endotoxin-Induced Liver Injury by Downregulating TLR4 Signaling in Kupffer Cells.” The American Journal of Surgery, vol. 196, no. 1, 2008, pp. 139–148., doi:10.1016/j.amjsurg.2007.09.045.

Yamada, Mami, et al. “Maternal Exercise Training Attenuates Endotoxin-Induced Sepsis in Mice Offspring.” Biochemistry and Biophysics Reports, vol. 15, 2018, pp. 19–24., doi:10.1016/j.bbrep.2018.06.001.

Yirmiya, Raz. “Endotoxin Produces a Depressive-like Episode in Rats.” Brain Research, vol. 711, no. 1-2, 1996, pp. 163–174., doi:10.1016/0006-8993(95)01415-2.

Zhao, Shu, et al. “TLR4 Expression Correlated with PD-L1 Expression Indicates a Poor Prognosis in Patients with Peripheral T-Cell Lymphomas.” Cancer Management and Research, Volume 11, 2019, pp. 4743–4756., doi:10.2147/cmar.s203156.

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