HEIRS Microbiology: Understanding LPS Endotoxin in Chronic Fatigue Syndrome and Other Diseases

We thought a good topic to write about today was endotoxin considering a research study was just published that a causal pathway from endotoxin has been implicated in chronic fatigue syndrome. (Maes) As we mentioned in one of our previous posts this is not surprising to us. To that end, we thought it was important for patients to get a clear picture of what endotoxin and LPS is…We can assure you the information will neither make you “cringe” or regret you already at lunch.  The details we provide here are just general facts but important ones for understanding their role in environmental illness.  There may be some misconception out there about what endotoxin is and what it isn’t. Hopefully, we can clear up some of the confusion for those readers.

The first thing to understand is that endotoxin is not bacteria but are the sugars that are attached to gram negative bacteria. There is some debate on the exact nature or production of endotoxin. According to the CDC, “they are antigenic, can cause fever and diarrhea and alter immune responses to other antigens and environmental contaminants.” Generally, they are only released when the cells are disrupted or destroyed including destruction by phagocytes which are immune cells of the host’s immune system. Dr. Todar, Ph.D  mentions that ” a small amount of endotoxin may be secreted  while the bacteria is growing. Lipid A only results in toxicity when the membrane is broken down such as is the case with phagocytosis or from antibiotic treatment.”  Huang describes this in a little differently explaining, “that when bacteria multiply, lyse and die the LPS is set free from the cellular surface and allowed to interact with host tissue. The toxicity is dependant on the host’s response and can result in a number of inflammatory mediators which can induce typical endotoxin effects independantly, synergistically or antagonistically.  The host can either be hyper-reactive or tolerant to the effects of LPS. The sensitivity of which has been attributed to IFN-gamma.”  (Huang) The exact nature of how IFN-gamma mediates hyper-reactiveness to LPS is not known but IFN-gamma sensitivity to LPS occurs before LPS hypersensitivity. (Max-Planck) It is interesting to note INF-gamma stimulates H2O2 from macrophages that could lead to faster antioxidant depletion and therefore would require a need for greater levels of glutathione and catalase. In some studies researchers have noted that the LPS induction of ROS results in inactivation of catalase. (Ding & Spolarics)  Considering that humans and all organisms are exposed to a variety of bacterial pathogens on a daily basis it is not uncommon for them to come into contact with endotoxins. This is true even though endotoxins are only found in combination with certain bacterial pathogens.  

LPS endotoxin is associated with gram negative bacteria “whether the bacteria is pathogenic or not.”  Todar explains that some of the common species of bacteria with endotoxin include E Coli, Shigella, Pseudomonas, H pylori (yes the stomach bugs that cause ulcers) etc. (A list of gram negative bacteria can be found here.) Todar also describes simply that the “biological activity of endotoxin is associated with the lipopolysaccharide (LPS). Toxicity is associated with lipid A which is the lipid component and the immunogenic part of the polysaccharide.” (Todar) 

As we mentioned, the toxicity of LPS is due to lipid A in the membrane and it is very good at activating the host’s immune system. In fact, the immune reactions are much the same as that for the pathogen itself and can “contribute to symptoms and the pathology of the disease leading to fever, changes in white blood cell counts and even more severe complications such as disseminated intravascular coagulation, hypotension, shock and death.   One thing that an unknown author noted is that while “endotoxin may seem allergenic it is not”. It activates complement that leads to its destruction. He also noted that while endotoxin alone may not cause an immune response, but if its exposure occurs is in concert with another agent such as dust or particulate matter the immune reaction can be much more severe than it would be for either on their own.  They are very imflammatory and release cytokines (CDC), cause endothelial dysfunction through the disuption of tight junctions in the lining of the intestinal tract and blood brain barrier and alter activity of transporters that carry molecules such as insulin and xenobiotics across these same barriers. (Gendelman)

Some other important facts are described in the book the Science and Practice of Pharmacy about lipopolysaccharides. The author discusses how LPS are so small they can slip through 0.2 filters as their molecular weight is only 10,000 daltons. Yes that is VERY small and can get through pretty much anything.  In addition to be found at levels in water sources (ie rural water supplies), they can be introduced into a patient through pharmaceuticals because of that ability to go through sterile filters during manufacturing. (Troy) In one study dated a few years ago, the researchers first believed nanoparticles were eliciting a response from dendritic cells which are the sentinels of the immune system. However, after further analysis they found the activation of the immune system was from contamination of those nanoparticles with endotoxin LPS. (Newswire Today)

In our other posts we have discussed the relationshop of LPS to environmental illness including asthma, colitis, sepsis etc. In addition, we have made it a point to address the effect of LPS in people who smoke because smoke and cigarettes contain high levels of LPS. Of course, there are many other sources of LPS which environmental illness patients seem to be particularly vulnerable to including air pollution. Ultra fine (UFPM) particles are a concern due to their size which are large enough to carry LPS as well as a variety of other contaminants and are commonly inhaled or ingested. (Ashwood & Powell) LPS make one more susceptible to heavy metal poisoning and heavy metal makes one more susceptible to LPS toxicity. Incidentally, in addition to chemical exposures, the combination of LPS and heavy metals has been implicated in the development of heavy metal induced autoimmune disease. (Abedi-Valugerdi, Rowley) In any case, UFPM are always an airborne hazard and become an occupational one for  agricultural workers in the textile and fabric industry because of bacterial contamination of the fibers (ie. cotton) while growing in the field. (Salem) According to another study that analyzed the amount of LPS endotoxin in homes, LPS levels are highest in home environments in the summer and fall and in homes with dogs. Of course, other potential sources for contamination therefore is livestock.  (Abraham)

Watch Can Your Home Trigger Asthma: Environmental Toxicologists Link Household Bacteria to Asthma – a short clip on how endotoxin inflames airways.

HEIRS Research Notes: More About Bugs in the Gut and LPS From the “Gist of Environmental Illness” By HEIRS…(Citations)

• Direct insult to intestinal wall, oxidative stress and leaky gut. Leaky Gut from LPS has been implicated in CFS and depression. (Maes)
• Disruption of normal transporter activity….disturbs normal intestinal motility. (Gendelman)
• There is accumulating evidence from animal studies that endotoxin influences response to toxic chemicals.  Liver injury is augmented from endotoxin by hepatotoxicants. (Roth)
• Glutathione and Catalase under normal conditions should be able to remove H2O2 from respiratory burst from killing microorganisms. (Hughes et al)
• Inhibits mucosal Na⁺-dependent D-galactose intestinal absorption and the Na⁺, K⁺-ATPase activity. Impairment of this system, glucose transporters, etc result in excessive excitotoxicity. (Amador)  (Hof)
• Mast cells and other immune cell generation.
• Bacterial LPS can stimulate insulin resistance, obesity and diabetes. (Cani)
• Alteration of vitamin stores including vitamin B12 and D.
• Probiotics promote intestinal epithelial integrity and reduce infection and diarrhea. (Seth)
• Superoxide signal macrophages and alter gene expression. (ScienceDaily – Cancer-causing Gut Bacteria Exposed).
• Adaptive mechanisms of gut bacteria over long periods may allow for the bacteria to become resistant to higher H2O2 levels but not normal intestinal cells. (Fuchs and Packer, pg 5)
• Non-toxic levels of H2S can potentiate the cytotoxic effects of H2O2. (Eghbal) Endogenous levels of H2S increase and increase in CSE gene expression after LPS administration.
• Absence of neuroprotection from serotonin with altered signalling. (Gershon)
• Dietary fats may transport LPS to different tissues after absorption in the intestines contributing to inflammatory responses or chronic diet-induced inflammation. (Ghoshal)

Related Posts:

• HEIRS Chronic Fatigue Syndrome: LPS Is Considered a Pathway in CFS
• HEIRS  Hypothesis: The Gist of Environmental Illness
• HEIRS Cell Biology Snippets: LPS Effects Blood Brain Barrier Efflux
• HEIRS Environmental Health: LPS Endotoxins and Breathing Bad Air
• Food Safety: More About Bugs In The Gut—Their Role in Leaky Gut
• HEIRS Research: Environmental Illness, IGF-1 and Nrf2. Studies in Environmental Medicine.

 

 

Unknown. Role of lps-hypersensitivity in the innate response to infection. http://www.citeulike.org/user/HEIRS/article/3846952 

Abedi-Valugerdi, M., Nilsson, C., Zargari, A., Gharibdoost, F., Depierre, J. W., and Hassan, M. (2005). Bacterial lipopolysaccharide both renders resistant mice susceptible to mercury-induced autoimmunity and exacerbates such autoimmunity in susceptible mice. Clinical & Experimental Immunology, 141(2):238-247. http://www.citeulike.org/user/HEIRS/article/244961 Abraham, J. H., Gold, D. R., Dockery, D. W., Ryan, L., Park, J. H., and Milton, D. K. (2005). Within-home versus between-home variability of house dust endotoxin in a birth cohort. Environmental health perspectives, 113(11):1516-1521. http://www.citeulike.org/user/HEIRS/article/3846191

Ashwood, P., Thompson, R. P., and Powell, J. J. (2007). Fine particles that adsorb lipopolysaccharide via bridging calcium cations may mimic bacterial pathogenicity towards cells. Experimental Biology and Medicine, 232(1):107-117. http://www.citeulike.org/user/HEIRS/article/3753797

Author Unknown. Endotoxins. Information from CDC. http://www.citeulike.org/user/HEIRS/article/3846060

Ding, A., Nathan, C., and Stuehr, D. (1988). Release of reactive nitrogen intermediates and reactive oxygen intermediates from mouse peritoneal macrophages. comparison of activating cytokines and evidence for independent production. J Immunol, 141(7):2407-2412. http://www.citeulike.org/user/HEIRS/article/876629

Gendelman, H. E. and Ikezu, T. (2008). Neuroimmune pharmacology. Springer. http://www.citeulike.org/user/HEIRS/article/3846810

Huang, H. (2004). INFLAMMATORY AND OXIDATIVE MECHANISMS IN ENDOTHELIAL CELL ACTIVATION AND DYSFUNCTION. PhD thesis. http://www.citeulike.org/user/HEIRS/article/3846907

Li, L., Bhatia, M., Zhu, Y. Z., Zhu, Y. C., Ramnath, R. D., Wang, Z. J., Anuar, F. B., Whiteman, M., Salto-Tellez, M., and Moore, P. K. (2005). Hydrogen sulfide is a novel mediator of lipopolysaccharide-induced inflammation in the mouse. FASEB J., pages 04-3583fje+. http://www.citeulike.org/user/HEIRS/article/3832114

Klot, V. S., Wolke, G., Tuch, T., Heinrich, J., Dockery, D. W., Schwartz, J., Kreyling, W. G., Wichmann, H. E., and Peters, A. (2002). Increased asthma medication use in association with ambient fine and ultrafine particles. Eur Respir J, 20(3):691-702. http://www.citeulike.org/user/HEIRS/article/3846189

We Maes, M., Mihaylova, I., and Leunis, J. C. (2007). Increased serum iga and igm against lps of enterobacteria in chronic fatigue syndrome (cfs): indication for the involvement of gram-negative enterobacteria in the etiology of cfs and for the presence of an increased gut-intestinal permeability. Journal of affective disorders, 99(1-3):237-240. http://www.citeulike.org/user/HEIRS/article/3843279

Maes, M., Kubera, M., and Leunis, J. (2008). The gut-brain barrier in major depression: Intestinal mucosal dysfunction with an increased translocation of lps from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuroendocrinology Letter, 29(1):117-124. http://www.citeulike.org/user/HEIRS/article/3843270

Maes, M. and Leunis, J.-C. C. (2008). Normalization of leaky gut in chronic fatigue syndrome (cfs) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of lps from gram-negative bacteria. Neuro endocrinology letters, 29(6). http://www.citeulike.org/user/HEIRS/article/3843226

Powell, J. J., Harvey, R. S., Ashwood, P., Wolstencroft, R., Gershwin, M. E., and Thompson, R. P. (2000). Immune potentiation of ultrafine dietary particles in normal subjects and patients with inflammatory bowel disease. Journal of autoimmunity, 14(1):99-105. http://www.citeulike.org/user/HEIRS/article/3846187

Rowley, B. and Monestier, M. (2005). Mechanisms of heavy metal-induced autoimmunity. Molecular immunology, 42(7):833-838. http://www.citeulike.org/user/HEIRS/article/3847090

Salem, H. and Katz, S. A. (2006). Inhalation Toxicology. CRC Press. http://www.citeulike.org/user/HEIRS/article/3846172

Spolarics, Z. and Wu, J.-X. (1997). Role of glutathione and catalase in h2o2 detoxification in lps-activated hepatic endothelial and kupffer cells. Am J Physiol Gastrointest Liver Physiol, 273(6):G1304-1311. http://www.citeulike.org/user/HEIRS/article/3728093

Todar, K. (2005) Mechanisms of bacterial pathogenicity: Endotoxins todar’s online textbook of bacteriology. http://www.citeulike.org/user/HEIRS/article/3846094

Troy, D. and Beringer, P. (2005). The Science and Practice of Pharmacy. University of the Sciences in Philadelphia. http://www.citeulike.org/user/HEIRS/article/3844999

The effects of contamination during nanoparticle production. Newswire Today. August 14, 2006. Retrieved on January 3, 2008.

Author Unknown. Gram Negative Bacteria. New York University.