Definition: Endotoxin: a toxic component of bacteria not excreted by live bacteria but induces the inflammatory cascade and production of NO. (Endotoxin)

 

Implications for Endotoxin As Causal Factors in Sickness Syndrome, MCS and Chronic Fatigue Syndrome

 

An increasing number of scientific publications support the hypothesis that endotoxin infection and sickness syndrome may be important factors in environmental illnesses including fibromyalgia, chronic fatigue syndrome and quite possibly MCS. In fact, sickness syndrome would be a reasonable and holistic approach for explaining many of the behavioral, physical and emotional complications that are common in environmental illness. Sickness syndrome is described as the presence of a variety of symptoms including malaise, fatigue, sleep disturbances, appetite changes, brain inflammation, mood changes such as anxiety and depression and a host of other symptoms that occur as a reponse to injury or infection.  These response occur both in humans and animals and some propose it is in part, adapative responses that are generated to alter the responses of the host and their social network. Over the past several years, there has been an significant amount of research on sickness syndrome. The occurence of which can be attributed to inflammatory cytokines that alter neurotransmission and genetic expression. There have been studies that show altered gene expression in environmental illnesses; the consequences of which can be quite severe and unexpected. Il-10 is an anti-inflammatory cytokine that has been shown to modulate the severity of sickness syndrome through interaction with HO-1. HO-1 is also a cytokine that is induced by activation of Nrf2, although there are other pathways that can induce this antioxidant. Recently, it has been demonstrated that the protective effect of an endogenous peptide thryotropin, against the damaging effect on the dopamine system from paraquat, is due to the chemicals ability to activate Nrf2 to reduce reactive species and increase the antioxidant glutathione. Other studies have demonstrated that thyrotropin is able to reverse hyperglycemia by increasing beta cell function and reducing programmed cell death. (Luo) Insulin resistance and diabetes are suspected to be important consequences of the sustained presence of inflammation and inflammatory cyokines that are characteristic of environmental illnesses.

 

A recent published study showed that there is brain disfunction in multiple chemical sensitivity (Orriols) and last week I suggested that some of the cognitive effects could be from an altered expression of BDNF. Of course, there are any number of factors such as malnutrition and inflammation that can influence cognitive function. Neurotransmitter regulate and can alter cognition and are modulated by factors that produce "sickness syndrome".  According to the author of the recent MCS study, SPECT scans showed alterations in the regions of the brain including the cingulus, striatum and the hippocampus in addition to others. Pekary et al explains that a common environmental toxin LPS has the potential to alter the expression of thyrotropin which may have an impact on LPS toxicity. The study showed elevations of cytokines and corticosterone after LPS with a transient drop in T3. Other results showed a decrease in thyrotropin-releasing hormone in certain areas of the brain while increasing it in others. Thyrotropin has been shown to improve recovery after neurological dysfunctions such as brain trauma and epilepsy in humans and animals and be neuroprotective against NMDA neurotoxicity. (Pizzi) These regions the author noted are areas that are associated with the neuroimmunomodulatory effects of sickness and injury and danger and appear to be similar to those effected in MCS SPECT scans. Also, a sustained elevation in TRH was present in b-cells accompanied by LPS-impaired insulin secretion. From these findings, the author concluded that thyrotropins can mediate and moderate the behavioral and toxic effects of LPS. In addition, LPS elevates inflammatory cytokines including Tnf-a, Il-6 and Il-1b and also increases expression of TLR receptors 2 and 4 and causes a prolonged sickness behavior in aged animals. Taking this information into account and the fact that thryotropin mediate their positive effects through Nrf2, then one can assume that alterations in the antioxidant system may exacerbate the toxic effects generated by LPS endotoxin  It is also important to mention that Nrf2 levels drop as a consequence of the aging process(Godbout). This could lead one to propose that Nrf2 alterations from aging and other impairments and LPS may at least in part, mediate the effects in MCS. There has been evidence that hyperglycemia (which can be reversed with thyrotropin) sensitizes TRPV1 receptors which is implicated in MCS and diabetes complications and TRPV1 may have direct or indirect effect on the release of neurotransmitters. (Pabbidi) Neuropeptides released from capsaicin-sensitive efferents provide a protective mechanism against LPS but also increase bronchoconstriction which can increase airway hyperresponse. (Elekes) From these results and other studies, I have suggested that insulin resistance and hyperglycemia from chemical exposures may contribute to some of the inflammatory responses in MCS. 

 

Endotoxin or LPS has been implicated as a possible pathway to the development of chronic fatigue syndrome. Above we noted that LPS increases the expression of toll-like receptors 2 and 4. Toll receptors recognize certain components on bacteria and transduces bacterial invasion through this recognition. According to Light they have important relevance in preventing infection and are expressed on a variety of cells including dendritic cells, B cells, neutraphils and macrophages. Defects in TLR expression can lead to an increase in susceptibility to infection from a number of pathogens while aberrant signaling of TLR such as from LPS are implicated in causing sepsis or inflammatory or autoimmune-type conditions. (Harding) Activation of TLRs can lead to initiation of the the inflammatory pathway NF-kappaB and LPS endotoxins are ligand of TL4. Interestingly, saturated fats (bad fat) can induce inflammatory markers through TLR4 and therefore, saturated fats can alter gene expression through TLR4 interaction. For instance, the main component of coconut oil, lauric acid, has been demonstrated to potentiate the inflammatory effects of LPS COX-2. (Lee)  The just published Light study on chronic fatigue syndrome shows an increase in TLR4 after exercise and Light suggests this is due to "lesser fitness" in CFS patients. Light goes on to further explain that Il-10 is upregulated in CFS patients after exercise and one of its roles is to inhibit the production of Tnf-a which is also consistent with recent reports of an anti-inflammatory profile in FM. This and other studies of CFS revealed symptom flares may be related to cytokine activity postexercise. Notably, Tnf-a was elevated in muscle and Light explains that fatigue and muscle pain in CFS might be from the enhanced activation of "fatigue" and "nociceptive" afferents supplying muscle. Other supporting evidence of muscle involvement included elevations of ASIC3 channels that are often increased by muscle and joint inflammation. The elevation of Il-10 in the Light study was correlated to those patients with prolonged fatigue and pain but who also had elevations in pro-inflammatory cytokines and evidence of overall enhanced immune response. LPS has been shown to have a close relationship with sensory nerves and TLR4 receptors have been found on sensory nerves. The interaction between LPS and TLR4 may enhance the complications of TRPV1 activation. (Clark) In addition, Suter demonstrated that TLR2 and TLR4 are necessary for nerve-induced microglia activation and pain sensitization. (Suter)The presence of nociceptors on trigeminal nerves that suggests they recognize bacterial products and contribute to pain during infection. (Ball)  

 

 

 

Lee, J. Y., Sohn, K. H., Rhee, S. H., and Hwang, D. (2001). Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through toll-like receptor 4. The Journal of biological chemistry, 276(20):16683-16689. http://www.citeulike.org/user/HEIRS/article/5847028

Lee, J. Y., Zhao, L., Youn, H. S., Weatherill, A. R., Tapping, R., Feng, L., Lee, W. H., Fitzgerald, K. A., and Hwang, D. H. (2004). Saturated fatty acid activates but polyunsaturated fatty acid inhibits toll-like receptor 2 dimerized with toll-like receptor 6 or 1. The Journal of biological chemistry, 279(17):16971-16979. http://www.citeulike.org/user/HEIRS/article/3328606

Pekary, A., Stevens, S., and Sattin, A. (2007). Lipopolysaccharide modulation of thyrotropin-releasing hormone (trh) and trh-like peptide levels in rat brain and endocrine organs. Journal of Molecular Neuroscience, 31(3):245-259. http://www.citeulike.org/user/HEIRS/article/5921624

Minelli, A., Conte, C., Grottelli, S., Bellezza, I., Emiliani, C., and Bolaños, J. P. (2009). Cyclo (his-pro) upregulates heme oxygenase 1 via activation of nrf2-are signalling. Journal of neurochemistry. http://www.citeulike.org/user/HEIRS/article/5779352

Orriols, R., Costa, R., Cuberas, G., Jacas, C., Castell, J., and Sunyer, J. (2009). Brain dysfunction in multiple chemical sensitivity. Journal of the neurological sciences.  http://www.citeulike.org/user/HEIRS/article/5909270

Luo, L., Luo, J. Z., and Jackson, I. M. (2008). Thyrotropin-releasing hormone (trh) reverses hyperglycemia in rat. Biochemical and biophysical research communications, 374(1):69-73. http://www.citeulike.org/user/HEIRS/article/5779517

Godbout, J. P., Chen, J., Abraham, J., Richwine, A. F., Berg, B. M., Kelley, K. W., and Johnson, R. W. (2005). Exaggerated neuroinflammation and sickness behavior in aged mice after activation of the peripheral innate immune system. FASEB J., 19(10):05-3776fje-1331. http://www.citeulike.org/user/HEIRS/article/4926105

Harding, C. V. (2007). gp96 leads the way for toll-like receptors. Immunity, 26(2):141-143. http://www.citeulike.org/user/HEIRS/article/5921629

Light, A. R., White, A. T., Hughen, R. W., and Light, K. C. (2009). Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects. The journal of pain : official journal of the American Pain Society. Pgs 1099-1112.

Clark, N., Keeble, J., Fernandes, E. S., Starr, A., Liang, L., Sugden, D., de Winter, P., and Brain, S. D. (2007). The transient receptor potential vanilloid 1 (trpv1) receptor protects against the onset of sepsis after endotoxin. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 21(13):3747-3755. http://www.citeulike.org/user/HEIRS/article/5921777

Suter, M. R., Wen, Y.-R. R., Decosterd, I., and Ji, R.-R. R. (2007). Do glial cells control pain? Neuron glia biology, 3(3):255-268. http://www.citeulike.org/user/HEIRS/article/5921818

Ball, J. S. (2007). Co-expression of tlr2 receptor on trpv1 positive trigeminal nociceptors. http://www.citeulike.org/user/HEIRS/article/5921835

Pabbidi, R., Yu, S. Q., Peng, S., Khardori, R., Pauza, M., and Premkumar, L. (2008). Influence of trpv1 on diabetes-induced alterations in thermal pain sensitivity. Molecular Pain, 4(1):9+. http://www.citeulike.org/user/HEIRS/article/2459457

Pizzi, M., Boroni, F., Benarese, M., Moraitis, C., Memo, M., and Spano, P. (1999). Neuroprotective effect of thyrotropin-releasing hormone against excitatory amino acid-induced cell death in hippocampal slices. European Journal of Pharmacology, 370(2):133-137. http://www.citeulike.org/user/HEIRS/article/5922749

Pall, Martin. (2007) Explaining Unexplained Illness. Harrington Park Press. pg. 118.

Elekes, K., Helyes, Z., Németh, J., Sándor, K., Pozsgai, G., Kereskai, L., Börzsei, R., Pintér, E., Szabó, A., and Szolcsányi, J. (2007). Role of capsaicin-sensitive afferents and sensory neuropeptides in endotoxin-induced airway inflammation and consequent bronchial hyperreactivity in the mouse. Regulatory peptides, 141(1-3):44-54. http://www.citeulike.org/user/HEIRS/article/5931401