Monday, December 5, 2011

Commensal Microorganisms in the Gut: Friend or Foe?

Before we leave a public bathroom, how many times do we see or hear the phrase, “Did you wash your hands?” Chances are, we have seen or heard this plenty of times. As children, we were often reminded by our parents to wash our hands before and after eating, after handling dirty items, or after going to the bathroom. The obvious reason is to eliminate the germs that we have come into contact with throughout the day. However, as we all know, bacteria are not entirely harmful to our well-being. In fact, some bacteria in our gut function to keep us healthy. They help digest food, aid us in acquiring vitamins and nutrients, train our immune system, and compete with pathogenic bacteria that may otherwise be harmful to us. As such, they are called commensal microorganisms. Certain diseases caused by pathogenic bacteria are treated by a process called fecal matter transplant. This medical procedure involves the introduction of the normal gut flora obtained from the stool of a healthy donor in order to restore the gut microbiota of the infected individual. The concept behind this procedure is that the commensal microorganisms obtained from the stool will eventually outcompete the pathogenic bacteria responsible for the disease. For example, Pseudomembranous colitis, which is caused by Clostridium difficile, uses fecal matter transplant as one feasible treatment option. In the process, non-pathogenic bacteria are introduced into the colon of the patient in order to outcompete C. difficile for resources. However, is the commensal microbiota as beneficial as it is portrayed? Studies aimed towards understanding the pathology of multiple sclerosis (MS) would beg to differ.

MS is an autoimmune disorder of the central nervous system (CNS) where the myelin sheath, which wraps around the axon and facilitates the conduction of nerve signaling, is attacked by the immune system. The resulting demyelination causes signals between neurons to be delayed and this consequence is manifested through clinical symptoms that include numbness, motor dysfunction, and vision problems. In terms of the immune response, MS is mostly associated with increased CD4+ T cell infiltration into the CNS. This T cell infiltration is also accompanied by increased production of autoantibodies by B cells, which can attack the specific myelin proteins that make up the myelin sheaths. Several studies are aimed towards understanding what goes awry in MS, however, numerous questions remain unanswered regarding this disorder. Microbial infection has been attributed to this autoimmune disorder (Ascherio et al. 2007). As mentioned earlier, the commensal microbiota has been linked to the treatment of certain diseases by outcompeting pathogenic microorganisms. Therefore, could the microbiota also play a role in treating MS? A recent study shows that in the case of MS, commensal microbiota triggered autoimmune demyelination instead of alleviating MS symptoms.

In a study by Berer et al. (2011), researchers discovered that the process of demyelination could not happen without the help of certain bacteria that exist in the gut. The authors used a murine model of MS called experimental autoimmune encephalomyelitis (EAE) in order to study the role of the commensal microbiota in the development of EAE. Specifically, the authors used the relapse-remitting (RR) EAE model, which mimics the relapse-remitting phase observed in the early stages of the human form of MS. The relapse-remitting phase is characterized by the tendency of the MS patient to undergo cycles of improvement and deterioration as the disease progresses. The RR-EAE model uses a specific strain of mice called SJL/J, which have transgenic T-cell receptors that can recognize the myelin oligodendrocyte glycoprotein (MOG) peptide 92-106 (one of the myelin proteins that make up the myelin sheaths) presented by MHC II molecules. These mice were housed under specific pathogen-free (SPF) conditions, in which the mice were guaranteed to lack specific pathogens. As stated earlier, the mice that were used in this study harbor transgenic T cell receptors specific for the MOG peptide 92-106. Past studies have shown that these animals spontaneously develop EAE throughout their lifespan (Pollinger et al. 2009). To determine whether the commensal microbiota plays a role in the spontaneous development of EAE, the authors first examined whether there is a difference in the incidence of spontaneous EAE between mice that were housed under SPF conditions and those that were housed under germ-free conditions. Results show that most of the SPF mice acquired EAE within 3-8 months, however, germ-free mice remained protected from EAE throughout their lifespan. Colonizing the germ-free mice with the conventional flora obtained from the SPF mice caused the germ free mice to develop spontaneous EAE. The authors then examined whether the levels of CD4+ T cells, which are the primary T cells that drive this autoimmune disease, were different between the germ-free mice and SPF mice. They found that the levels of Th17 cells, a type of CD4+ T cells, were markedly decreased in germ-free mice compared to that in SPF mice. In agreement with this finding, there were lower levels of IL-17, a cytokine produced by Th17, in germ-free mice compared to SPF mice. However, when the authors recolonized the germ-free mice, they observed that IL-17 was restored to normal levels, suggesting that the microbiota that was introduced into these mice played a role in triggering the production of IL-17. Supporting this theory, the authors also found that the microbial signals in the SPF mice appear to influence local T cells. When the authors treated the mice with antibiotics in order to temporarily eliminate the gut flora, T cell proliferation decreased in the lamina propia, suggesting that the gut microbiota modulates T cell proliferation.
As mentioned earlier, in addition to autoreactive T cells, B cells are also needed in order to elicit the full autoimmune response found in MS. The authors found that germ-free mice did not have activated autoimmune T cells, possibly due to a lack of microbial stimuli. The lack of activated autoimmune T cells was accompanied by a decrease in anti-MOG autoantibody produced by B cells. This was expected considering that B cells need help from the activated T helper cells in order for the B cells to migrate to the germinal center, become activated, and start secreting antibodies. Furthermore, the authors found that autoantibody production depended on the presence of the target myelin autoantigen, MOG. RR mice that lacked the ability to express MOG did not produce anti-MOG autoantibodies despite the fact that their gut microbiota was normal, suggesting that both the commensal microbiota and the MOG antigen are needed in order to elicit the immune response.
The findings of this research have several implications in the pathogenesis of MS. It has been highly debated whether MS originates from changes in the CNS or whether it originates from changes in the immune system. This research supports the latter hypothesis and several studies agree with this concept as well. For instance, other inflammatory diseases, such as rheumatoid arthritis, appear to be modulated by the gut environment. Diet can also modulate the gut microbiota composition. For instance, in a study by Wu et al. 2011, examination of fecal sample from 98 individuals reveal an association between the existence of certain types of bacteria and diet. In a controlled-feeding study, they also revealed that there was a corresponding change in the gut microbiota composition with changes in the diet. Dietary risk factors have also been contributed to the incidence of MS. In a study of the incidence rates of MS in Norway, researchers found there was a lower MS prevalence rate in the northern part of the country compared to the southern part of the country. This difference corresponded with fish and seafood consumption, which may offer protective roles against MS (Swank et al. 1952). The pathogenesis of MS has yet to be fully elucidated although this research serves a step towards understanding this disease. Although the authors utilized an in vivo model to support their claim, an in vitro experiment would serve to further strengthen their claim. Furthermore, in stating that the mice were raised in specific pathogen free conditions, the authors did not specify which pathogens were lacking in these mice. The next step in this research is determining which gut bacteria is specifically responsible for triggering the autoimmune demyelination observed in these mice.
Works Cited
Ascherio, A., and K. L. Munger. "Environmental Risk Factors for Multiple Sclerosis. Part I: The Role of Infection." Annals of Neurology 61.4 (2007): 288-99. Print.
Berer, K., et al. "Commensal Microbiota and Myelin Autoantigen Cooperate to Trigger Autoimmune Demyelination." Nature 479.7374 (2011): 538-41. Print.
Knip, M., et al. "Dietary Intervention in Infancy and Later Signs of Beta-Cell Autoimmunity." The New England journal of medicine 363.20 (2010): 1900-8. Print.
Lauer, K. "Environmental Risk Factors in Multiple Sclerosis." Expert review of neurotherapeutics 10.3 (2010): 421-40. Print.
Pollinger, B., et al. "Spontaneous Relapsing-Remitting EAE in the SJL/J Mouse: MOG-Reactive Transgenic T Cells Recruit Endogenous MOG-Specific B Cells." The Journal of experimental medicine 206.6 (2009): 1303-16. Print.
Swank R, Lerstad O, Strøm A, Backer J. “Multiple sclerosis in rural Norway. Its
geographic and occupational incidence in relation to nutrition.” N. Engl. J. Med. 246, 721-728 (1952).
Vaahtovuo, J., et al. "Fecal Microbiota in Early Rheumatoid Arthritis." The Journal of rheumatology 35.8 (2008): 1500-5. Print.
Wu, G. D., et al. "Linking Long-Term Dietary Patterns with Gut Microbial Enterotypes." Science (New York, N.Y.) 334.6052 (2011): 105-8. Print.

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