ACTRIMS/ECTRIMS 2014 – Part 4
Does multiple sclerosis begin in the gut?
Multiple sclerosis is believed to be due to a problem in the immune response, in which activated immune cells (T and B cells) attack the body’s own tissues. One of the key functions of the immune system is to detect “Stranger and Danger” signals from the body’s interactions with the environment. So all of the body’s points of contact with the environment – skin, mouth, nose, etc. – are highly immune active.
This is especially true in the gastrointestinal tract: the esophagus, stomach, small and large intestine. Much of the body’s supply of immune tissue is found there (where it’s called gut-associated lymphoid tissue, or GALT). As in other parts of the body, immune cells sample substances from the environment to identify threats, such as viruses, toxins and the like. What makes the immune system’s job especially difficult is that it’s working in an environment in which normal gut bacteria – needed for digestion and metabolism – outnumber everything else. In fact, the number of bacteria in the GI tract is about 10 times greater than the number of cells in the entire body.
A growing area of research interest is the relationship between the highly immune active environment of the gut and the immune damage caused by MS. For many years, it has been generally assumed that what’s going on in the gut has nothing to do with what’s happening in the central nervous system (CNS). But there’s an accumulating amount of research suggesting that brain and gut are very connected.
One area that is still in its infancy is how the nervous system in the gut (the enteric nervous system, or ENS) communicates with the CNS. One theory is that infections in the gut can travel along nerve fibres to the brain (Deretzi and colleagues. Med Hypotheses 2009;73:781-787), but this area needs to be studied further.
A more developed line of research is how GI bacteria, collectively called the “gut microbiome”, influence the body’s overall immune response. The bacterial population in the gut changes over time as a result of diet, nutritional supplements (e.g. probiotics, yogurt), infections, antibiotics and other factors. Some of these differences may be important. For example, a University of British Columbia study compared the bacterial populations in the guts of children with MS and healthy subjects (Tremlett et al. ECTRIMS 2014; abstract P615). The children with MS were more likely to have disease-causing bacteria in their gut. In part this may be because they were more likely to have been exposed to antibiotics, immunomodulatory drugs and other medications. A second study found differences in the bacterial population – notably fewer anti-inflammatory bacteria – in adults with MS compared to healthy individuals (Gandhi and colleagues. ECTRIMS/ACTRIMS 2014; abstract P616). At the moment these are just observations, and it isn’t clear if a different bacterial population has a significant impact on MS. Nor do these findings suggest that people should take probiotics – there are (theoretical) reasons for and against taking a probiotic for MS, so it’s best to wait for more research to come in.
A new study has suggested a more direct link between changes in the gut bacteria and the autoimmune response in an animal model of MS (Joscelyn & Kasper. Mult Scler 2014; epublished July 28, 2014; Wang and colleagues. ECTRIMS/ACTRIMS 2014; abstract P614). Of particular interest is one type of bacteria (called Bacteroides fragilis), which produces a substance called PSA (polysaccharide A) that promotes an anti-inflammatory effect. In animals fed PSA, T cells became regulatory T cells (Tregs), which act to dampen the autoimmune response (Ochoa-Reparaz et al. Mucosal Immunol 2010;3:487-495).
A new study extended this work from animals to people (Kasper et al. ECTRIMS 2014; abstract P611). Blood cells exposed to PSA also increased their production of Tregs and decreased production of inflammatory substances. This is the first study to show that a substance produced by gut bacteria can contribute to a regulatory T cell response in humans.
This beneficial effect may not be limited to immune cells. Other studies have found that PSA can activate neurons in the ENS (Mao et al. Nat Commun 2013; 4:1465), which may in turn have an impact on the CNS.
One implication of these studies is that altering the diet may shift the bacterial population in the gut, which may result in less CNS inflammation. The proportion of PSA-producing bacteria is higher in people in people who eat a mixed or vegetarian diet, and lower in strict carnivores, but it’s too early to say if cutting down on meat will have any effect on MS.
Another area that needs to be explored further is how gut bacteria interact with genetic factors. For example, when bacteria break down gluten, one of its constituents (gliadin) can resemble tissues in the gut; in genetically-susceptible people (e.g. with celiac disease), gliadin is mistaken for the tissues lining the small intestine so the body initiates an autoimmune attack. MS may act in a similar way, with certain substances promoting inflammation in susceptible people – but the target is tissues in the brain rather than in the gut.
Mount Sinai Hospital in New York and the University of California-San Francisco have now combined forces to form the MS Microbiome Consortium. The group will look more closely at how the gut microbiome is affected by diet and immunomodulatory therapies, and try to determine if gut bacteria can influence the severity and progression of MS (Baranzini et al. ECTRIMS 2014; abstract P618).
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