Multiple Sclerosis: The faeces is out of kilter

30. November 2015

It is still unclear which events lead to MS-genesis. Environmental factors and genetic predisposition do however seem to play a role. The eyes of the researchers are now focused on the intestine: its bacterial community could be acting as an MS trigger.

A study published in PLOS ONE suggests that there are characteristic differences in bacterial colonisation of the gut (microbiota) between individuals with and without MS. In order to carry out their analysis, researchers led by Prof. Masahira Hattori of the University of Tokyo and Dr. Takashi Yamamura of the National Institute of Neuroscience in Tokyo (Japan) examined stool samples from Japanese MS patients and healthy control subjects by looking at ribosomal 16S-rRNA.

The samples differed only slightly with respect to biodiversity; however, the researchers identified 21 bacterial species whose frequency differed between MS patients and healthy volunteers: 2 of them (Streptococcus thermophilus and Eggerthella lenta) occurred more frequently and 19 more infrequently among the MS patients. The under-represented species belong among others to the genera Faecalibacterium. Anaerostipes, Bacteroides. Clostridium and Prevotella.

On the trail of the trigger

The idea that the change in the composition of the intestinal microbiota might be not only a result, but even the cause, of multiple sclerosis is one which Prof. Hartmut Wekerle from the Max Planck Institute of Neurobiology in Munich (Germany) also finds convincing: “The microbiota have crucial significance as a trigger of multiple sclerosis”. Evidence submitted so far has emerged mainly from animal experiments. The best studied MS animal model is the one that exists for experimental autoimmune encephalomyelitis (EAE). EAE mice develop a T-cell mediated autoimmune disease characterised by demyelination. One way to make the mice sick is to inject them with myelin antigens (induced EAE). If one kills a large portion of the colon microbiota through antibiotic treatment, the animals are more resistant to an induced EAE disease.

Another possible way of inducing EAE is achieved through genetic manipulation, in which the animals carry transgenes that cause their immune system to express an abnormally high proportion of autoimmune T-cells. Among these animals, the probability of spontaneously developing EAE is dependent [Paywall] on the hygiene conditions of the animals’ environment: the cleaner the mice are maintained, the lower the frequency at which the EAE appears in the population. Completely aseptic transgenic mice [Paywall] are protected against EAE, but fall ill once they are exposed to normal intestinal flora. “Obviously in this model the autoimmune response to the tissue of the central nervous system is controlled remotely by the colon microbiota”, Prof. Wekerle explains.

Good germ or bad germ? A question of context

Intestinal microbiota and immune system influence each other in many ways, at the local as well as at the systemic level. Microbial products constantly manage to get into the bloodstream by diffusion and can thus modulate the immune response in the periphery. This explains why a broad-spectrum antibiotic therapy, for example, leads to a dampening of B- and T-cell activity. The colon microbiota is thus beneficial to health as a teacher and sparring partner for the immune system, but the benefit of having this colon dweller carries its price: for instance, the risk of cross-reactivity between commensal and pathogenic bacteria and with the body’s own structures does exist.

Since the microorganisms of the gut and the immune system are so closely interwoven, this raises the question of what role food plays in this process. The “Western” diet seen in industrialised countries is typically characterised by its lack of fibre in the form of complex plant polysaccharides. This has fatal consequences for the immune system, because under normal conditions the fermentation of fibre by intestinal bacteria produces large amounts of short chain fatty acids such as butyrate, which have in turn anti-inflammatory and immunosuppressive properties [Paywall]. Among people with a predisposition to autoimmunity, under such conditions the basal inflammatory effect of certain commensal bacteria could therefore already be sufficient to allow the immune system to get out of control.

In addition, food has a great influence on the composition of the intestinal microbiota. A dysbiosis induced as such, for example, would be able to reduce the amounts of bacterial immunoregulatory molecules in the gut. Studies have actually shown that polysaccharide A (PSA) formed from the commensal gut bacteria Bacteroides fragilis can induce the activation and proliferation of immune cells, and that PSA treatment leads to prophylactic and therapeutic effects in the MS mouse model. Moreover, it was able to be demonstrated [Paywall] that PSA intestinal afferent neurons of the enteric nervous system activate our “second brain”. This shows that there is a close link between microbiota, intestines and the nervous system.

Sauerkraut instead of syringe?

In many industrialised countries it is known that the incidence rate of multiple sclerosis has been increasing for many decades: In Norway it has more than quadrupled since 1953; the same increase was noted in Japan [Paywall] within just 30 years. The cause was previously only able to be discussed speculatively; alongside improved diagnosis and an increased awareness of the disease, environmental factors such as sun exposure and a related Vitamin D deficiency were also discussed as causes.

The discovery that altered bowel microbiota could be playing a role, potentially through a more urban lifestyle involving a modified diet, is a relatively new discovery. What are the new treatment options arising from this though? On the one hand direct intervention through diet is a conceivable option. The Italian researchers Paolo Riccio and Rocco Rossano recommend therefore that patients with multiple sclerosis have a high-fibre diet that is low in proinflammatory food constituents such as saturated animal fats, trans fats, red meat, sugar and salt. It is also conceivable that action via prebiotics and probiotics, or antibiotics, directed at the composition of the intestinal flora, is an option, the aim being to influence the functions of the microbiota over a targeted pathway.

So-called stool transplantation is one more radical alternative. The therapeutic benefits of this method have been proven when dealing with intestinal conditions such as those involving Clostridium difficile; no doubt such treatment might prove to be useful when dealing with autoimmune diseases such as MS as well. While there are indeed no systematic studies on this subject, in at least three cases involving MS patients who due to constipation had undergone a stool transplant there was a permanent improvement in their MS symptoms. It might be worthwhile therefore to explore this therapeutic approach further. It might probably be some time though before research delivers new therapies with proven efficacy and safety.

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