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Gut Bacteria May Impact Multiple Sclerosis Progression

NEW YORK (GenomeWeb) – A pair of newly published studies has established a potential role for specific gut bacteria in the progression of multiple sclerosis (MS), suggesting therapeutic targeting of the microbiota as a potential treatment for the disease.

MS is an autoimmune neurodegenerative disorder that leads to progressive loss of vision, weakness, tremors, and problems with balance and coordination. Severe cases can cause paralysis. The disease occurs when the immune system attacks the body's myelin that wraps around nerve cells. While researchers have learned much about MS over the past decades, they are still struggling to identify why a patient's immune system actually assails the body's myelin.

In one new study, published yesterday in Proceedings of the National Academy of Sciences, a team led by University of California, San Francisco researchers discovered specific gut microbes connected to MS in patients, demonstrating that these microbes engage in regulating immune responses in mouse disease models and suggesting that the microbes play a role in the neurodegeneration inherent in MS.

In the study, UCSF postdoctoral researcher Egle Cekanaviciute (now a biologist at the NASA Ames Research Center) and her collaborators sequenced the gut microbiome of 71 MS patients as well as 71 healthy control subjects. They identified distinct species of bacteria that were in higher concentrations in people with MS than in the general population. The team then shifted to the much more challenging task of investigating how these differences in gut bacteria could influence the immune system's attack on myelin in MS.

The UCSF-based team first examined whether components of these bacteria could regulate T lymphocyte-mediated adaptive immune responses. The researchers initially exposed human immune cells in laboratory dishes to the bacterial extracts, and found that Akkermansia muciniphila and Acinetobacter calcoaceticus, two species that were more common in people with MS, triggered the cells to become pro-inflammatory. Parabacteroides distasonis, a bacteria found at lower than usual levels in MS patients, triggered an immune-regulatory response as well.   

To understand how these bacteria might alter the immune system as a whole, the researchers introduced each of the three species into mice that lacked a microbiome and discovered that the bacteria had a similar effect: A. muciniphila and A. calcoaceticus exacerbated inflammatory immune responses, while P. distasonis mitigated inflammation.

The experiments, however, only examined the impact of a single bacterial species at a time. The researchers still wondered how the complex microbial ecosystems of MS patients could impact neurodegeneration. The team decided to perform fecal transplants on mice with an experimentally induced form of MS. They discovered that swapping the mice's microbiomes with those of MS patients caused the animals to lose key immune-regulatory cells and instead develop more severe neurodegeneration, indicating that the microbiome alone could affect the progression of MS.   

In another study published in the same issue of PNAS, a team led by researchers from the Max Planck Institute of Neurobiology with contributions from Cekanaviciute and UCSF colleague Sergio Baranzini compared the gut microbiota of 34 monozygotic twin pairs discordant for MS. While they found no major differences in the overall human microbial composition, the researchers saw a significant increase in bacteria such as A. muciniphila.

When the researchers transferred human-derived microbiota into transgenic mice expressing a myelin autoantigen-specific T-cell receptor, they found that microbiome fecal transplants could exacerbate MS symptoms. The data suggests that MS-derived microbiota potentially contain factors that precipitate an MS-like autoimmune disease in mice, and more importantly, in humans.

"Two different groups, using two separate cohorts of patients and controls, and two distinct mouse models of the disease, saw very similar results," Cekanaviciute said in a statement.

The recent findings indicate that the microbiome may play a crucial role in MS's origin. The authors believe future research will center on figuring out how the bacteria influence the development and progression of MS.

For example, the researchers found that at least one MS-associated bacteria could confuse the immune system into attacking myelin as well as the bacteria. Researchers also noted that P. distasonis may help the immune system learn to control its response to non-threatening microbes. Lacking this bacteria might encourage the immune system to overreact to harmless microbes in people with MS, causing harmful inflammation.  

"To be clear, we don't think the microbiome is the only trigger of MS," added Cekanaviciute. "But it looks like these microbes could be making the disease progression worse or better — pushing someone with genetic predisposition across the threshhold into disease or keeping them safe."

The authors believe that the study's results may eventually provide a basis for the development of microbiome-based therapeutics in autoimmune diseases, and novel therapies for patients with MS.

"The microbiome is very malleable… you could relatively easily change it in an adult who has MS or is susceptible — something you cannot do with genetics," Baranzini said in a statement.