Researchers find new way to protect against disease in MS model

By Sally Robertson, B.Sc.Nov 26 2019

Researchers at Brigham and Women's Hospital have found a new and unexpected way of preventing disease in a preclinical model of multiple sclerosis (MS).

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The team discovered that treating susceptible mice with a synthetic version of a microRNA that increases during peak disease altered the microbiome in such a way that prevented disease.

While clinical trials testing the safety and efficacy of the approach in humans will be needed before the results can be translated into a therapy for patients, the researchers say their findings are both exciting and unexpected.

"It's unexpected and perhaps counter-intuitive that something we find in the microbiome during peak disease could provide protection," says senior author Shirong Liu… "But we hypothesize that the effects we're seeing represent a protective mechanism."

The team investigated how an altered gut microbiome influences the course of MS

Senior author Howard Weiner says the gut microbiome is known to play an important role in disease, and the team was curious to see how altered gut microbiome affects the course of MS.

As reported in the journal Cell Host & Microbe, Weiner, Liu and colleagues studied the gut microbiome and microRNAs present in an experimental autoimmune encephalomyelitis (EAE) mouse model of MS.

To their surprise, they found that transferring fecal matter from EAE mice that were at peak disease, provided protection against disease in mice that received the transfer. They also discovered that it was not live bacteria, but rather a specific microRNA called miR30d that was responsible for this protection.

The team also found that miR30d was increased in untreated patients with relapsing-remitting MS.

Investigating the effects of a synthetic form of the microRNA

To investigate the potential therapeutic effects of the microRNA, the researchers made a synthetic form of miR30d and administered it orally to mice. They found that giving the mice this synthetic version also protected against disease.

Next, the researchers examined the microbiome to find out which components were changing in response to miR30d. They found that a specific bacterium called Akkermansia muciniphila, which has previously been reported to have anti-inflammatory properties, was growing and flourishing in the animals' guts.

The researchers then investigated the effect that miR30d and A. muciniphila had on immune cells called regulatory T cells (Tregs). They found that once miR30d allowed A. muciniphila to expand in the gut, the number of Tregs also increased, which helped to suppress symptoms in the mice.

The findings "may have applicability for MS and many other diseases"

"We've discovered a new mechanism to regulate the microbiome and treat human disease that hadn't been known before," says Weiner. "The gut microbiome is known to play an important role in MS and other diseases. Our findings, which show that a microRNA can be used to target and influence the microbiome with precision, may have applicability for MS and many other diseases, including diabetes, ALS, obesity, and cancer."

Liu says that although it seems counter-intuitive that a component found in the microbiome during peak disease could resolve disease, the team thinks the effects they observed represent a protective mechanism: "Most patients with relapsing-remitting MS spontaneously recover from acute attacks. What we've found here may be a part of that recovery rather than a reflection of disease progression."

The team acknowledges that their work so far is only preclinical research and that their approach will need testing in human clinical trials before it can be translated into a therapy for patients, but the researchers are optimistic and are now taking the next steps to bring their research closer to having a clinical impact.

A major question in the field today is how to modulate the microbiome with specificity. We find that microRNAs may hold the answer"

Senior author Howard Weiner