Gut microbiome associated with multiple sclerosis risk and disease development

Gut microbiome associated with multiple sclerosis risk and disease development

An international research consortium led by scientists at UC San Francisco has demonstrated significant differences between the gut bacterial profiles of patients with multiple sclerosis (MS) and healthy individuals, and between MS patients receiving different drug treatments. While some of these changes have been reported previously, most are being reported for the first time. The group also uncovered new mechanisms by which these bacteria may influence disease development and response to treatment.

In recent years, scientists have increasingly made links between gut bacteria and a range of diseases - not just diseases of the gut - including diabetes and arthritis. The field of microbiome studies really opened up with advances in DNA sequencing in the early 2010s, which allowed scientists to get a detailed picture of what bacteria are present in samples of stool, blood, mucosal tissue and skin.

Until recently, most experimental evidence linking gut bacteria and MS came from research on mice. Human studies had produced conflicting results - partly due to smaller numbers of participants and a failure to examine the effects of the environment on a person's microbiome. Where you live – in the country or in the city, on a mountaintop or next to an oil refinery – plays a big role in the bacteria our bodies harbor.

To overcome these limitations, the consortium of scientists participating in the International Multiple Sclerosis Microbiome Study (IMSMS) recruited large numbers of MS patients from three continents and selected genetically unrelated controls from the same households as the patients. It was the first time this methodology was used in such a large study. The study, published September 15, 2022 in Cell, describes differences between the gut microbiome profiles of 576 patients and an equal number of household controls in the United States, the United Kingdom, Spain and Argentina. The findings could lead to new therapeutics involving either manipulation of the microbiome or dietary interventions.

This is the reference study that will be used by the industry in the coming years.”

Sergio Baranzini, PhD, Heidrich Family and Friends Endowed Chair in Neurology and member of the UCSF Weill Institute for Neurosciences

Sergio Baranzini is the lead author of the new study.

Using their innovative protocol, Baranzini and his colleagues were able to identify dozens of new bacterial species associated with MS and confirm other species previously only associated with the disease. “We were surprised by the number of species that were differentially present in MS compared to controls,” Baranzini said. They also found that the greatest source of variation in bacterial species was related to the participants' geographic location, confirming the importance of location and local variations in diet to the gut microbiome. The second largest source of variation was a participant's disease status, which the researchers expected.

The study was the second in a series conducted by iMSMS, an international consortium founded in 2015 to determine the role of gut bacteria in MS susceptibility, progression and response to therapy. The first study validated the household control protocol and demonstrated that it increases statistical power in population-based microbiome studies.

The results of the study are primarily descriptive, admits Baranzini. “When you look at the microbiome, there are two questions that are typically asked,” he said. "The first is 'Who is there?' That's what we're trying to answer in this article. The second is 'What are they doing?'"

Answering the second question requires mechanistic studies with individual bacteria to understand their metabolic profiles. Still, the researchers got some clues about what the bacteria they found do by examining the potential pathways these bacteria encode.

“If we know which genes of which type we can identify in cases and controls, we can now begin to reconstruct which potential signaling pathways are active in patients and controls,” said Baranzini.

For example, some of the bacteria the team has linked to MS appear to play a role in helping people process fiber from plants, the byproducts of which tend to be found at elevated levels in MS patients. Other species appear to have an impact on inflammation and the cell's energy production machinery.

Researchers also found that patients treated with an immunomodulator known as interferon beta-1a, the oldest treatment for MS, had lower levels of short-chain fatty acids in their stool and higher levels in their blood. Short-chain fatty acids are known for their anti-inflammatory properties, suggesting that interferon works by increasing the transport of these molecules from the gut into the bloodstream, which Baranzini says may be one of interferon's mechanisms of action.

The iMSMS group will continue to recruit patients and expand into Germany and Canada until the total number of participants in the cohort reaches 2000. Starting this fall, she will also follow a subset of patients over two years to see how their gut microbiota changes in response to treatment, lifestyle changes and disease progression. All data from these studies will be publicly available.

“This is an example of how great science can only be achieved together,” he added. “In iMSMS we have truly brought together the best and brightest researchers in microbiome research and multiple sclerosis, and they are all pulling together.”

Source:

University of California – San Francisco

Reference:

iMSMS Consortium., (2022) Gut microbiome of multiple sclerosis patients and paired healthy household controls reveal associations with disease risk and progression. Cell. doi.org/10.1016/j.cell.2022.08.021.

.