An international research consortium led by scientists at UC San Francisco has shown significant differences between the gut bacteria profiles of patients with multiple sclerosis (MS) and healthy individuals, as well as between patients with of MS receiving different drug treatments. While some of these changes have been reported before, most are being reported for the first time. The group also discovered new mechanisms by which these bacteria can potentially influence disease development and response to treatment.
In recent years, scientists have increasingly linked gut bacteria to a number of diseases, not just bowel disease, including diabetes and arthritis. The field of microbiome studies really opened up with advances in DNA sequencing in the early 2010s that allowed scientists to get a detailed picture of the bacteria present in stool, blood, mucous and skin tissues.
Until recently, most of the experimental evidence suggesting a link between gut bacteria and MS came from research on mice. Studies in humans had offered inconsistent results, in part due to the smaller number of participants and the inability to rule out the effects of the environment on an individual’s microbiome. Where we live – rural or urban, on a mountaintop or next to an oil refinery – plays a big role in the bacteria our bodies harbor.
To circumvent these limitations, the consortium of scientists participating in the International Multiple Sclerosis Microbiome Study (IMSMS) recruited a large number of MS patients from three continents and selected genetically unrelated controls from the same households than patients. It was the first time that this methodology had been used in such a large study. The study, which was published in Cell on September 15, 2022, describes differences between the gut microbiome profiles of 576 patients and an equal number of home controls in the US, UK, Spain and Argentina. The findings could lead to new therapies involving either manipulation of the microbiome or dietary interventions.
This is the benchmark study that will be used by the estate for years to come.”
Sergio Baranzini, PhD, Heidrich Family and Friends Endowed Chair in Neurology and Fellow 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 species of bacteria 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 geographical location of the participants, confirming the importance of location and local variations in diet for the gut microbiome. The second biggest source of variation was a participant’s health status, which the researchers expected.
The study was the second in a series conducted by iMSMS, an international consortium established in 2015 to determine the role of gut bacteria in MS susceptibility, progression and response to treatment. The first study validated the household control protocol, showing that it increases statistical power in population-based microbiome studies.
The results of the study are primarily descriptive, acknowledges Baranzini. “When you look at the microbiome, there are two questions that are usually asked,” he said. “The first is ‘Who’s 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 are doing by studying the potential pathways these bacteria encode.
“Knowing which genes of which species we are able to identify in cases and controls, we can now begin to reconstruct which potential pathways are active in patients and controls,” Baranzini said.
For example, some of the bacteria the team found associated with MS appear to play a role in helping humans process plant fibers, the byproducts of which tend to be found in increased concentrations in MS patients. SEP. Other species appear to influence inflammation and the cell’s energy-producing machinery.
The researchers also found that patients treated with an immunomodulator known as interferon beta-1a, the oldest treatment for MS, had lower concentrations of short-chain fatty acids in their stools and higher 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 to the bloodstream, which Baranzini suggests could be one mechanisms of action of interferon.
The iMSMS group will continue to recruit patients, expanding to Germany and Canada, until the total number of cohort participants reaches 2,000. Starting this fall, they 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.
“It’s an example of how great science can only be achieved in collaboration,” he added. “In the iMSMS, we’ve really brought together the best and the brightest researchers in the field of microbiome research and in multiple sclerosis, and they’re all pulling towards the same goal.”
University of California – San Francisco
iMSMS Consortium., (2022) Gut microbiome of multiple sclerosis patients and matched healthy controls reveal associations with disease risk and course. Cell. doi.org/10.1016/j.cell.2022.08.021.