ST. LOUIS ― Patients with multiple sclerosis (MS) who take the disease-modifying treatment (DMT) ocrelizumab (Ocrevus, Genentech/Roche) exhibit intriguing changes in gut bacteria, according to new research.

These preliminary findings from an ongoing study funded by the National Institute of Neurological Disorders and Stroke add to mounting evidence of a critical relationship between the gut microbiome and MS, the researchers note.

The data also suggest that "changes in the gut microbiota may comprise part of the mechanism of action for a variety of MS disease-modifying therapies, including ocrelizumab," said lead author Erin Longbrake, MD, PhD, Yale University, New Haven, Connecticut. Longbrake has consulted or done scientific advisory board work for Biogen, Genzyme, EMD Serono, Alexion, and Celegene.

"Identifying how the gut microbiota change could ultimately lead to interventions targeted towards correcting specific pathologic changes in the gut microbes," she told Medscape Medical News.

The findings were presented here at ANA 2019: 144th Annual Meeting of the American Neurological Association.

Depleting B Cells

DMTs such as ocrelizumab tackle MS by depleting B cells. But with little understanding of the mechanisms behind those effects, the possible role of gut bacteria and their metabolites ― known regulators of the immune response system ― has grabbed focus.

"We hypothesized that ocrelizumab, a B-cell depleting monoclonal antibody used to treat MS, would normalize the phenotype and metabolic profiles of gut bacteria, promoting an anti-inflammatory immune milieu," the investigators explain.

In the ongoing study, they are enrolling patients with new-onset MS and are evaluating longitudinal samples of paired blood and stool with advanced techniques. These include IgA-Seq, a novel tool that allows the differentiation of immune-reactive (IgA-coated) bacteria from those not eliciting an immune response (IgA-uncoated).

Here at the ANA meeting, Longbrake reported on the first results, in which eight patients with MS were compared with five participants who acted as a matched control group.

Results showed a "normalizing" of certain components of the fecal microbiome in the MS group at 1 month post ocrelizumab treatment compared with baseline measures.

Multiple members of the MS group had very high IgA-coating indices for selected bacteria in the butyrate-producing Lachnospiraceae family at baseline. Following ocrelizumab treatment, the patients showed a reduction in the IgA coating index for these butyrate producers.

In addition, butyrate was significantly decreased at baseline in the MS group compared with the healthy control group (P = .045). However, the difference in butyrate levels was lost following treatment (P = .106). No differences were observed in acetate and propionate values.

"Our data suggest that a subset of butyrate-producing gut bacteria is recognized as pathogenic by the immune system of untreated MS patients, based on high levels of IgA coating," the investigators note.

"This phenomenon could impact the amount of butyrate produced and affect the differentiation of circulating immune cells," they add.

Future Targeted Treatment?

The reduction of the IgA coating index of butyrate-producing bacteria as a result of ocrelizumab treatment could play an important role in the efficacy of B-cell depletion in MS, Longbrake pointed out. "Bringing in more patients is certainly key to confirming the findings," she said.

However, "our most interesting observation was that certain bacterial species were highly IgA coated, [indicative of] being recognized by the native immune system as pathologic in a proportion of the MS patients but not in the healthy individuals," she told Medscape Medical News. "The proportion of IgA-coated cells then decreased after patients had been treated with ocrelizumab."

Notably, the study is the first to report utilization of IgA-Seq in patients with MS; it will benefit from a population of other patients with MS and similar characteristics, Longbrake added.

"Prior studies of adult MS patients have been very heterogeneous in their population composition, including all ages or varying times since diagnosis. Our study will be among the first to really focus on a very clean, clinically homogeneous population of individuals with MS at the time of their diagnosis," she said.

Improved understanding of how these drugs work "will eventually allow us to use them in a targeted, personalized fashion," Longbrake said.

She added that the implications of such research could go beyond understanding drugs' effects and offer broader insights into other ways in which gut microbiota influence MS.

"Changes in the gut microbiota could provide a mechanism by which known environmental risk factors for MS, such as vitamin D deficiency or smoking, cause the immune changes leading to MS," she said.

In the meantime, the investigators plan to expand the analysis to include long-amplicon sequencing, which would allow species-level detection of organisms, and metabolomic analysis.

"I expect that we may see additional detectable differences with use of these analytic techniques," Longbrake said.

Diet Makes a Difference

"The study's results are intriguing, but the sample size is small, so it is difficult to make conclusions," Robert Paul Friedland, MD, chair of neurology at the University of Louisville, Kentucky, told Medscape Medical News when asked for comment.

"The work suggests that microbiota influence MS, which supports other studies showing an involvement of gut bacteria in the disease," he said. Friedland was not involved with the current research and reports no relevant financial relationships.

He added that when it comes to efforts to regulate gut bacteria, diet can always make a difference.

"It should be pointed out that persons can increase their production of short-chain fatty acids by gut bacteria by changing their diet and increasing consumption of fiber-containing fruits and vegetables," Friedland noted.

Ilana Katz Sand, MD, an assistant professor of neurology at the Icahn School of Medicine at Mount Sinai and associate medical director at the Corinne Goldsmith Dickinson Center for MS, the Mount Sinai Hospital, in New York City, agreed that, though small, the study holds important insights.

"This study adds to the growing body of work suggesting a link between gut microbiota and MS," she told Medscape Medical News.

"This is the first longitudinal study evaluating the impact of B-cell therapy on gut microbial composition in MS. The sample size is very small; however, these preliminary results allow for the generation of hypotheses for future study."

The enrollment of primarily treatment-naive participants early in the disease course is important, she noted.

"This certainly helps reduce noise in the data set created by prior treatments and the disease course itself," Katz-Sand said.

A caveat of the study was the inclusion of several patients undergoing treatment with steroids, which are known to have broad systemic effects, including known effects on gut microbiota, she added.

"Enrolling participants who have recently received steroids does not allow isolation of the effects of ocrelizumab vs steroids," Katz-Sand explained.

"This is a challenge, as many MS patients who are newly diagnosed are going to have had recent steroid exposure. It will likely be helpful to repeat the stool collection several months down the line," she said.

With respect to the broader chicken-and-egg issue of gut dysbiosis having a causative role in disease or vice versa, Katz-Sand noted that "we do not know the answer to this, and the relationship is probably bidirectional.

"That is, we hypothesize that unfavorable differences in gut microbiota contribute to a break in tolerance and promote the development of autoimmunity," she said. "However, once the disease starts and there is systemic inflammation, that likely has an impact on the gut microbial profile as well."

ANA 2019: 144th Annual Meeting of the American Neurological Association: Abstract M325, presented October 14, 2019.

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