The multiple sclerosis microbiome?

Humans comprise of trillions of microbes; >90% reside in our guts. The cost of sequencing microbial genes has greatly diminished, facilitating interrogation of the gut microbiota. Gut-brain communications likely involve the immune system (1,2); of particular relevance in multiple sclerosis (MS). MS is an inflammatory and neurodegenerative immune-mediated disease, often impacting young adults, with many unmet needs. The exact cause(s) are unknown, current drugs are modestly effective, not without risk, and are not indicated for all. Further, there are few good measures or biomarkers of disease activity.

Jangi and colleagues (3) sequenced stool samples (16S rRNA) from 60 relapsing-remitting MS cases attending a Boston hospital clinic and 43 controls from a genetics-related study. While global measures of gut diversity (alpha, beta) were similar between groups, taxa-level (Genera) findings differed. The MS cases exhibited higher abundances of Methanobrevibacter (Archaea) and Akkermansia and lower Butyricimonas (P<0.05, false discovery rate threshold was 0.1). However, the cases had longstanding MS (average disease duration =12.8 years), were older than controls (by >7 years) and included more men (32% vs. 14%, respectively). Despite these differences, some findings may be informative while others may be a consequence of physiological changes related to MS. For instance, the methane producing Methanobrevibacter are associated with constipation and irritable bowel syndrome (4), and may indicate underlying bowel dysfunction which is common in MS (5). Future studies could assess gut transit times to help tease out the direction of this relationship. Over half the cases were also exposed to an MS immunomodulatory drug (>6 months), and compared to the non-exposed had higher Prevotella and Sutterella and decreased Sarcina (P<0.05, false discovery rate threshold was 0.1). A potential disruption in the microbiota-host immune balance was also observed. Immune-related gene expression in peripheral blood was assessed in a subset of 18 cases and 18 controls with particularly high or low Methanobrevibacter. Differences were observed between the relative abundances of these Archaea (and two other genera—Akkermansia and Butyricimonas), with the direction and strength of association (correlation) differing between cases and controls and by MS immunomodulatory drug exposure.

Jangi et al. also found higher levels of methane in the breath of 41 different MS cases relative to 32 controls, concurring with the earlier Methanobrevibacter findings. While of interest, it does not tease out consequence from causality.

In conclusion, these findings, combined with others (3,6-11), suggest subtle, rather than large differences in the MS gut microbiota composition. Similar modest differences, are reported in other autoimmune disease and are suggestive of ongoing inflammation (12,13). Further, gut microbiota composition has also been associated with relapse risk in paediatric MS (11). Larger, longitudinal studies are needed to better understand potential confounders, from comorbidity to concomitant medications. Whether observed changes pre-date MS or are a consequence of MS, its treatment or related comorbidities remains unknown. While the potential for harnessing the gut microbiota to improve outcomes in MS, or use as a biomarker of disease activity have yet to be realized, important first steps have been made to characterize the MS microbiome. Further work is needed to clarify the causality of such findings.

Acknowledgements

None.

Footnote

Conflicts of Interest: H Tremlett (none in relation to this work) is the Canada Research Chair for Neuroepidemiology and Multiple Sclerosis. She currently receives research support from the National Multiple Sclerosis Society, the Canadian Institutes of Health Research, the Multiple Sclerosis Society of Canada and the Multiple Sclerosis Scientific Research Foundation. In addition, in the last five years she has received research support from the Multiple Sclerosis Society of Canada (Don Paty Career Development Award); the Michael Smith Foundation for Health Research (Scholar Award) and the UK MS Trust; speaker honoraria and/or travel expenses to attend conferences from the Consortium of MS Centres [2013], the National MS Society (2012, 2014, 2016), Teva Pharmaceuticals [2011], ECTRIMS (2011, 2012, 2013, 2014, 2015, 2016), UK MS Trust [2011], the Chesapeake Health Education Program, US Veterans Affairs [2012], Novartis Canada [2012], Biogen Idec [2014], American Academy of Neurology (2013, 2014, 2015, 2016). All speaker honoraria are either declined or donated to an MS charity or to an unrestricted grant for use by her research group. E Waubant has no conflicts of interest to declare.

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