The Role of the Gut Microbiome in Multiple Sclerosis Risk and Progression: Towards Characterization of the "MS Microbiome"

Abstract

Multiple sclerosis (MS) is the prototypic complex disease, in which both genes and the environment contribute to its pathogenesis. To date, > 200 independent loci across the genome have been associated with MS risk. However, these only explain a fraction of the total phenotypic variance, suggesting the possible presence of additional genetic factors, and, most likely, also environmental factors. New DNA sequencing technologies have enabled the sequencing of all kinds of microorganisms, including those living in and around humans (i.e., microbiomes). The study of bacterial populations inhabiting the gut is of particular interest in autoimmune diseases owing to their key role in shaping immune responses. In this review, we address the potential crosstalk between B cells and the gut microbiota, a relevant scenario in light of recently approved anti-B-cell therapies for MS. In addition, we review recent efforts to characterize the gut microbiome in patients with MS and discuss potential challenges and future opportunities. Finally, we describe the international MS microbiome study, a multicenter effort to study a large population of patients with MS and their healthy household partners to define the core MS microbiome, how it is shaped by disease-modifying therapies, and to explore potential therapeutic interventions.

Keywords: B cells; Gut microbiome; consortia; dysbiosis; genetics; multiple sclerosis; progression.

Fig. 1

Putative mechanisms of gut–brain communication in the context of dysbiosis and neuroinflammation in multiple sclerosis (MS). The gut mucosal interface is a zone of intensive interaction between the gut microbiota in the luminal space and the immune cells situated in the lamina propria and enriched in lymphoid follicles, the Peyer’s patches. Putative mechanisms by which dysbiosis in the gut can influence central nervous system inflammation in patients with MS are through immune cells through a dysbalance of pro- and anti-inflammatory cytokines (e.g., an excess of T helper 17-promoting bacteria) or molecular mimicry. Other routes of communication include humoral immunity, bacterial molecules (fatty acids, etc.), direct bacterial translocation leading to activation of the innate immune system, and direct communication via the vagus nerve or the release of gut hormones (e.g., 5-hydroxytryptamine). mIgA = monomeric IgA; sIgA = secretory IgA