A gut feeling about multiple sclerosis

Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system (CNS) that constitutes the leading cause of neurologic disability in young adults (1). Th1 and Th17 effector T cells (Teffs) are thought to play a central role in the pathogenesis of MS (2, 3). Thus, the study of the mechanisms that control Teffs and the regulatory T cells (Tregs) that suppress them is likely to shed light on MS pathogenesis, while identifying potential targets for therapeutic intervention. Multiple genetic factors have been found to control the immune response in MS (4), but environmental exposures are also known to contribute to disease pathogenesis (5).

The commensal microbiota is an important modulator of the immune response (6). Indeed, perturbations in commensal communities (referred to as dysbiosis) have been linked to multiple inflammatory conditions (7). Changes in the gut microbiota, for example, have been described in patients with MS and are thought to contribute to disease pathogenesis (8–13). However, little is known about the mechanisms involved. In PNAS, two independent studies describe the analysis of well-defined patient cohorts in combination with the use of in vitro and in vivo experimental systems to provide unique insights into the role of the gut microbiome in T cell dysregulation in MS (14, 15).

The MS Microbiome

Cekanaviciute et al. (14) found that bacterial extracts isolated from stool samples from patients with MS show an impaired ability to promote the differentiation of Tregs in peripheral blood mononuclear cell (PBMC) cultures. Moreover, gut microbiota transplants from patients with MS into germ-free mice worsened the development of experimental autoimmune encephalomyelitis (EAE), a model of MS induced by immunization with a myelin antigen (14). In complementary studies, Berer et al. used mice bearing a myelin-specific T cell receptor (TCR), which spontaneously develop relapsing-remitting EAE (RR-EAE) when their commensal microbiota is intact, but not under germ-free conditions (16). Using samples isolated from monozygotic twin pairs discordant for MS, Berer et al. (15) found that microbiota transplants from twins with MS increased the incidence of spontaneous RR-EAE development in TCR transgenic mice. Thus, components of the gut MS microbiome boost T cell-dependent CNS autoimmunity.

The combined analysis of the microbiome of patients with MS and microbiota-transplanted EAE mice identified specific candidates involved in the regulation of the T cell response. In agreement with previous MS microbiome studies (8), Akkermansia muciniphila was found to be increased in MS samples (14), Interestingly, A. muciniphila extracts boosted the differentiation of human effector Th1 cells. Members of the genera Acinetobacter were also increased in MS stool samples, and Akkermansia calcoaceticus extracts boosted human Th1 and suppressed Treg differentiation (14).

Conversely, commensal bacteria have also been shown to promote the development of Tregs (17). Interestingly, both studies showed that the MS gut microbiota displays a decreased ability to promote Treg responses, particularly those mediated by IL-10⁺ T cells. By analyzing stool samples from healthy controls and patients with MS, the immune compartment of monocolonized mice, and the effects of bacterial extracts on human PBMCs, Baranzini and coworkers identified Parabacteroides distasonis as a gut commensal decreased in patients with MS that drives the differentiation of IL-10⁺ Tregs (14). Taken together, these findings demonstrate that the MS microbiome promotes pathogenic T cell responses, while it has an impaired ability to induce IL-10⁺ Tregs.

The mechanisms involved in the regulation of the T cell response by the commensal microbiota are still unclear. The cross-reactivity between self- and microbial pathogens has been postulated to contribute to the development of autoimmune disorders (18). Thus, epitopes expressed by components of the MS microbiome may induce pathogenic CNS cross-reactive T cell responses in MS. Although this molecular mimicry may contribute to the worsening of EAE by MS microbiota transplants, it is unlikely to affect Teff and Treg differentiation in PBMC cultures from healthy donors.

Microbial metabolites, however, are known to modulate Teffs and Tregs directly, and also indirectly by acting on antigen-presenting cells. For example, polysaccharide A (19, 20) and aryl hydrocarbon receptor agonists (21, 22) promote IL-10 production in T cells that suppress CNS inflammation. Microbial metabolites may play additional roles in MS. CNS-resident cells, such as microglia and astrocytes, are thought to promote inflammation and neurodegeneration in MS (1, 23, 24). Interestingly, it has been shown recently that microbial metabolites regulate the activity of microglia (25, 26) and astrocytes (27). Thus, through the production of immunoregulatory metabolites, the commensal flora may affect processes relevant to MS pathogenesis in the periphery and also within the CNS.

Potential limitations of the current studies are the relatively small size of the cohort analyzed, which, in combination with differences in cohort genetics, location, diet, and treatment, may explain the association of specific bacteria to MS in the University of California, San Francisco cohort (14), but not in the monozygotic twin pairs analyzed by Berer et al. (15). In addition, as discussed by Berer et al. (15), these studies are based on the analysis of fecal samples, which may not accurately reflect subtle but biologically relevant differences in the microbial composition of the small intestine. Finally, it should be noted that the studies with bacterial extracts described by Cekanaviciute et al. (14) were limited by the availability of culturable strains available from the American Type Culture Collection.

Future Directions

Future studies are expected to expand these initial findings, for example, by analyzing larger cohorts and also longitudinal samples to associate changes in the gut flora with disease progression or response to therapy. In addition, although these studies are focused on the gut microbiome, it is likely that commensal microbiota in other tissues also contributes to MS pathogenesis. Indeed, Flügel and coworkers (28) identified the lung as an important site for the maturation of myelin-reactive pathogenic T cells before they access the CNS. Thus, future studies should explore the contribution to MS pathogenesis of microbiota in other tissues, such as the lung and skin.

In conclusion, the studies by Berer et al. (15) and Cekanaviciute et al. (14) constitute a major advance in our understanding of the role of the gut microbiota on MS and, potentially, other inflammatory diseases. These studies define potential mechanisms through which the commensal microbiota may control CNS T cell autoimmunity. Once the molecular pathways involved are identified, these studies may guide new approaches for therapeutic intervention, for example, by using probiotics optimized to produce antiinflammatory metabolites. Alternatively, synthetic analogs of microbial antiinflammatory metabolites can be developed, designed not only to act on the periphery but also to reach the CNS and limit the pathogenic activity of CNS-resident cells.