Summary
Over the years, many microbes have been proposed as potential multiple sclerosis (MS) triggers, but firm evidence for causality has never been provided. A seminal murine study, however, exploiting germ-free mice engineered to develop spontaneous experimental autoimmune encephalomyelitis (EAE) suggested that commensal gut bacteria contribute to the disease process.
Original Article
Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis
Neurology
Delphine Sterlin, Martin Larsen, Jehane Fadlallah, Christophe Parizot, Marina Vignes, Gaëlle Autaa, View ORCID ProfileKarim Dorgham, Catherine Juste, Patricia Lepage, Jennifer Aboab, Savine Vicart, View ORCID ProfileElisabeth Maillart, Olivier Gout, Catherine Lubetzki, Romain Deschamps, Caroline Papeix, View ORCID ProfileGuy Gorochov
Abstract
Objective Based on animal models and human studies, there is now strong suspicion that host/microbiota mutualism in the context of gut microbial dysbiosis could influence immunity and multiple sclerosis (MS) evolution. Our goal was to seek evidence of deregulated microbiota-induced systemic immune responses in patients with MS.
Methods We investigated gut and systemic commensal-specific antibody responses in healthy controls (n = 32), patients with relapsing-remitting MS (n = 30), and individuals with clinically isolated syndromes (CISs) (n = 15). Gut microbiota composition and diversity were compared between controls and patients by analysis of 16S ribosomal ribonucleic acid (rRNA) sequencing. Autologous microbiota and cultivable bacterial strains were used in bacterial flow cytometry assays to quantify autologous serum IgG and secretory IgA responses to microbiota. IgG-bound bacteria were sorted by flow cytometry and identified using 16S rRNA sequencing.
Results We show that commensal-specific gut IgA responses are drastically reduced in patients with severe MS, disease severity being correlated with the IgA-coated fecal microbiota fraction (r = −0.647, p < 0.0001). At the same time, IgA-unbound bacteria elicit qualitatively broad and quantitatively increased serum IgG responses in patients with MS and CIS compared with controls (4.1% and 2.5% vs 1.9%, respectively, p < 0.001).
Conclusions Gut and systemic microbiota/immune homeostasis are perturbed in MS. Our results argue that defective IgA responses in MS are linked to a breakdown of systemic tolerance to gut microbiota leading to an enhanced triggering of systemic IgG immunity against gut commensals occurring early in MS.
