PT - JOURNAL ARTICLE AU - Delphine Sterlin AU - Martin Larsen AU - Jehane Fadlallah AU - Christophe Parizot AU - Marina Vignes AU - Gaëlle Autaa AU - Karim Dorgham AU - Catherine Juste AU - Patricia Lepage AU - Jennifer Aboab AU - Savine Vicart AU - Elisabeth Maillart AU - Olivier Gout AU - Catherine Lubetzki AU - Romain Deschamps AU - Caroline Papeix AU - Guy Gorochov TI - Perturbed Microbiota/Immune Homeostasis in Multiple Sclerosis AID - 10.1212/NXI.0000000000000997 DP - 2021 Jul 01 TA - Neurology - Neuroimmunology Neuroinflammation PG - e997 VI - 8 IP - 4 4099 - http://nn.neurology.org/content/8/4/e997.short 4100 - http://nn.neurology.org/content/8/4/e997.full SO - Neurol Neuroimmunol Neuroinflamm2021 Jul 01; 8 AB - 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.CFU=colony-forming unit; CIS=clinically isolated syndrome; EAE=experimental autoimmune encephalomyelitis; EDSS=Extended Disability Status Scale; EI=enrichment index; GBS=Guillain-Barré syndrome; IMD=immunomodulatory; MBP=myelin basic protein; MS=multiple sclerosis; OTU=operational taxonomic unit; PBS=phosphate buffer saline; PCR=polymerase chain reaction; rRNA=ribosomal ribonucleic acid; RR=relapsing-remitting; TNF=tumor necrosis factor