Interactions between the host genome and the gut microbiome determine susceptibility to CNS autoimmunity

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system. The etiology of MS is multifactorial, with disease risk determined by genetics and environmental factors. An emerging risk factor for several immune-mediated diseases, including MS, is an imbalance in the gut microbiome. However, the identity of gut microbes functionally associated with disease risk, their mechanisms of action, and the interactions with the host's genetics remain unknown. To address these questions, we utilized the principal autoimmune model of MS, experimental autoimmune encephalomyelitis (EAE), together with a genetically diverse mouse model representing 29 unique host genotypes, interrogated by microbiome sequencing and targeted microbiome manipulation strategies. We identified specific gut bacteria and their metabolic functions associated with EAE susceptibility, implicating short-chain fatty acid metabolism as a key element conserved across multiple host genotypes. However, the microbial associations across multiple host genotypes were heterogeneous and of modest effect size, suggesting an explanation for the lack of consensus across human MS microbiome studies. In parallel, we used a reductionist approach by focusing on the two most disparate microbiome phenotypes identified in our screen. Manipulation of the gut microbiome by transplantation and cohousing demonstrated that transfer of these microbiomes into genetically identical hosts was sufficient to yield differences in EAE susceptibility and systemic metabolite profiles. Parallel bioinformatic approaches identified Lactobacillus reuteri as a commensal species capable of exacerbating EAE, which was confirmed by bacterial isolation and commensal colonization studies. Taken together, these results demonstrate the existence of complex interactions between host genetics and gut microbiota modulating susceptibility to CNS autoimmune disease, providing new insights into microbiome-directed strategies aimed at lowering the risk for autoimmune disease, and highlighting the need to consider host genetics, timing and mode of exposure, and baseline gut microbiome composition for such strategies.