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

Abstract

Abstract Multiple sclerosis (MS) is a chronic autoimmune central nervous system (CNS) disease and the leading cause of non-traumatic neurological disability in young adults. The etiology of MS is multifactorial and polygenic, with 30% of risk genetic and 70% environmental. Recent studies identified an imbalance in the human gut microbiome within MS patients, including depletion of the Lactobacillus genus. Animal models support a causal role of the gut microbiome in MS, though the mechanisms remain unclear. Here, we leverage natural genetic variation in wild-derived PWD/PhJ (PWD) mice as compared to classic C57BL/6J (B6) mice, modeling human genetic diversity to identify host genome and gut microbiome interactions governing disease susceptibility. In a model of MS, experimental autoimmune encephalomyelitis (EAE), 27 consomic strains carrying PWD chromosomes on the B6 background demonstrated that PWD-derived loci exhibit bidirectional and sex-specific effects on disease severity. 16S rRNA gene sequencing of the gut microbiome in consomic and parental strains identified strain-specific profiles and metabolic functions associated with differential susceptibility to EAE. Functionally, manipulation of the gut microbiome by co-housing or transplantation, demonstrated direct host genotype-dependent effects of the microbiome on EAE susceptibility, with transfer of signature Lactobacillus species associated with changes in circulating indole metabolites and altered EAE severity. These studies reveal the presence of complex bidirectional interactions between the host genome and gut microbiome that modulate susceptibility to CNS autoimmunity, and identify specific microbiome constituents as potential therapeutic candidates.