Lactobacillaceae Differentially Impact Butyrate-producing Gut Microbiota to Drive CNS Autoimmunity

Background: Short-chain fatty acids (SCFAs), produced by the gut microbiota, are thought to exert an anti-inflammatory effect on the host immune system. The levels of SCFAs and abundance of the microbiota that produce them are depleted in multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS). The mechanisms leading to this depletion are unknown. Using experimental autoimmune encephalomyelitis (EAE) as a model for MS, we have previously shown that gut microbiomes divergent in their abundance of specific commensal () and (), differentially impact CNS autoimmunity. To determine the underlying mechanisms, we employed colonization by and in disparate gut microbiome configurations and , profiling their impact on gut microbiome composition and metabolism, coupled with modulation of dietary fiber in the EAE model.

Results: We show that stable colonization by , but not , exacerbates EAE, in conjunction with a significant remodeling of gut microbiome composition, depleting SCFA-producing microbiota, including , , and , with a net decrease in bacterial metabolic pathways involved in butyrate production. In a minimal microbiome culture model , directly inhibited SCFA-producer growth and depleted butyrate. Genomic analysis of isolates revealed an enrichment in bacteriocins with known antimicrobial activity against SCFA-producing microbiota. Functionally, provision of excess dietary fiber, as the prebiotic substrate for SCFA production, elevated SCFA levels and abrogated the ability of to exacerbate EAE.

Conclustions: Our data highlight a potential mechanism for reduced SCFAs and their producers in MS through depletion by other members of the gut microbiome, demonstrating that interactions between microbiota can impact CNS autoimmunity in a diet-dependent manner. These data suggest that therapeutic restoration of SCFA levels in MS may require not only dietary intervention, but also modulation of the gut microbiome.