A diet-dependent host metabolite shapes the gut microbiota to protect from autoimmunity

Diet can protect from autoimmune disease; however, whether diet acts via the host and/or microbiome remains unclear. Here, we use a ketogenic diet (KD) as a model to dissect these complex interactions. A KD rescued the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in a microbiota-dependent fashion. Dietary supplementation with a single KD-dependent host metabolite (β-hydroxybutyrate, βHB) rescued EAE whereas transgenic mice unable to produce βHB in the intestine developed more severe disease. Transplantation of the βHB-shaped gut microbiota was protective. Lactobacillus sequence variants were associated with decreased T helper 17 (Th17) cell activation in vitro. Finally, we isolated a L. murinus strain that protected from EAE, which was phenocopied by the Lactobacillus metabolite indole lactic acid. Thus, diet alters the immunomodulatory potential of the gut microbiota by shifting host metabolism, emphasizing the utility of taking a more integrative approach to study diet-host-microbiome interactions. ### Competing Interest Statement P.J.T. is on the scientific advisory boards for Pendulum, Seed, and SNIPRbiome; there is no direct overlap between the current study and these consulting duties. P.A.C. has served as an external consultant for Pfizer, Inc., Abbott Laboratories, Janssen Research & Development and Selah Therapeutics. J.C.N. is scientific co-founder and stockholder for BHB Therapeutics (which provided the ketone ester) and Selah Therapeutics. All other authors have no relevant declarations.