Dietary tryptophan links encephalogenicity of autoreactive T cells with gut microbial ecology

Impaired host-microbiota interaction in the gut may result in dysregulated systemic T cell responses contributing to autoimmune diseases in distant organs such as rheumatoid arthritis or autoimmune neuroinflammation. Commensal intestinal bacteria control the differentiation of antigen-specific T cells into protective regulatory T cells (Treg) cells or pro-inflammatory T helper (TH) 17 cells11. The gut microbiota ecology is influenced by specific dietary constitutents such as salt, fibre or fermentation-derived short-chain fatty acids (SCFA), which also have a known impact on organ autoimmunity. Here, we report that omission of a single essential amino acid - tryptophan (trp) - abrogates CNS autoimmunity in a mouse model of multiple sclerosis (MS). Dietary trp restriction (DTR) results in impaired encephalitogenic T cell responses, which is accompanied by an inflammatory response in the colonic mucosa and a profound shift of the gut microbiota. Protective effects of DTR on neuroinflammation are abrogated in germ-free (GF) mice, but are independent of the canonical host sensors of trp or its metabolites - general control non-derepressible (GCN2) and aryl hydrocarbon receptor (AHR) pointing to trp-dependent signals of the commensal microbiota impacting encephalitogenic T cell responses. Our data provide insight into the regulation of CNS autoimmunity by a single essential dietary constituent, intestinal inflammation and their interaction with microbial ecology in the gut. This link between gut microbiota and trp may offer novel therapeutic strategies for protection from autoimmune neuroinflammation.