Commensal Lactobacillus reuteri tryptophan catabolism promotes host susceptibility to CNS autoimmunity

Abstract

Abstract Members of the Lactobacillus genus have a long-standing history in food processing and probiotic industries, generally being characterized as safe and/or beneficial for the mammalian host. Despite this fact, current literature points to pro- and anti-inflammatory roles, with little consensus as to the mechanisms governing these divergent outcomes. We and others have previously shown that commensal colonization with Lactobacillus reuteri (L. reuteri) enhances host susceptibility to experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. To identify underlying mechanisms, we characterized the genome of commensal L. reuteri isolates, present within our model microbiomes, using whole genome sequencing and comparative genomics. The enzymatic machinery necessary to catabolize dietary tryptophan (Trp) into immunomodulatory indole derivatives, was enriched in the L. reuteri genome. Metabolite profiling of L. reuteri monocultures and serum of L. reuteri-colonized mice revealed active depletion of kynurenines and production of a wide array of Trp-derived AhR ligands, including indole acetate, indole acrylate, tryptamine, and imidazole derivatives, suggesting that Trp catabolism by L. reuteri may drive the enhancement of autoimmunity. Consistently, dietary Trp was required for L. reuteri dependent EAE exacerbation, while depletion of Trp suppressed disease activity and inflammatory T cell responses in the CNS. Our data suggests that Trp catabolism by gut commensals can enhance autoimmunity by production of immunoregulatory indole derivatives and by competition with the host for production of Trp metabolites such as kynurenines. Supported by NIH R01 NS097596 T32 Training Grant 5T32AI055402-15 F31 Ruth L. Kirschstein NRSA Fellowship 5 F31 NS120381-02