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

Abstract

The interaction between the mammalian host and its resident gut microbiota is known to license adaptive immune responses. Nutritional constituents strongly influence composition and functional properties of the intestinal microbial communities. Here, we report that omission of a single essential amino acid - tryptophan – from the diet abrogates CNS autoimmunity in a mouse model of multiple sclerosis. Dietary tryptophan restriction results in impaired encephalitogenic T cell responses and is accompanied by a mild intestinal inflammatory response and a profound phenotypic shift of gut microbiota. Protective effects of dietary tryptophan restriction are abrogated in germ-free mice, but are independent of canonical host sensors of intracellular tryptophan metabolites. We conclude that dietary tryptophan restriction alters metabolic properties of gut microbiota, which in turn have an impact on encephalitogenic T cell responses. This link between gut microbiota, dietary tryptophan and adaptive immunity may help to develop therapeutic strategies for protection from autoimmune neuroinflammation.

Indolepropionic Acid, a Metabolite of the Microbiome, Has Cytostatic Properties in Breast Cancer by Activating AHR and PXR Receptors and Inducing Oxidative Stress

“…Tryptophan and its downstream metabolites, including indoles, exert their effects through the AHR and PXR receptors [ 91 , 92 , 93 ]. A dietary restriction of tryptophan that subsequently limits indole production has immunosuppressive effects in an AHR-dependent fashion [ 94 ], which correlates well with the antitumor immune response we observed in our study. High TnaA expression is indicative of higher IPA production, and it is directly proportional with the number of tumor-infiltrating lymphocytes.…”

Oncobiosis and Microbial Metabolite Signaling in Pancreatic Adenocarcinoma

“…AHR activation is a key element in the regulation of the immune system [133,217]. A tryptophan-poor diet has immunosuppressive effects in an AHR-dependent fashion [218]. By modulating mucosal immunity through AHR, indole derivatives influence the composition of the gut microbiome.…”

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

“…These microbial-derived Trp metabolites act as ligands for AhR through which they modulate the microglia-astrocyte crosstalk to reduce inflammation in MS (131). This suggests that the gut-brain axis could be targeted therapeutically in MS. Another contribution of microbial-mediated Trp catabolism in EAE was demonstrated in a study in which a Trp-restricted diet limited the expansion and function of autoreactive T cells (132). An interpretation of these seemingly opposite results may be that microbial-derived Trp metabolites have different modulating properties on immune responses in the microglia in the CNS compared to T cells in the periphery.…”