Microbiota-derived tryptophan metabolites shape Th2 lymphocyte responses via the aryl hydrocarbon receptor and metabolic reprogramming.

Allergic diseases are linked with changes in gut microbiota composition and metabolism, but the direct mechanisms linking microbial metabolism to T helper 2 (Th2) lymphocyte differentiation are still poorly understood. Colonization of gnotobiotic animals with Bifidobacterium longum and Clostridium sporogenes resulted in high levels of tryptophan-derived indole-3-lactic acid (ILA), indole-3-acrylic acid (IA), and indole-3-propionic acid (IPA), which correlated with suppressed Th2 responses. Indoxyl-3-sulfate (I3S) and IA reduced interleukin (IL)-4, IL-5 and IL-13 secretion from human Th2 polarized lymphocytes in an aryl-hydrocarbon receptor (AHR)-dependent manner. IA and IPA induced broader metabolic rewiring by reducing Th2 cell mitochondrial oxidative phosphorylation and reactive oxygen species damage. Microbial tryptophan metabolism may modulate human Th2 cell polarization, differentiation and function thereby linking allergy development to microbial processes. In addition, we have identified novel links between mitochondrial metabolic programs and Th2 lymphocyte polarization that are impacted by the microbial Stickland pathway derived metabolites IA and IPA.