Tryptophan Catabolites from Microbiota Engage Aryl Hydrocarbon Receptor and Balance Mucosal Reactivity via Interleukin-22

Abstract

Endogenous tryptophan (Trp) metabolites have an important role in mammalian gut immune homeostasis, yet the potential contribution of Trp metabolites from resident microbiota has never been addressed experimentally. Here, we describe a metabolic pathway whereby Trp metabolites from the microbiota balance mucosal reactivity in mice. Switching from sugar to Trp as an energy source (e.g., under conditions of unrestricted Trp availability), highly adaptive lactobacilli are expanded and produce an aryl hydrocarbon receptor (AhR) ligand-indole-3-aldehyde-that contributes to AhR-dependent Il22 transcription. The resulting IL-22-dependent balanced mucosal response allows for survival of mixed microbial communities yet provides colonization resistance to the fungus Candida albicans and mucosal protection from inflammation. Thus, the microbiota-AhR axis might represent an important strategy pursued by coevolutive commensalism for fine tuning host mucosal reactivity contingent on Trp catabolism.

Oral microbiota in autoimmune polyendocrine syndrome type 1

“…C. albicans can form biofilms with many oral bacteria, including streptococci [40], which have synergistic or antagonistic influences on C. albicans . Noteworthy, recent work has highlighted the critical role of metabolic products from specific gut microbiota such as lactobacilli in priming IL-22 dependent mucosal immune responses by innate lymphoid cells via the aryl hydrocarbon receptor, which is fundamental for protection against uncontrolled local Candida expansion [41]. Further, a shift in salivary microbiota has been linked to the risk of oral cancer in selected groups of patients [42].…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Nonetheless, NKp46 + ILC3 may have other important non‐redundant roles during C. rodentium infection, as infected mice lacking NKp46 + ILC3 exhibited severe caecal damage 84. In addition, intestinal ILC3‐derived IL‐22 may also contribute to immunity roles in a diverse range of clinically relevant infections in the gut including the nosocomial pathogen Clostridium difficile ,119 rotavirus,120 the fungal pathogen Candida albicans ,121 as well as gastrointestinal helminths 78. In contrast, some enteric pathogens have evolved to circumvent and exploit the ILC3 response to infection.…”

CARD9 et colite : un pont entre dysbiose et immunité

“…AhR est un récepteur intracellulaire qui, par sa fonction de régulateur transcriptionnel, agit sur de nombreux gènes impliqués dans la détoxification, le déve-loppement ou la modulation du système immunitaire [17]. Le tryptophane peut être métabolisé soit par les bactéries intestinales en dérivés indoles, comme l'indole-3-acétique acide (IAA), soit par les cellules hôtes en kynurénine 3 [15,18]. Les dérivés indoles sont des ligands d'AhR connus pour induire une production locale d'IL-22 par les cellules immunitaires [18].…”