Dietary tryptophan-mediated aryl hydrocarbon receptor activation by the gut microbiota alleviates Escherichia coli-induced endometritis in mice

The intestinal microbiota-mediated aryl hydrocarbon receptor (AhR) activation plays an important role in host-microbiota interactions and disease development. However, it is unclear whether AhR activation mediates infection-induced inflammation in the remote organs. The present study aimed to assess the effects and underlying mechanism of AhR activation and gut microbiota-mediated dietary tryptophan (Trp) metabolism on infection-induced inflammation using Escherichia coli (E. coli)-induced endometritis model in mice. We found that AhR activation by 6-formylindolo (3,2-b) carbazole (Ficz), an AhR agonist derived from the photooxidation of Trp, alleviated E. coli-induced endometritis by repairing barrier function and inhibiting inflammatory responses, while inhibition of AhR by CH223191, a synthetic AhR antagonist, aggravated endometritis caused by E. coli. Gut dysbiosis damaged AhR activation and exacerbated E. coli-induced endometritis in mice, which were responded to the reduced abundance of AhR ligand producers, such as Lactobacillus spp. In addition, supplementation with dietary Trp ameliorated E. coli-induced endometritis in a microbiota-dependent manner, which was associated with the production of AhR ligands. Administration with AhR ligands, including indole and indole aldehyde, but not indole-3-propionic acid, rescued the protective effect of Trp on E. coli-induced endometritis in dysbiotic mice. Moreover, consumption of Lactobacillus reuteri (L. reuteri) containing AhR ligand-producing capability also alleviated E. coli-induced endometritis in mice in an AhR-dependent manner. Our results demonstrate that microbiota-mediated AhR activation is a key factor to fight against pathogen caused inflammation, leading to the potential strategy to regulate the gut microbiota and metabolism by dietary Trp or probiotic for the intervention of infectious diseases and reproductive health.