Tryptophan metabolism mediated by the gut microbiota inhibits pyroptosis via the AhR signaling pathway to maintain intestinal epithelial homeostasis

BACKGROUND: The intestinal epithelial barrier protects the gut from pathogen invasion as well as exposure to food antigens and toxins. Increasing evidence has linked the gut microbiota to the function of the intestinal epithelial barrier. Fecal microbiota transplantation (FMT) can treat various intestinal diseases by reshaping the gut microbiota. However, the mechanisms by which FMT exerts its effects across different gastrointestinal conditions remain unclear. Moreover, its limitations are significant, including issues related to donor selection, the complexity of the microbiome, potential infection risks, inconsistent clinical responses, and ethical and legal considerations. Therefore, exploring the microbes and metabolites that mediate the effects of FMT as a replacement for traditional FMT is of great importance. In this study, we aim to investigate the gut microbiota and its metabolites to support the therapeutic role of FMT in intestinal barrier damage and elucidate its potential molecular mechanisms. RESULTS: Our findings indicate that FMT prevents Lipopolysaccharide (LPS)-induced pyroptosis and damage to the colonic epithelial barrier. Mechanistically, FMT treatment reprograms the composition of gut microbiota, increasing the relative abundance of Lactobacillus reuteri and the levels of tryptophan metabolites (ILA, IAld, and IAA) in the colon, thereby inhibiting pyroptosis and protecting the intestinal epithelial barrier. Importantly, the AhR/NLRP3 axis is essential for the pyroptosis-inhibitory effects of Lactobacillus reuteri and its tryptophan metabolites. CONCLUSIONS: Our results provide the first evidence that targeting the regulation of Lactobacillus reuteri and tryptophan metabolism is a promising strategy for inhibiting pyroptosis and improving intestinal epithelial homeostasis. Video Abstract.