Dietary tryptophan ameliorates metalaxyl-induced colitis by restoring microbial tryptophan metabolism and aryl hydrocarbon receptor activation.

INTRODUCTION: The extensive production of environmental pollutants has heightened susceptibility to intestinal disorders, potentially through alterations in the gut microbiota. However, the precise role of the gut microbiota in environmental pollutant-induced inflammation remains incompletely understood. METHODS: In this study, wild-type and IL-10-/- mice were employed to simulate the responses of healthy individuals and those genetically predisposed to inflammatory bowel disease (IBD) to environmental toxicants. Mice were exposed to metalaxyl, and an integrated multi-omics approach combining microbiome and metabolome profiling with machine learning was conducted to investigate the underlying mechanisms. Additionally, dietary tryptophan supplementation was administered to evaluate its protective effects. RESULTS: Metalaxyl exposure induced low-grade colonic inflammation in wild-type mice and triggered severe colitis in IBD-susceptible mice. Multi-omics analysis revealed that metalaxyl significantly disrupted gut microbial composition, reduced the synthesis of endogenous tryptophan-derived metabolites, and inhibited aryl hydrocarbon receptor (AhR) signaling, ultimately initiating intestinal barrier dysfunction and inflammatory cascades. Notably, dietary tryptophan restored gut tryptophan metabolite levels, strengthened AhR signaling, mitigated intestinal inflammation, and repaired barrier defects. DISCUSSION: This study identifies the gut microbiota as a central mediator of environmental pollutant-induced IBD and demonstrates that a high-tryptophan diet exerts beneficial effects against environmental colitis via the AhR axis. Furthermore, the stable phenotypes and high reproducibility of this dual-genotype mouse model underscore its utility as an ideal platform for investigating the enterotoxic effects of environmental pollutants.