Gut Microbiota–Derived Tryptophan Indole Metabolites Ameliorate Collagen‐Induced Arthritis in Mice Via Aryl Hydrocarbon Receptor Activation

OBJECTIVE: Our study's objective is to investigate the specific role of tryptophan metabolism, especially that of microbiome-derived metabolites, in the development of rheumatoid arthritis (RA). METHODS: We employed metabolomics to profile metabolites in 53 individuals at high risk for RA (PreRA), 30 patients with established RA, and 38 healthy individuals. Fecal microbiota transplantation (FMT) and collagen-induced arthritis (CIA) mouse models were used to investigate the impact of gut microbiome on arthritis severity, gut barrier function, and metabolic change. Treg cell differentiation and epithelial cells' barrier function were assessed by flow cytometry, immunofluorescence staining, and Western blotting. Co-immunoprecipitation and luciferase were applied for molecular mechanism studies. RESULTS: Dysregulated tryptophan metabolism exists in individuals with RA and PreRA, as well as in FMT mice, characterized by a shift toward the kynurenine pathway and reduced activity of serotonin and indole pathways. Indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA) significantly alleviated arthritis in CIA mice by expanding Treg cells via the classical aryl hydrocarbon receptor (AhR)-aryl hydrocarbon receptor nuclear translocator-xenobiotic response element signaling pathway. Moreover, ILA repaired the leaking gut by increasing Zo-1 and occludin expression in Caco-2 cells, which was blocked by AhR antagonist CH223191. Moreover, CH223191 treatment could significantly reverse the improving effects of ILA and IAA on arthritis in mice. CONCLUSION: These findings indicate that tryptophan indole metabolites may play a negative regulatory role in the progression of RA by affecting Treg cell development and intestinal gut barrier function.