The study investigates the role of the commensal bacterium Dubosiella newyorkensis (Dub) and its human homologue Clostridium innocuum (Clos) in modulating immune tolerance in dextran sulfate sodium (DSS)-induced colitis. Dub and Clos produce L-Lysine (Lys), which activates the aryl hydrocarbon receptor (AhR)-indoleamine-2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn) pathway in dendritic cells (DCs), promoting the generation of regulatory T cells (Tregs) and suppressing Th17 cells. This metabolic pathway helps restore mucosal barrier integrity and alleviate colitis symptoms. The study shows that Dub and Clos enhance the production of short-chain fatty acids (SCFAs), particularly propionate, and Lys, which contribute to immune tolerance. Lys activates AhR, leading to IDO1 expression and Kyn production, which in turn promotes Treg function and suppresses inflammatory responses. The findings highlight the importance of microbial metabolites in maintaining gut homeostasis and suggest that the AhR-IDO1-Kyn pathway could be a therapeutic target for inflammatory bowel diseases. The human homologue Clos also produces Lys and exerts similar protective effects in colitis models, indicating a conserved mechanism across species. The study underscores the role of microbial metabolites in immune regulation and provides insights into potential therapeutic strategies for inflammatory bowel diseases.The study investigates the role of the commensal bacterium Dubosiella newyorkensis (Dub) and its human homologue Clostridium innocuum (Clos) in modulating immune tolerance in dextran sulfate sodium (DSS)-induced colitis. Dub and Clos produce L-Lysine (Lys), which activates the aryl hydrocarbon receptor (AhR)-indoleamine-2,3-dioxygenase 1 (IDO1)-kynurenine (Kyn) pathway in dendritic cells (DCs), promoting the generation of regulatory T cells (Tregs) and suppressing Th17 cells. This metabolic pathway helps restore mucosal barrier integrity and alleviate colitis symptoms. The study shows that Dub and Clos enhance the production of short-chain fatty acids (SCFAs), particularly propionate, and Lys, which contribute to immune tolerance. Lys activates AhR, leading to IDO1 expression and Kyn production, which in turn promotes Treg function and suppresses inflammatory responses. The findings highlight the importance of microbial metabolites in maintaining gut homeostasis and suggest that the AhR-IDO1-Kyn pathway could be a therapeutic target for inflammatory bowel diseases. The human homologue Clos also produces Lys and exerts similar protective effects in colitis models, indicating a conserved mechanism across species. The study underscores the role of microbial metabolites in immune regulation and provides insights into potential therapeutic strategies for inflammatory bowel diseases.