The gut microbiota-IPA axis mediated by catalpol alleviates DSS-induced colitis through AhR activation

Current management strategies for colitis predominantly involve broad immunosuppression, underscoring the urgent need for strategies that restore essential homeostatic pathways. Insufficient activation of the aryl hydrocarbon receptor (AhR) by microbial metabolites compromises its crucial role in maintaining mucosal integrity, a defect commonly observed in colitis. While the natural compound catalpol exhibits preventive potential, its precise function within host-microbiota crosstalk remained undefined. This study aims to investigate the protective effects of catalpol on colitis, focusing on the role of gut microbiota and its metabolite, indole-3-propionic acid (IPA). A mouse model of DSS-induced colitis was utilized. The protective outcomes and mechanisms were assessed through integrated multi-omics analyses, functional validation via microbial manipulation, and molecular studies confirming the activation of the AhR pathway. In this study, catalpol protects against DSS-induced colitis in mice, and this protection is associated with alterations in gut microbiota composition. Integrated multi-omics analysis suggests that catalpol treatment is associated with increased relative abundance of Lachnospiraceae at the family level and with elevated levels of the microbial metabolite indole-3-propionic acid. Functional validation through fecal microbiota transplantation from catalpol-treated mice or direct IPA supplementation partially reproduced several protective effects, suggesting that IPA may be a downstream mediator contributing to the protective effects of catalpol. Molecular analyses indicate that both catalpol and IPA can physically interact with AhR. Importantly, pharmacological suppression of AhR partially reversed the protective effects, suggesting that AhR activation contributes to the protective effects of catalpol. Collectively, these findings suggest that catalpol protects against DSS-induced colitis, and this effect is associated with increased relative abundance of Lachnospiraceae at the family level and elevated IPA levels, potentially contributing to a microbiota-IPA-AhR axis. This work highlights the preventive potential of restoring host-microbiota metabolic crosstalk and provides a rationale for developing microbiota-targeted protective strategies.