Metabolic Engineering of Commensal Bacteria for Producing 5-Hydroxyindoleacetic Acid as a Therapeutic Strategy for Colitis.

Abstract

Numerous studies have demonstrated a strong association between gut microbiota dysbiosis and the progression of colitis, potentially mediated by disruptions in microbial tryptophan metabolism. Targeting commensal bacterial tryptophan metabolism may offer a promising therapeutic strategy. However, a broader spectrum of active substances is necessary to diversify engineered probiotics and enhance the efficacy and precision of treatments. In this study, using a dextran sulfate sodium (DSS)-induced murine colitis model for active substance screening, we observed a significant alteration of the gut microbiota structure concurrent with a pronounced decrease in the level of the microbial-derived tryptophan metabolite, 5-hydroxyindoleacetic acid (5-HIAA). Exogenous supplementation with 5-HIAA restored intestinal epithelial barrier integrity and alleviated colitis symptoms. Mechanistically, 5-HIAA activates the aryl hydrocarbon receptor (AhR), leading to enhanced transcription of IL-10 and subsequent modulation of the NF-κB p65/MLCK/pMLC signaling pathway in intestinal epithelial cells. This cascade promotes increased expression of tight junction proteins, thereby improving intestinal barrier function and attenuating colitis. Furthermore, we engineered a facultative anaerobic commensal bacterium capable of delivering 5-HIAA directly to the gut and evaluated its efficacy in a mouse model of colitis. Our findings indicate that targeted modulation of the key microbial metabolite 5-HIAA effectively suppresses the onset and progression of colitis. The use of engineered bacteria for site-specific 5-HIAA delivery represents a novel and promising therapeutic approach for inflammatory bowel disease (IBD).