Fermented Lacticaseibacillus Paracasei Cultures Ameliorate Colitis by Modulating Microbiota-Derived Tryptophan Metabolism and Macrophage Polarization.

High-density solid-state fermented probiotic products, combining live bacteria with microbial and substrate-derived bioactives, offer a potential solution to address dysregulation of gut microbiota-immune homeostasis associated with inflammatory bowel disease (IBD). However, their synergistic efficacy against IBD remains elusive. Here, we discuss our high-density solid-state fermented Lacticaseibacillus paracasei culture (PYW) and its effects on dextran sulfate sodium (DSS)-induced colitis. Comparison of the effects of PYW, enriched with viable cells and bioactive metabolites-obtained via fermentation with wheat bran-with those of its thermally inactivated postbiotic (SPYW) shows superior efficacy of PYW than SPYW, with a viable bacterial load of ≥ 5 × 10(10) CFU g(-1) being indispensable. PYW effectively restores microbiota structure, restructures the gut tryptophan metabolic network, enriching indole-3-lactic acid (ILA) and indole-3-acetic acid (IAA), which activate the aryl hydrocarbon receptor (AhR) signaling pathway, suppress pro-inflammatory mediators, and strengthen mucosal barriers. Antibiotic depletion abolishes the effects of PYW, while fecal microbiota transplantation from PYW-treated donors and exogenous ILA/IAA supplementation replicate its anti-colitic benefits. These findings suggest that PYW alleviates colitis via microbiota-dependent enrichment of ILA/IAA and subsequent AhR pathway activation, highlighting its potential as a probiotic therapeutic targeting the microbiota-metabolism-immunity regulatory axis in IBD.