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

ABSTRACT 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.