Gut Bacterial Indole-3-acetic Acid Induced Immune Promotion Mediates Preventive Effects of Fu Brick Tea Polyphenols on Experimental Colitis

Ulcerative colitis has been consistently associated with gut microbiota imbalance and disturbed immune system. Emerging research suggests a protective function of polyphenols on prevention and treatment of ulcerative colitis, yet underlying mechanisms remain unclear. Fu brick tea, a postfermented tea, contains abundant polyphenols with anti-inflammatory and antioxidant properties. In the present study, we found that prophylactic supplementation of polyphenols extracted from Fu brick tea (FBTP) dose-dependently alleviated colitis symptoms, immune cells infiltration, and pro-inflammatory cytokines secretion in mice suffering dextran sulfate sodium induced murine colitis. FBTP substantially reshaped gut microbiota and promoted microbial transformation of tryptophan into indole-3-acetic acid (I3A), thereafter leading to aryl hydrocarbon receptor (AHR)-mediated protection from colitis through enhanced expressions of IL-22 and tight junction proteins (i.e., ZO-1, occluding and claudin-1) in colon. Multiomics integration analyses revealed strong connections between I3A, tryptophan-metabolizing bacteria, AHR activity, and pathological phenotypes of colitis. Notably, FBTP failed to significantly alleviate colitis symptoms in the absence of gut microbiota, while intragastric administration of I3A could imitate benefits of FBTP on colitis alleviation and intestinal epithelial homeostasis through a direct enhancement in AHR activity in microbiota-depleted mice. These findings further determine the key role of gut microbiota controlled I3A-AHR signaling in mediating the FBTP on colitis alleviation. This study provides the first data proposing the FBTP as a natural prebiotic for colitis alleviation through the gut microbiota-dependent modulation of the AHR pathway. Most importantly, we also identified I3A as a key microbial metabolite targeted by FBTP for exhibiting health-promoting effects.