Wumei Wan alleviates intestinal fibrosis via the microbiota-metabolite-YAP-mechanotransduction axis.

[BACKGROUND] Intestinal fibrosis is a common complication of Crohn's disease, for which effective therapies remain lacking. Wumei Wan (WMW), a classical traditional Chinese medicine formula, has been used for nearly two millennia to treat inflammatory bowel disease and its complications.

[PURPOSE] This study aimed to evaluate the antifibrotic effects of WMW and to elucidate its underlying mechanisms.

[METHODS] The therapeutic effects of WMW were evaluated in a dextran sulfate sodium-induced mouse model of intestinal fibrosis and further validated in a colitis-associated colorectal cancer model. Multi-omics sequencing and bioinformatics analyses were used to elucidate the pharmacological mechanisms of WMW, and complementary experiments were performed to verify the roles of butyrate and butyrate-associated bacteria.

[RESULTS] WMW exhibited significant antifibrotic efficacy in mouse models. Further analysis revealed that WMW alleviated fibrosis by remodeling the gut microbiota and promoting endogenous butyrate production, thereby suppressing FAK-Src-mediated mechanotransduction, preventing Yes-associated protein nuclear translocation, and inhibiting colonic fibroblast activation. In microbiota-depleted mice, the inhibitory effects of WMW on butyrate production and mechanotransduction were markedly diminished. Notably, supplementation with Bacteroides fragilis produced antifibrotic effects concordant with those of WMW and butyrate and effectively reduced intestinal fibrosis.

[CONCLUSION] This study demonstrates that WMW alleviates intestinal fibrosis by targeting the microbiota-metabolite-mechanotransduction axis. WMW and butyrate-associated bacteria may therefore represent promising antifibrotic strategies.