ShenQiGan Extract Mitigates Intestinal Oxidative Stress in Weaned Piglets Through Bile Acid Metabolism Regulation and Gut Microbiota Remodeling via the Nrf2/Keap1 Pathway

Background: Weaning stress induces intestinal oxidative imbalance, barrier dysfunction, and gut microbial disturbances in piglets. ShenQiGan Extract (CAG), a traditional herbal-derived additive, has shown potential antioxidant and intestinal protective properties; however, the underlying mechanisms remain unclear. This study investigated whether CAG protects weaned piglets against oxidative stress through modulation of the gut microbiota–bile acid (BA) axis and antioxidant signaling pathways. Methods: Eighty 28-day-old weaned piglets were assigned to control, 0.1%, 0.5%, or 1.0% CAG supplementation groups for 28 days. Serum antioxidant parameters, intestinal and hepatic histomorphology, bile acid profiles in feces and serum, gut microbiota composition, and intestinal expression of BA metabolism- and Nrf2/Keap1-related molecules were analyzed. Furthermore, HDCA, 7-ketoLCA, and CDCA, identified as differential bile acids associated with CAG supplementation, were evaluated in an H2O2-induced oxidative stress model using IPEC-J2 cells. Results: CAG supplementation improved systemic antioxidant status, intestinal morphology, mucus barrier integrity, and hepatic histological damage in weaned piglets. CAG reshaped the gut microbial community by increasing microbial richness and Lactobacillus abundance, which was associated with alterations in BA profiles, particularly increased HDCA, 7-ketoLCA, and CDCA levels. CAG also regulated intestinal BA metabolism-related molecules, including BA synthesis, transport, and signaling pathways, and activated Nrf2/Keap1 antioxidant signaling. In vitro, HDCA, 7-ketoLCA, and CDCA alleviated H2O2-induced oxidative stress and improved epithelial barrier function, with CDCA showing the most consistent regulatory effects with the in vivo response. Conclusions: CAG supplementation protects weaned piglets against oxidative stress and intestinal barrier impairment by remodeling the gut microbiota–BA axis, regulating BA metabolism, and activating Nrf2/Keap1 antioxidant signaling. Among the identified differential BAs, CDCA may represent an important mediator contributing to the intestinal protective effects of CAG.