Lactiplantibacillus plantarum AR113 alleviates Western Diet-Induced colitis and liver injury via bidirectional modulation of the Intestinal-Hepatic FXR signaling axis

AR113 protects intestinal epithelial cells by reducing inflammation, enhancing tight junctions, and upregulating bile acid detoxification genes. It mitigates DCA-induced apoptosis and modulates bile acid metabolism, inhibiting intestinal FXR activation. This restores enterohepatic circulation, reactivates hepatic FXR signaling, and alleviates both colitis and liver injury. • Identifies AR113 as a gut probiotic capable of reducing toxic DCA accumulation. • Demonstrates bidirectional regulation of FXR signaling in both intestine and liver. • Reveals a new mechanism linking bile acid homeostasis to intestinal-liver protection. • Suggests a microbiota-targeting strategy for colitis and associated liver injury. Bile acids are involved in a variety of diseases in the host. However, the alterations in bile acid enterohepatic circulation during colitis and the pathological mechanisms underlying associated hepatic injury remain poorly understood. Additionally, the role of probiotics in this process has yet to be elucidated. In this study, we elucidated the mechanism through which Lactiplantibacillus plantarum AR113 ameliorates Western diet-induced colitis and hepatic injury by modulating bile acid metabolism. Under Western diet conditions, colitis was induced in mice using 3% dextran sodium sulfate (DSS). Bile acid levels, hepatic inflammation, colitis severity, and intestinal barrier function were then evaluated following interventions with: (1) oral gavage of AR113, (2) oral gavage of deoxycholic acid (DCA), and (3) intraperitoneal injection of GW4064 (an Farnesoid X Receptor agonist). In turn, the mechanisms behind AR113′s ability to mitigate intestinal and hepatic injury were uncovered. AR113 treatment significantly reduced serum and fecal DCA levels, upregulated the expression of ZO-1 and occludin (by 19% and 124%, respectively, compared to the PBS group), enhanced the expression of key bile acid detoxification genes (Cyp3a13, Cyp2c55, and Sult1d1) while suppressing pro-inflammatory factor release (IL-1β and TNF-α), thereby mitigating DCA’s proapoptotic effects on intestinal epithelial cells. Mechanistically, AR113 restores the homeostasis of enterohepatic bile acid circulation by activating hepatic FXR signaling while antagonizing its activity in the intestine. This dual regulatory action operates through two pathways: (1) facilitating bile acid return to the liver, thereby activating hepatic FXR signaling and suppressing CYP7A1-mediated excessive bile acid synthesis; and (2) mitigating intestinal epithelial cell dysfunction caused by FXR overactivation, thereby disrupting the pathogenic cycle of “inflammation-bile acid accumulation-intestinal barrier disruption.” AR113 intervention alleviates western diet-aggravated colitis and associated liver damage, laying the groundwork for subsequent preclinical studies and facilitating the development of novel therapies.