<i>Lactobacillus reuteri</i> targets FXR-dependent bile acid homeostasis to ameliorate alcoholic liver disease

Alcoholic liver disease (ALD) is characterized by gut dysbiosis, yet the functional contribution of specific commensals remains largely unexplored. Here, we identify a significant reduction of Lactobacillus reuteri in both ALD patients and mouse models compared with their respective healthy controls. Using fecal microbiota transplantation (FMT), we first establish a causative role of the dysbiotic gut microbiota in driving ALD pathophysiology. In line with this finding, oral supplementation with L. reuteri ameliorates ALD phenotypes. Mechanistically, L. reuteri activates the farnesoid X receptor (FXR) signaling pathway, thereby restoring bile acid homeostasis, as evidenced by reduced levels of cholic acid (CA) and deoxycholic acid (DCA). The functional importance of FXR is further validated in Fxr-/- mice, where the protective effects of L. reuteri on both ALD and bile acid metabolism are largely abrogated. Moreover, both in vitro and in vivo experiments confirm that CA and DCA directly compromise hepatocyte viability and exacerbate liver injury, reinforcing their roles as pathogenic effectors downstream of FXR dysregulation. Expanding upon these mechanistic insights, we identify the natural compound echinacoside as a gut microbiota-targeting intervention that not only enriches L. reuteri but also potentiates FXR signaling, leading to significant improvement of ALD. Collectively, our findings define a microbiota-host metabolic axis centered on L. reuteri and FXR-dependent bile acid homeostasis, offering a conceptual framework for targeting host-microbe interactions in alcoholic liver disease.