Blautia coccoides Alleviates Acute Pancreatitis via Bile Salt Hydrolase-mediated Deoxycholic Acid Production and Farnesoid X Receptor Signaling.

Abstract

BACKGROUND & AIMS: Gut dysbiosis is involved in the pathogenesis of acute pancreatitis (AP), yet therapeutic interventions remain limited. Our previous study found the relative abundance of Blautia is significantly decreased in AP, suggesting its protective role. METHODS: We quantified Blautia coccoides in patients with AP and tested its effects in AP mice. Untargeted metabolomics identified deoxycholic acid. Farnesoid X receptor (FXR) signaling was tested with agonists and antagonists. 16S rRNA sequencing was applied to explore changes of gut microbiota. In vitro co-culture assays verified the microbial interaction. The role of bile salt hydrolase (BSH) was confirmed through experiments involving inhibitor and BSH-engineered E coli. RESULTS: We observed reduced B coccoides in patients with AP that correlated with disease severity. In AP mice, gavage of B coccoides mitigated pancreatic and intestinal injury. Untargeted metabolomics revealed the increased level of deoxycholic acid (DCA), which could reproduce the protective phenotype of B coccoides. We further found that DCA acts primarily within the intestine to activate FXR, which suppressed pro-inflammatory nuclear factor κB (NF-κB) and NLRP3 pathways. FXR activation also induced production of fibroblast growth factor 15 (FGF15), which protected pancreatic acinar cells. 16S rRNA sequencing showed that B coccoides increased the abundance of BSH-producing genera, Parabacteroides and Bacteroides. In vitro, B coccoides supernatant promoted the growth of representative strains from these genera. Inhibition of BSH abrogated the protective effects of B coccoides, whereas administration of BSH-engineered E coli could ameliorate AP. CONCLUSIONS: B coccoides alleviated AP by reshaping gut microbiota composition, enhancing BSH-mediated DCA production, and activating the intestinal FXR-FGF15 signaling to suppress inflammation.