Vinegar-processed Paeonia lactiflora Pall. ameliorates alcoholic liver disease through the modulation of gut microbiota and FXR-FGF15 gut-liver axis.

Abstract

<p>ETHNOPHARMACOLOGICAL RELEVANCE: Paeonia lactiflora Pall. (PR) is a traditional Chinese medicine (TCM) renowned for its actions in nourishing blood and soothing liver. Guided by the theory of "vinegar processing into the liver meridian", vinegar-processed PR (PRV) is clinically preferred for liver diseases owing to its enhanced properties in soothing liver and ameliorating liver injury. Nevertheless, the efficacy differences and underlying mechanisms of PR and PRV against alcoholic liver disease (ALD) remain unclear. AIM OF THE STUDY: This study aimed to systematically evaluate the efficacy of PR and PRV against ALD, and to elucidate the underlying mechanism of enhanced hepatoprotective effects of PRV from the perspective of the gut-liver axis by multi-omics approaches. MATERIALS AND METHODS: UHPLC-Q-Exactive Orbitrap mass spectrometry combined with multivariate data analysis was employed to identify the chemical composition of PR and PRV. A Lieber-DeCarli liquid ethanol diet-induced ALD mice model was established in C57BL/6 mice, and the effects of PR and PRV on ALD-related liver injury and steatosis were evaluated using biochemical and histopathological analyses. Alterations of gut microbiota composition and bile acid (BA) profiles were assessed by 16S rRNA gene sequencing and LC-MS/MS, respectively. Furthermore, we conducted quantitative Real Time-PCR and western blotting to determine the mRNA and protein expression levels of Farnesoid X Receptor (FXR)-fibroblast growth factor 15 (FGF15) signaling pathway, respectively, which are involved in BAs metabolism and enterohepatic circulation. Fecal microbiota transplantation (FMT) was utilized to validate the mechanism underlying the enhanced therapeutic efficacy of PRV against ALD. RESULTS: Vinegar processing significantly altered the phytochemical profile of PR, increasing phenolic acids and specific monoterpene glycosides components. PRV demonstrated superior efficacy over PR in alleviating dyslipidemia, hepatic steatosis, and inflammatory damage, while effectively restoring intestinal barrier integrity and reducing endotoxin translocation. Moreover, PRV modulated the composition of gut microbiota associated with ALD risk, such as Parasutterella, Allobaculum, Paramuribac ulum, and CAG_485. Mechanistically, this microbial restructuring was associated with BA metabolism normalization and intestinal FXR-FGF15 axis activation, which in turn suppressed hepatic Cyp7A1 expression, thereby reducing hepatic cholesterol accumulation and lipogenesis in the ALD model. CONCLUSION: Our findings indicate that PRV alleviates ALD by restoring BA metabolism and activating the FXR/FGF15 pathway by regulating gut microbiota balance. These findings provide valuable data supporting the vinegar processing efficacy enhancement theory of TCM, thereby facilitating the clinical application of PRV and guiding future drug and dietary supplement development efforts.</p>