Niacin and B. animalis subsp. lactis F1-7 Additively Attenuate Alcohol-Induced Liver Injury in a Gut Microbiota-Dependent Manner via the HCAR2-NLRP3 Pathway

Objectives: This study explored whether the combined administration of niacin and B. animalis subsp. lactis F1-7 exerts a protective effect against alcohol-induced liver injury via the gut-liver axis, with a specific focus on the HCAR2-NLRP3 signaling pathway, and further investigated the functional roles of gut microbiota and metabolites. Methods: A mouse model of alcoholic fatty liver disease was established via chronic ethanol feeding with the Lieber–DeCarli liquid diet. Experimental animals were divided into six intervention groups: control group, model group, niacin alone, F1-7 alone, combined niacin and F1-7 (NF), and antibiotic pretreatment followed by NF intervention. Results: The NF intervention significantly improved serum lipids, reduced ALT/AST, alleviated hepatic steatosis and inflammation, and restored intestinal barrier integrity, while upregulating HCAR2 and suppressing NLRP3 activation; these effects were largely abolished by antibiotics. The 16S rRNA sequencing revealed that NF intervention reshaped the gut microbiota, enriching beneficial genera such as Lactobacillus, Bifidobacterium, and Faecalibaculum. Untargeted metabolomics showed that NF intervention enriched the ketone body β-hydroxybutyrate, which was positively correlated with the abundance of beneficial bacteria; this metabolite was identified as a key node in the ketone-body synthesis/degradation pathway and ranked among the top differential metabolites by VIP score. Conclusions: The combination additively alleviates alcohol-induced hepatic and intestinal injury in a gut microbiota-dependent manner. Intestinal β-hydroxybutyrate was enriched following the combined intervention in a microbiota-dependent fashion, and this enrichment was associated with HCAR2 activation and NLRP3 inhibition. These findings demonstrate that the protective action is largely dependent on an intact gut microbiota and support the combined intervention as a promising strategy against alcoholic liver disease.