FOS alleviates alcoholic fatty liver disease by modulating gut microbiota and activating the hepatic AMPK/FASN pathway through arachidonic acid.

Alcoholic fatty liver disease AFLDrepresents a significant global health challenge that cannot be overlooked. Clinically available treatments for AFLD are limited and often associated with substantial side effects. Consequently, there is an urgent need for novel, effective therapeutic agents targeting AFLD. Fructooligosaccharides FOS represent a superior class of prebiotics characterized by both natural origin and functional activity, exhibiting multiple biological effects including lipid-lowering, blood glucose regulation, and immune enhancement. However, systematic research on the protective efficacy of FOS in AFLD and its underlying molecular mechanisms remains scarce.METHODS: An AFLD mouse model was established by feeding Lieber-DeCarli alcohol liquid diet. Following FOS intervention, the protective effects on liver injury and lipid deposition in AFLD mice were evaluated using serum and liver biochemical indicators, HE staining, Oil Red O staining, and Nile Red staining. Combining non-targeted metabolomics, 16S rRNA high-throughput sequencing, transcriptomics, Western blotting, and real-time quantitative PCR, we systematically elucidated the potential molecular mechanisms by which FOS ameliorates AFLD.RESULTS: Four weeks of alcohol feeding significantly induced liver injury, disrupted hepatic lipid metabolism, and caused hepatic fat deposition in mice. Alcohol also induced dysbiosis of the gut microbiota and altered the gut metabolome in mice. Following prebiotic FOS intervention, significant improvements were observed in alcohol-induced gut microbiota dysbiosis, altered gut metabolite composition, and increased arachidonic acid metabolite concentration. This intervention also markedly alleviated alcohol-induced hepatic lipid accumulation and injury in mice. Molecular mechanism analysis revealed that FOS enhances AMPK phosphorylation activity in alcohol-induced mouse livers via the gut microbiota metabolite arachidonic acid. This activates PPAR expression while suppressing FASN and SREBP-1C expression , thereby regulating lipid metabolism and improving alcoholic fatty liver disease.CONCLUSIONS: FOS effectively alleviates alcoholic fatty liver disease in mice through a potential mechanism involving regulation of the gut microbiota-metabolome balance. By activating the hepatic AMPK/FASN pathway via the enteric metabolite arachidonic acid, FOS inhibits hepatic lipid synthesis and promotes expression of genes related to lipid degradation. This reduces alcohol-induced hepatic fat accumulation, thereby improving AFLD.