Unsaturated alginate oligosaccharides alleviate insulin resistance and fatty liver in non-obese NAFLD mice by regulating bile acid metabolism through gut microbiota

Despite the rising global incidence of non-obese non-alcoholic fatty liver disease (NAFLD), this condition has received limited attention. Unsaturated alginate oligosaccharides (UAOS) have shown promising potential in the management of metabolic diseases. In this study, we used liver-specific growth hormone receptor (GHR) knockout mice as a model for non-obese NAFLD and treated them with UAOS. Our findings demonstrated that UAOS effectively ameliorated insulin resistance and hepatic steatosis in GHR-deficient mice. Additionally, UAOS improved intestinal barrier integrity, altered gut microbiota composition, and increased the relative abundance of beneficial bacteria, including <i>Dubosiella</i>, <i>Akkermansia</i>, <i>Lachnoclostridium</i>, <i>Faecalibaculum</i>, <i>Romboutsia</i>, and <i>Turicibacter</i>, while reducing the prevalence of harmful bacteria. Fecal metabolomics analysis revealed significant reductions in taurohyodeoxycholic acid and isodeoxycholic acid. Furthermore, UAOS may modulate the synthesis and secretion of secondary bile acids through the gut microbiota, potentially inhibiting hepatic bile acid synthesis and contributing to the maintenance of bile acid homeostasis via the FGF15-FGFR4-CYP7A1 signaling pathway. These mechanisms ultimately contributed to improved hepatic lipid metabolism. Together, these results position UAOS as a promising prebiotic candidate for the treatment of non-obese NAFLD.