Modified Freshwater Fish Oil Ameliorates Metabolic Disorders by Modulating Gut Microbiota and Liver Metabolism in High-Sucrose High-Fat Diet-Fed Mice

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major global health issue, largely driven by high-sugar and high-fat diets (HSHF). In this study, enzymatically modified grass carp fish oil (MFO), rich in medium- and long-chain triglycerides composed of medium-chain and long-chain fatty acids, was developed to investigate its protective effect on HSHF-induced MASLD in C57BL/6 mice. MFO supplementation significantly alleviated obesity, hepatic steatosis, dyslipidemia, and improved liver function. It remodeled the gut microbiota, elevating beneficial bacterial genera, increasing fecal short-chain fatty acid (SCFA) levels, and strengthening intestinal barrier integrity. Lipidomics and transcriptomics revealed that MFO regulated hepatic glycerophospholipid metabolism and modulated key genes, including Mboat1, Lpin1, and Pnpla3. A system-level mechanism underlying MFO’s metabolic benefits was elucidated through an integrated network that linked gut microbiota, SCFAs, lipid species, and host gene expression. MFO supplementation was a promising nutraceutical strategy for MASLD intervention, achieved through targeted modulation of a gut-liver axis.