Prebiotic xylooligosaccharides ameliorate metabolic dysfunction-associated steatotic liver disease via modulating gut microbiota and metabolites

The study investigated the dose-dependent protective effects of xylooligosaccharides (XOS) against metabolic dysfunction-associated steatotic liver disease (MASLD) in mice, focusing on gut microbiota and microbial metabolites. Male C57BL/6 mice were fed either a low-fat diet(LFD), a high-fat diet (HFD), HFD supplemented with low-dose XOS (0.38 g/kg), or HFD supplemented with high-dose XOS (1.0 g/kg) for 16 weeks. Hepatic histology, serum biochemistry, ileal morphology, gut microbiota composition (16 S rRNA gene sequencing), and fecal metabolites profiles were analyzed. High-dose XOS, but not low-dose, significantly reduced serum Alanine aminotransferase (ALT) and Triglycerides (TG) levels, alleviated hepatic steatosis, and improved the villus height–to–crypt depth ratio. It attenuated HFD-induced enrichment of Ruminococcaceae and Lachnospiraceae, while restoring the abundance of Bacteroidaceae, Bifidobacteriaceae and Bacillaceae. Metabolomic analysis revealed rebalancing of the tryptophan–indole and arachidonic-acid pathways, with reduced pro-inflammatory eicosanoids and kynurenine derivatives, and increased hepatoprotective indole derivatives and omega-3 polyunsaturated fatty acids. High-dose XOS reconstructs the gut microbiota-metabolite network toward an anti-inflammatory, hepatoprotective state in HFD-fed mice, underscoring the importance of dose optimization in XOS-based interventions for MASLD.