Medium-chain inulin reshapes the gut microbiome-metabolome axis to counteract high-fat diet-induced obesity

BACKGROUND: Inulin, a natural dietary fiber, exerts diverse health benefits that are closely linked to its molecular structure. However, the biological activity of medium-chain inulin and its role in high-fat diet (HFD)-induced obesity remain poorly characterized. OBJECTIVE: This study aimed to determine whether medium-chain inulin could alleviate high-fat diet (HFD)-induced obesity by modulating the gut microbiota and metabolome, thereby restoring metabolic homeostasis. METHODS: Forty male C57BL/6 mice were fed either a standard chow diet or an HFD with 1%, 3%, or 5% medium-chain inulin (average degree of polymerization = 12) for 12 weeks. Body weight (BW), physiological indices, gut microbiota, and metabolome were analyzed to elucidate the underlying mechanisms. Short-chain fatty acids (SCFAs) were quantified by gas chromatography. Cecal microbiota and metabolome were analyzed using 16S rRNA sequencing and LC-MS/MS, respectively. Correlation and pathway analyses were conducted to identify key microbe-metabolite interactions. RESULTS: Medium-chain inulin supplementation significantly reduced BW gain (by 16% and 20% at 3% and 5% doses, respectively), increased acetic and butyric acid levels, and improved serum and hepatic lipid profiles. It reshaped the gut microbiota by enriching Faecalibaculum, Bifidobacterium, Parasutterella, Clostridium_sensu_stricto_1, Bacteroides, Lactobacillus, and Akkermansia. Metabolomic analysis revealed elevated levels of eight key metabolites related to tryptophan metabolism and bile acid metabolism, correlating with improved metabolic indicators. CONCLUSION: Medium-chain inulin alleviated HFD-induced obesity by remodeling the gut microbiome-metabolome axis and promoting SCFA production. These findings highlight its potential as a functional prebiotic candidate for obesity-related metabolic disorders.