3-Fucosyllactose Prevents Nonalcoholic Fatty Liver Disease by Modulating the Gut Microbiota-Derived Pantothenate in Mice

Nonalcoholic fatty liver disease (NAFLD) is a growing global health threat. Human milk oligosaccharides (HMOs) exhibit prebiotic properties that may alleviate NAFLD progression. Herein, our study demonstrates that 3-fucosyllactose (3-FL), a distinctive and crucial HMO, significantly attenuates body weight gain, enhances hepatic lipid metabolism, and reduces inflammation in a high-fat diet (HFD)-induced NAFLD mouse model. These findings suggest its potential as a dietary supplement for preventing and alleviating NAFLD progression. Subsequently, fecal metagenomic and nontargeted metabolomics analyses revealed that 3-FL treatment significantly alleviated HFD-induced gut microbiota dysbiosis, with a specific enhancement of the pantothenate (vitamin B5) metabolic pathways. Our targeted metabolite analysis further revealed a significant increase in both hepatic and fecal pantothenate concentrations, which contributed to the enhancement of the coenzyme A (CoA)-mediated lipid metabolism pathway. Furthermore, the subsequent population cohort analyses revealed a significant correlation between serum pantothenate levels and the progression of NAFLD, thereby reinforcing its candidacy as a noninvasive diagnostic biomarker. These findings show that 3-FL acts as an effective prebiotic to alleviate NAFLD symptoms, in part by enhancing the gut microbiota-mediated pantothenate/CoA metabolic pathway.