Gut microbiota regulates hepatic ketogenesis and lipid accumulation in ketogenic diet-induced hyperketonemia by disrupting bile acid metabolism

The ketogenic diet (KD) induces prolonged hyperketonemia, characterized by elevated circulating level of β-hydroxybutyrate. However, the KD can negatively affect host metabolic health by altering the gut microbial community. Despite this, the regulatory effect of the gut microbiota on hepatic ketogenesis and triacylglycerol (TAG) accumulation during a KD remains poorly understood. Here, we hypothesized that the commensal bacterium regulates hepatic lipid metabolism in association with KD-induced hyperketonemia. The KD disrupts the remodeling of the gut microbiota following antibiotic-induced depletion. The capacity for ketogenesis and the severity of TAG accumulation in the liver closely correlated with changes in the gut microbial composition and the up-regulation of hepatic farnesoid X receptor (<i>FXR</i>), peroxisome proliferator-activated receptor alpha (<i>PPARα</i>), and diacylglycerol O-acyltransferase 2 (<i>DGAT2</i>), which were modulated by bile acid metabolism through the gut-liver axis. The commensal bacterium <i>Clostridium perfringens</i> type A is particularly implicated in prolonged hyperketonemia, exacerbating hepatic ketogenesis and steatosis by disrupting secondary bile acid metabolism. The increased conversion of deoxycholic acid to 12-ketolithocholic acid represents a critical microbial pathway during <i>C. perfringens</i> colonization. These findings illuminate the adverse effects of the gut microbiota on hepatic adaptation to a KD and highlight the regulatory role of <i>C. perfringens</i> in ketonic states.