Gut Microbiota-Mediated Bile Acid Disruption Exacerbates Ketogenic Diet-Induced Hepatic Metabolic Disorders

Recently, Professor Cao Suizhong’s team from the College of Veterinary Medicine at Sichuan Agricultural University published a research paper titled “Gut Microbiota Regulates Hepatic Ketogenesis and Lipid Accumulation in Ketogenic Diet-Induced Hyperketonemia by Disrupting Bile Acid Metabolism” in the journalGut Microbes. This study elucidates the molecular mechanisms through which a ketogenic diet induces hepatic metabolic disorders via the gut microbiota–bile acid metabolism axis, identifying a crucial “behind-the-scenes player”—Clostridium perfringens.

Although the ketogenic diet is widely employed for weight loss and the management of metabolic diseases, its associated persistent hyperketonemia can lead to hepatic fat accumulation and metabolic disorders. While it is established that gut microbiota are closely related to nutrient metabolism, the specific role they play in ketogenic diet-induced hepatic metabolic dysfunction remains unclear. The research team found that the ketogenic diet alters gut microbiota homeostasis, resulting in an imbalance in gutmicrobiota-mediated bile acid metabolism that subsequently induces hepaticlipidaccumulation. Through fecal microbiota transplantation experiments, the team discovered that mice transplanted with gut microbiota from hyperketonemic donors exhibited significantly elevated levels of ketone bodies in their blood and hepatic lipid accumulation, along with a marked increase in the “activity” ofClostridium perfringensin the gut. Expression levels of key enzymes involved in de novo lipogenesis and hepatic ketogenesis, such as HMGCS2, BDH1, and DGAT2, were significantly upregulated. To confirm whether the intestinal commensalClostridium perfringensacts as a “metabolic steward” disrupting bile acid metabolism, the research team conducted in vitro culturing andoralinterventionof bacterium, revealing thatClostridium perfringensdisrupted the metabolic balance of deoxycholic acid (DCA) conversion to 12-ketolithocholic acid (12-ketoLCA), activating the FXR-PPARα signaling axis and contributing to hepatic metabolic imbalance.

This study is a continuation of the team’s previous clinical cohort and multi-omics investigations into the association between perinatal cow gut microbiota and ketosis (related research results have been published in journals such asmSystems,Microbiology Spectrum, and theJournal of Dairy Science) and further elucidates the regulatory mechanisms governing the interactions between gut microbiota and bile acid metabolism on liver lipid metabolism. In the future, targeted interventions based on the gut symbiotic bacteriumClostridium perfringensand its associated metabolites are anticipated to become a significant focus for the management of metabolic diseases.

Dr. Zhengzhong Luo and Dr. Yixin Huang from theCollege of Veterinary Medicine at Sichuan Agricultural University, and Associate Professor.Yong Kang from Chongqing Three Gorges Polytechnic Collegeserved as co-first authors of the paper. The corresponding authors are Professor.SuizhongCaofrom theCollege of Veterinary Medicine at Sichuan Agricultural University and Associate Professor.Baoning Wangfrom the West China School of Basic Medical Sciences and Forensic MedicineatSichuan University. This work was supported by the Natural Science Foundation of Sichuan, China, the Science and Technology Research Program of Chongqing Municipal Education Commission, China, and Key R and D Program Supported by the Department of Science & Technology of Xizang Autonomous Region, China .

Paper information:https://www.tandfonline.com/doi/full/10.1080/19490976.2025.2496437?src=exp-la