Hyodeoxycholic Acid Ameliorates Metabolic Syndrome Through Pathways of Primary Bile Acid Synthesis and Fatty Acid Degradation: Insights From a Rat Model

Meimei Chen,1,2,* Kaiyue Huang,1,2,* Wenqian Luo,1,2 Fei Zhang,1,2 Huijuan Gan,1,2 Zhaoyang Yang1– 3 1College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, People’s Republic of China; 2Fujian Key Laboratory of TCM Health Status Identification, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, People’s Republic of China; 3Key Laboratory of Orthopedics & Traumatology of Traditional Chinese Medicine and Rehabilitation Ministry of Education, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, People’s Republic of China*These authors contributed equally to this workCorrespondence: Huijuan Gan; Zhaoyang Yang, Email [email protected]; [email protected]: Bile acids (BAs) play a crucial role in metabolic regulation, but their specific functions in metabolic syndrome (MS) remain unclear. Hyodeoxycholic acid (HDCA) has shown potential effects in non-alcoholic fatty liver disease (NAFLD), yet its role in MS is unexplored.Aim: This study aims to assess whether HDCA is a characteristic BA of MS and to investigate its intervention effects and potential mechanisms.Methods: We employed 16S rDNA sequencing and UHPLC-MS/MS to investigate the dynamics of the gut microbiota and BA profiles in rats and conducted a correlation study between indices, identifying HDCA as the potential characteristic BA. We then examined its interventional effects in MS rats comparing efficacy with the positive drug of MS (metformin). Subsequently, liver RNA sequencing (RNA-seq), gene set enrichment analysis (GSEA), and Wes Automated Simple Western assays were employed to investigate mechanisms of HDCA ameliorating MS.Results: HDCA was identified as a characteristic BA for MS, exhibiting a significant positive correlation with beneficial gut bacteria and a negative correlation with harmful bacteria, and highly inversely related to various abnormal MS indexes. HDCA treatment led to significant improvements in metabolic abnormalities in MS rats, with a central role in altering serum BA profiles and profoundly modifying the gut microbiome composition. The results of RNA-seq and GSEA indicated that HDCA influenced the expression of genes related to primary bile acid synthesis and fatty acid degradation (p< 0.05). Wes assays validated that FXR, CYP7A1, CYP7B1, PPARα, CPT1, CPT2, FABP1, HMGCS1 and HMGCS2 proteins in MS rats exhibited significant changes after HDCA treatment (p< 0.05), and this was more effective than metformin treatment.Conclusion: These study is the first to highlight HDCA as a therapeutic candidate for MS and provides new insights into the BA-MS axis, though further validation is needed. Keywords: metabolic syndrome, bile acid, gut microbiota, hyodeoxycholic acid, animal model, obesity