Chen Meimei, Huang Kaiyue, Luo Wenqian, Zhang Fei, Gan Huijuan, Yang Zhaoyang
College of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, People's Republic of China.
Fujian Key Laboratory of TCM Health Status Identification, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, 350122, People's Republic of China.
Drug Des Devel Ther. 2025 May 1;19:3611-3630. doi: 10.2147/DDDT.S514189. eCollection 2025.
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.
This study aims to assess whether HDCA is a characteristic BA of MS and to investigate its intervention effects and potential mechanisms.
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.
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 (<0.05), and this was more effective than metformin treatment.
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.
胆汁酸（BAs）在代谢调节中起关键作用，但其在代谢综合征（MS）中的具体功能仍不清楚。猪去氧胆酸（HDCA）在非酒精性脂肪性肝病（NAFLD）中已显示出潜在作用，但其在MS中的作用尚未得到探索。
本研究旨在评估HDCA是否为MS的特征性胆汁酸，并研究其干预效果和潜在机制。
我们采用16S rDNA测序和超高效液相色谱-串联质谱（UHPLC-MS/MS）研究大鼠肠道微生物群和胆汁酸谱的动态变化，并进行指标间的相关性研究，确定HDCA为潜在的特征性胆汁酸。然后，我们比较了HDCA与MS阳性药物（二甲双胍）在MS大鼠中的干预效果。随后，采用肝脏RNA测序（RNA-seq）、基因集富集分析（GSEA）和Wes全自动简单蛋白质印迹分析来研究HDCA改善MS的机制。
HDCA被确定为MS的特征性胆汁酸，与有益肠道细菌呈显著正相关，与有害细菌呈负相关，且与各种MS异常指标高度负相关。HDCA治疗使MS大鼠的代谢异常得到显著改善，在改变血清胆汁酸谱和深刻改变肠道微生物群组成方面起核心作用。RNA-seq和GSEA结果表明，HDCA影响与初级胆汁酸合成和脂肪酸降解相关的基因表达（p<0.05）。Wes分析验证，MS大鼠中的法尼醇X受体（FXR）、细胞色素P450 7A1（CYP7A1）、细胞色素P450 7B1（CYP7B1）、过氧化物酶体增殖物激活受体α（PPARα）、肉碱棕榈酰转移酶1（CPT1）、肉碱棕榈酰转移酶2（CPT2）、脂肪酸结合蛋白1（FABP1）、3-羟基-3-甲基戊二酰辅酶A合成酶1（HMGCS1）和3-羟基-3-甲基戊二酰辅酶A合成酶2（HMGCS2）蛋白在HDCA治疗后表现出显著变化（<0.05），且比二甲双胍治疗更有效。
本研究首次强调HDCA作为MS的治疗候选药物，并为胆汁酸-MS轴提供了新的见解，不过仍需进一步验证。
