Gut microbiota contributes to gestational diabetes mellitus by interfering with bile acid metabolism and resistin.

Abstract

INTRODUCTION: Gestational diabetes mellitus (GDM) affects 6% to 15% of pregnancies globally, as a severe metabolic disorder that impairs offspring health. Mounting evidence highlights the critical role of gut microbiota in metabolic regulation, yet the causal relationship between gut microbiota and GDM pathogenesis remains unclear. This study aimed to clarify this causal link and explore the underlying mechanisms. METHODS: An innovative human microbiota transplantation approach was adopted. Gut microbiota from GDM patients was transplanted into antibiotic-treated C57BL/6J mice. 16S rRNA sequencing was used to analyze the structural changes of gut microbiota in recipient mice, and metabolomics was employed to detect changes in circulating bile acid levels. For mechanism exploration, Luminex assay was used to detect multiple inflammatory factors, enzyme-linked immunosorbent assay (ELISA) was applied to measure lipopolysaccharide (LPS) levels, and Western blot (WB) was utilized to determine the expression of intestinal barrier protein. RESULTS: Transplantation of gut microbiota from GDM patients directly induced glucose intolerance in pregnant antibiotic-treated C57BL/6J mice. 16S rRNA sequencing showed significant structural reorganization of the gut microbiota in GDM microbiota recipients, characterized by decreased abundance of Lachnospiraceae__group and increased abundance of Akkermansia, Faecalibaculum, and Bilophila. These microbiota dysregulations led to reduced expression of the intestinal barrier protein Claudin-1, elevated serum lipopolysaccharide (LPS) levels, and increased resistin and matrix metalloproteinase 9 (MMP-9) levels. Metabolomic analysis revealed decreased circulating primary bile acids (cholic acid [CA] and chenodeoxycholic acid [CDCA]) and secondary bile acid deoxycholic acid (DCA). Correlation analysis indicated a positive correlation between Faecalibaculum and DCA, CDCA, as well as resistin. DCA and CDCA were significantly negatively correlated with HOMA-IR, while resistin was significantly positively correlated with GTT-AUC, FINS, and HOMA-β%. CONCLUSION: These findings suggest that the imbalance in bile acid metabolism and mild inflammatory response caused by dysregulated gut microbiota is an adjustable environmental driving factor in the pathophysiological process of GDM.