2132-P: Vertical Transmission of Gut Microbiota Affects Offspring Liver Development and Metabolism from Gestational Diabetes Mellitus Patients via Hyodeoxycholic Acid-RNA Methylation

Introduction and Objective: Gestational Diabetes Mellitus (GDM) threatens maternal and offspring health; mechanisms are unclear. Previous studies show abnormal bile acids and RNA methylation in offspring. We aimed to identify key abnormally transmitted microbiota and elucidate how they affect offspring liver development and metabolism. Methods: We recruited 15 GDM and 15 healthy mothers, collecting serum and fecal samples pre- and post-delivery, plus offspring feces. Clinical and bile acid metabolomics identified key microbiota. Fecal transplants into germ-free mice generated offspring. Metabolic indicators and bile acids were measured. Liver MeRIP-seq screened pathways, and hyodeoxycholic acid (HDCA) supplementation validated findings. Results: GDM patients and their offspring exhibited distinct gut microbiota characteristics, with reduced HDCA levels in both. The gut microbiota from GDM patients induced abnormal glucose metabolism in both the humanized microbiota mice and their offspring. Furthermore, the gut microbiota from GDM patients downregulated liver development and impaired metabolic function in the offspring of humanized mice, accompanied by decreased hepatic RNA methylation levels and reduced expression of the methyltransferase METTL14. The methylation modification level of hepatic CYP7A1 was also reduced. Further investigation using a cross-generational animal model of gestational hyperglycemia clarified the signaling pathways through which HDCA influences liver development and metabolism. Conclusion: Abnormal microbiota transmission reduces HDCA in GDM offspring, impairing glucose metabolism via hepatic CYP7A1 RNA methylation. These findings link microbiome, bile acids, and RNA methylation in gestational diabetes intergenerational inheritance.