Intestinal Flora Modulates Blood Glucose via Regulating the Secretion of GLP-1 Induced by Propionate in mouse models of Gestational Diabetes Mellitus

Purpose: Intestinal flora has been reported to be associated with metabolic homeostasis. However, the detailed functions of intestinal flora in GDM pathogenesis have not yet been fully elucidated. To investigate the roles and mechanisms of intestinal flora in GDM development. Materials and Methods: We used high fat diet (HFD) to induce mouse models of GDM. The composition, metabolic characteristics and roles of the intestinal florawere investigated using 16S rRNA gene sequencing, targeted metabolomics, and fecal microbiota transplantation. The specific mechanism was analyzed mainly using cell cultures, transfection, western blot. Results: We found HFD successfully induced mouse models of GDM, particularly increased the weight, blood glucose, and decreased GLP-1 concentration in C57BL/6 female mice. The composition and metabolism of intestinal flora in GDM individuals were also significantly changed, including the increased Firmicutes and reduced α-diversity and propionate levels, which negatively correlated with blood glucose. After transplanting the intestinal flora of GDM mice, propionate, GLP-1 secretion and glucose had corresponding changes. By adjusting the diet, especially increasing the intake of OFS, the composition and metabolism of gut microbiota could be reshaped, which further affected GLP-1 secretion and blood glucose. Then, we found that wnt/β-catenin/TCF7L2 signaling pathway participated in the regulation of GLP-1 by propionate. Conclusions: The composition of intestinal flora in GDM mice changed and thereby reduced its metabolite propionate in the intestine, further inhibiting of Wnt /β-catenin/TCF7L2 signaling pathway, resulting in decrease of GLP-1 secretion and increase of blood glucose. These findings suggested gut microbiota may be used as a potential target for the treatment of GDM.