The Short Chain Fatty Acid Receptor, Free Fatty Acid-2 Receptor (FFA2), Contributes to Gestational Glucose Homeostasis through a Novel Relationship Between Pancreatic Beta Cells, Short Chain Fatty Acids and the Gut Microbiota

The structure of the human GI microbiota can change during pregnancy, which may influence gestational metabolism; however, the mechanism that it influences metabolism through is unclear. Here we observed that in wildtype (WT) mice, the relative abundance of Actinobacteria and Bacteroidetes increased during pregnancy. Along with these changes, short chain fatty acids (SCFAs), which are mainly produced through gut microbiota fermentation, significantly changed in both the cecum and peripheral blood throughout gestation in these mice. SCFAs are recognized by G protein coupled receptors (GPCRs) such as FFA2, and we have previously demonstrated that the Ffar2 expression is higher in pancreatic islets during pregnancy. Using female Ffar2-/- mice, we explored the physiological relevance of signaling through this GPCR and found that Ffar2-deficient female mice developed fasting hyperglycemia and impaired glucose tolerance in the setting of impaired insulin secretion as compared to WT mice during, but not prior to, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational beta cell mass, observing that Ffar2-/- mice had diminished gestational expansion of beta cells during pregnancy. Interestingly, mouse genotype had no significant impact on the composition of the gut microbiome, but did affect the observed SCFA profiles, suggesting a functional difference in the microbiota. Evaluation the offspring of these mice revealed that maternal FFA2 expression and impaired glucose tolerance during pregnancy had no effect on the growth rates, ad lib glucose and glucose tolerance in the offspring between 3 and 6 weeks of age. Next, Ffar2-null mice (Ffar2-/-) and wild-type (WT) mice were chronically treated with broad range antibiotics to modulate the composition of the gut microbiota. Antibiotic treatment resulted in elevated blood plasma SCFAs and altered the relative concentrations of the individual SCFAs, acetate, propionate and butyrate. Along with these changes in SFCAs, gestational glucose tolerance in WT mice, but not Ffar2-/- mice improved while on antibiotics. Additional data showed that gestational glucose tolerance worsened in Ffar2-/- mice during a second pregnancy. Together, these results suggest a potential link between increased Ffar2 expression in islets and the alteration of circulating SCFA levels, possibly explaining how changes in the gut microbiota contribute to gestational glucose homeostasis.