title: The short-chain fatty acid receptor, FFA2, contributes to gestational glucose homeostasis.
abstract: The structure of the human gastrointestinal microbiota can change during pregnancy, which may influence gestational metabolism; however, a mechanism of action remains unclear. Here we observed that in wild-type (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 free fatty acid receptor-2 (FFA2), and we have previously demonstrated that the fatty acid receptor-2 gene (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 compared with WT mice during, but not before, pregnancy. Insulin tolerance tests were similar in Ffar2-/- and WT mice before and during pregnancy. Next, we examined the role of FFA2 in gestational β-cell mass, observing that Ffar2-/- mice had diminished gestational expansion of β-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. 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 microbiome contribute to gestational glucose homeostasis.
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Miles
authors.initials: M
authors.lastname: Fuller
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Medha
authors.initials: M
authors.lastname: Priyadarshini
authors.affiliation: Graduate Program in Biophysical Sciences, University of Chicago, Chicago, Illinois; Institute for Genomic and Systems Biology, Argonne National Laboratory, Argonne, Illinois;
authors.forename: Sean M
authors.initials: SM
authors.lastname: Gibbons
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Angueira
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: Michael
authors.initials: M
authors.lastname: Brodsky
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: M Geoffrey
authors.initials: MG
authors.lastname: Hayes
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Petia
authors.initials: P
authors.lastname: Kovatcheva-Datchary
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden;
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Graduate Program in Biophysical Sciences, University of Chicago, Chicago, Illinois; Institute for Genomic and Systems Biology, Argonne National Laboratory, Argonne, Illinois; Department of Ecology and Evolution, University of Chicago, Chicago, Illinois; Marine Biological Laboratory, Woods Hole, Massachusetts; College of Environmental and Resource Sciences, Zhejiang University, Hangzhou, China; Department of Surgery, University of Chicago, Chicago, Illinois; and.
authors.forename: Jack A
authors.initials: JA
authors.lastname: Gilbert
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
authors.forename: William L
authors.initials: WL
authors.lastname: Lowe
authors.affiliation: Division of Endocrinology, Metabolism and Molecular Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois b-layden@northwestern.edu.
authors.forename: Brian T
authors.initials: BT
authors.lastname: Layden
mesh_terms: D039903:Actinobacteria / Q000145:classification / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism; D000818:Animals; D041963:Bacteroidetes / Q000145:classification / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism; D002432:Cecum / Q000378:metabolism / Q000382:microbiology; D016640:Diabetes, Gestational / Q000097:blood / Q000378:metabolism* / Q000382:microbiology; D005232:Fatty Acids, Volatile / Q000097:blood / Q000378:metabolism*; D005260:Female; D005285:Fermentation; D005766:Gastrointestinal Contents / Q000737:chemistry / Q000382:microbiology; D000069196:Gastrointestinal Microbiome; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058889:Molecular Typing; D011247:Pregnancy; D011255:Pregnancy Maintenance; D025341:Principal Component Analysis; D011956:Receptors, Cell Surface / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D008973:Tenericutes / Q000145:classification / Q000254:growth & development / Q000302:isolation & purification / Q000378:metabolism; D046509:Tissue Culture Techniques; D043562:Receptors, G-Protein-Coupled
chemical_list: D005232:Fatty Acids, Volatile; D007328:Insulin; D011956:Receptors, Cell Surface; C506481:Ffar2 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: free fatty acid receptor-2; gut microbiome; islets