Gut Microbiota And Metabolomic Profiling Of Women With Gestational Diabetes Mellitus And Their Infants

ObjectiveGestational diabetes mellitus（GDM）is defined as any degree of glucose intolerance with onset or first recognition during pregnancy.GDM reflects an increased risk of developing type 2 diabetes（T2D）postpartum.Offspring born to mothers with GDM are at an elevated risk of obesity,T2D and metabolic syndrome at a young age.Recent studies have found that alterations in gut microbiota and metabolome during pregnancy may underlie these associations.The current study was designed to characterize the gut microbiota composition and metabolic profiling of women diagnosed of GDM and their offspring,and to provide new evidence on maternal and fetal characteristics of the gut microbiota and metabolomics associated with GDM.Methods:Patients at full-term pregnancy were recruited in 2 medical centres.Faecal samples and peripheral fasting plasma sample were obtained from GDM patients and Controls at full-term.Cord blood plasma samples were obtained within 5 min of delivery and prior to delivery of the placenta.Meconium were collected within 48h of birth.Based on the Illumina HiSeq Sequencing System,the V3-V4 region of 16S rDNA were analyzed.Maternal and fetal cord blood plasma were studied by UPLC-Q/TOF-MS technology.Results:1.We recruited 165 pregnant women and their newborns,including 88 gestational diabetes mellitus pregnant women and their newborns and 77 controls.There was no significant difference in age,gestational age,pre-pregnancy and prenatal BMI and blood pressure between the GDM group and the control group.The fetal birth weight of the GDM group was higher than that of the healthy group,but it was not statistically significant.2.Glycosylated hemoglobin（HbAlc）and glycated albumin（GA）were higher in GDM patients than healthy controls,which was statistically significant.Free fatty acid（FFA）in the GDM group was higher than the control group,but it was not statistically significant.3.2130 OTUs and 549 OTUs were unique to GDM and control mothers,and 1150 OTUs and 2282 OTUs were unique to GDM and control babies,respectively.4.a diversity analysis showed that ACE、Chao1、Observed_species、Shannon index were significantly higher in GDM mothers compared to controls,and were lower in GDM babies compared to controls.5.PCoA analysis showed that the overall compositions of the gut microbiota were significantly different between GDM and control groups,and the separation trend was obvious.6.The abundance of Firmicutes in the maternal GDM group was significantly lower than that in the control group.The abundance of Acidobacteria and Actinobacteria in GDM group was higher than that in the control group.The abundance of Delta Proteobacteria,Desulfovibrionales,Desulfarculaceae,and Desulfovibrio in the Proteobacteria were significantly higher in the GDM group than in the healthy control group.7.OTU₁03（Alistipes_shahii）,OTU₆7（s_arabacteroides_distasonis）,OTU₁9（s_Bacteroides_fragilis）were enriched in maternal GDM group,OTU₇（s_Roseburia_inulinivorans）,OTU₉1（Eubacterium_hallii）,OTU₆1（butyrate-producing bacterium GM2/1）were enriched in maternal healthy controls.8.Maternal OTU₃（s_Escherichia_coli）was positively correlated with maternal HOMA-IR index,and maternal OTU₇（s_Roseburia_inulinivorans）was negatively correlated with fasting blood glucose,HbA1c,cholesterol and triglyceride.9.The abundance of genus Phyllobacterium,Bacteroides,Veillonella,Actinomyces were higher in fetal GDM group.The abundance of genus Prevotella were higher in the control group.10.OTU₃59（s_Bacteroides_thetaiotaomicron）and OTU₁9（s_Bacteroides_fragilis）were enriched in fetal GDM group.OTU 199（s_Ruminococcus_sp_Marseille-P328）、OTU₈7（Bradyrhizobium_elkanii）were enriched in the control group.11.The abundance of fetal OTU₃（s_Escherichia coli）was positively correlated with cord blood glucose,free fatty acid and C-peptide.The abundance of OTU₁9（s_Bacteroides_fragilis）was positively correlated with free fatty acid.12.The mother and fetal gut microbiota had 166 identical OTUs,of which 76 OTUs have the same distribution trend in GDM and the control group.A total of 64 OTUs were positively related,including OTU₃ Escherichia coli,OTU₉（Bacteroides_plebeius）,OTU₁78（Anaerostipes hadrus）,OTU 359（Bacteroides_thetaiotaomicron）,OTU 23（Ruminococcus_bromii）.13.In metabolomics,in the model of OPLS-DA,maternal and fetal cord blood metabolomics were significantly different in GDM group and controls.The separation trend was obvious.14.Based on the OPLS-DA model,The discriminatory power of each metabolite was quantified by means of variable importance for the projection（VIP）parameters.A metabolite with a>1.0 VIP score was considered important in the discrimination.A total of 1268 metabolites were obtained.This study found that the levels of isoleucine,tyrosine,threonine and serotonin in maternal peripheral blood and fetal cord blood in the GDM group were higher than the controls.The blood levels of butyric acid in maternal and fetal plasma were significantly higher than those in GDM group.15.Serotonin which i s enriched in maternal GDM group was positively correlated with maternal free fatty acids and triglycerides.Umbilical cord blood serotonin level was positively correlated with fetal triglyceride,free fatty acid and hsCRP.16.A total of 168 metabolites shared by mother and fetus were at the same distribution trend in 2 groups.Among these,phenylacetic acid,uric acid,dityrosine,and linoleic acid were enriched in the GDM group,and betaine,oleic acid,2-Oxo-4-methylthiobutanoic acid were enriched in healthy controls.17.Metabolic pathway analysis revealed abnormalities in glycophospholipid metabolism,cysteine and methionine metabolism in GDM group.18.Maternal plasma and umbilical cord blood plasma betaine levels in the GDM group were lower than those in the control group,and were negatively correlated with maternal fasting blood glucose.Conclusion:There were significant differences in the gut microbiota and metabolomics between the GDM group and the control group in both mothers and fetus.Correlations between mothers and fetuses were observed in gut microbiota and metabolomics.The abundance of B.fragilis was increased,and the abundance of butyrate-producing bacteria was significantly reduced in maternal and fetal GDM group.Serotonin and homocysteine were enriched in GDM group,whereas butyrate and betaine were enriched in the control group.The current study provides new data about the gut microbiota and metabolic profile characteristic of GDM mothers and fetuses,which help to provide insight into the underlying mechanisms and metabolic consequences of GDM.