Abstract-The risk of developing pregnancy-induced hypertension and preeclampsia is higher in obese pregnant women.In obesity, the composition of the gut microbiota is altered. Obesity is also associated with low-grade inflammation.Metabolites from the gut microbiota may contribute to both hypertension and inflammation. The aim of this study is to investigate whether the composition of the gut microbiota in overweight and obese pregnant women is associated with blood pressure and levels of plasminogen activator inhibitor-1. The composition of the gut microbiota was determined with 16S ribosomal RNA sequencing in 205 women at 16 weeks gestation from the SPRING study (the Study of Probiotics in Gestational Diabetes). Expression of butyrate-producing genes in the gut microbiota was assessed by realtime polymerase chain reaction. Plasminogen activator inhibitor-1 levels were measured in fasting serum of a subset of 70 women. Blood pressure was slightly but significantly higher in obese compared with overweight women. The abundance of the butyrate-producing genus Odoribacter was inversely correlated with systolic blood pressure. Butyrate production capacity was decreased, but plasminogen activator inhibitor-1 concentrations increased in obese pregnant women. Plasminogen activator inhibitor-1 levels were inversely correlated with expression of butyrate kinase and Odoribacter abundance. This study shows that in overweight and obese pregnant women at 16 weeks gestation, the abundance of butyrate-producing bacteria and butyrate production in the gut microbiota is significantly negatively associated with blood pressure and with plasminogen activator inhibitor-1 levels. Increasing butyrate-producing capacity may contribute to maintenance of normal blood pressure in obese pregnant women. Gomez-Arango et al Blood Pressure and Gut Microbiome Butyrate Production 975The SCFA butyrate is produced from dietary fiber by bacteria in the gastrointestinal lumen. There are 2 main enzymes catalyzing butyrate production: butyrate kinase (Buk) and butyryl-CoA:acetate CoA-transferase (But), which are often used as biomarkers for the detection of butyrate-producing bacteria.11 Buk catalyzes the formation of butyrate from butyryl-CoA, releasing ATP in the process. 12,13 But catalyzes the reaction of butyryl-CoA with exogenous acetate to form butyrate and acetyl-CoA.13,14 Some butyrate-producing bacteria only express But or Buk, whereas others express both. 12The main butyrate producers in the human gut belong to the Firmicutes phylum (Coprococci, Eubacterium, Roseburia, and Faecalibacterium genera), 14 but members of other phyla, especially Bacteroidetes (Odoribacter and Alistipes genera), often contribute to the overall butyrogenic pool. SCFAproducing bacteria may affect blood pressure by direct effects of SCFA on vasodilation or through plasminogen activator inhibitor-1 (PAI-1). n-Butyrate increases PAI-1 mRNA in cultured hepatocytes, 15 and SCFA enemas stimulate rectal microcirculation and PAI-1 after aortic graft surgery. 16 It is uncl...

Overweight and obese women are at a higher risk for gestational diabetes mellitus. The gut microbiome could modulate metabolic health and may affect insulin resistance and lipid metabolism. The aim of this study was to reveal relationships between gut microbiome composition and circulating metabolic hormones in overweight and obese pregnant women at 16 weeks' gestation. Fecal microbiota profiles from overweight (n = 29) and obese (n = 41) pregnant women were assessed by 16S rRNA sequencing. Fasting metabolic hormone (insulin, C-peptide, glucagon, incretin, and adipokine) concentrations were measured using multiplex ELISA. Metabolic hormone levels as well as microbiome profiles differed between overweight and obese women. Furthermore, changes in some metabolic hormone levels were correlated with alterations in the relative abundance of specific microbes. Adipokine levels were strongly correlated with Ruminococcaceae and Lachnospiraceae, which are dominant families in energy metabolism. Insulin was positively correlated with the genus Collinsella. Gastrointestinal polypeptide was positively correlated with the genus Coprococcus but negatively with family Ruminococcaceae. This study shows novel relationships between gut microbiome composition and the metabolic hormonal environment in overweight and obese pregnant women at 16 weeks' gestation. These results suggest that manipulation of the gut microbiome composition may influence pregnancy metabolism.The increasing prevalence of maternal obesity and its subsequent health outcomes are a significant public health concern and a major challenge for obstetrics practice. In early pregnancy, overweight and obese women are at an increased risk of metabolic complications that affect placental and embryonic development (1). Metabolic adjustments, such as a decline in insulin sensitivity and an increase in nutrient absorption, are necessary to support a healthy pregnancy (2,3); however, these metabolic changes occur on top of preexisting higher levels of insulin resistance in overweight and obese pregnant women, increasing the risk of overt hyperglycemia because of a lack of sufficient insulin secretion to compensate for the increased insulin resistance (3).The potential role of the gut microbiome (the composite of the bacteria present in the gastrointestinal tract) in pregnancy has become the subject of considerable interest. In normal pregnancy, the maternal gut microbiota changes from first to third trimester with a decline in butyrate-producing bacteria and an increase in Bifidobacteria, Proteobacteria, and lactic acid-producing bacteria. Inflammation and weight gain that occurs during pregnancy might be the result of microbe-driven processes to increase energy supply for the fetus (4). These alterations might also be linked with the maternal metabolic profile and thereby contribute to the development of pregnancy complications (5,6) as well as affect the metabolic and immunological health of the offspring (7). In summation, modifications in the metabolic hormone milieu du...

ANZCTR 12611001208998, registered 23/11/2011.

OBJECTIVEGiven the role of gut microbiota in regulating metabolism, probiotics administered during pregnancy might prevent gestational diabetes mellitus (GDM). This question has not previously been studied in high-risk overweight and obese pregnant women. We aimed to determine whether probiotics (Lactobacillus rhamnosus and Bifidobacterium animalis subspecies lactis) administered from the second trimester in overweight and obese women prevent GDM as assessed by an oral glucose tolerance test (OGTT) at 28 weeks' gestation. Secondary outcomes included maternal and neonatal complications, maternal blood pressure and BMI, and infant body composition. RESEARCH DESIGN AND METHODSThis was a double-blind randomized controlled trial of probiotic versus placebo in overweight and obese pregnant women in Brisbane, Australia. RESULTSThe study was completed in 411 women. GDM occurred in 12.3% (25 of 204) in the placebo arm and 18.4% (38 of 207) in the probiotics arm (P = 0.10). At OGTT, mean fasting glucose was higher in women randomized to probiotics (79.3 mg/dL) compared with placebo (77.5 mg/dL) (P = 0.049). One-and two-hour glucose measures were similar. Preeclampsia occurred in 9.2% of women randomized to probiotics compared with 4.9% in the placebo arm (P = 0.09). Excessive weight gain occurred in 32.5% of women in the probiotics arm (55 of 169) compared with 46% in the placebo arm (81 of 176) (P = 0.01). Rates of small for gestational age (<10th percentile) were 2.4% in the probiotics arm (5 of 205) and 6.5% in the placebo arm (13 of 199) (P = 0.042). There were no differences in other secondary outcomes. CONCLUSIONSThe probiotics used in this study did not prevent GDM in overweight and obese pregnant women.Clinical trial reg. no. ACTRN12611001208998, www.anzctr.org.au This article is part of a special article collection available at http://care.diabetesjournals.org/ gdm-new-evidence.

Over the past decade, the role of the microbiome in regulating metabolism, immune function and behavior in humans has become apparent. It has become clear that the placenta is not a sterile organ, but rather has its own endogenous microbiome. The composition of the placental microbiome is distinct from that of the vagina and has been reported to resemble the oral microbiome. Compared to the gut microbiome, the placental microbiome exhibits limited microbial diversity. This review will focus on the current understanding of the placental microbiota in normal healthy pregnancy and also in disease states including preterm birth, chorioamnionitis and maternal conditions such as obesity, gestational diabetes mellitus and preeclampsia. Factors known to alter the composition of the placental microbiota will be discussed in the final part of this review.

Outcomes in pregnancies complicated by preexisting diabetes (type 1 and type 2) and gestational diabetes mellitus have improved, but there is still excess morbidity compared with normal pregnancy. Management strategies appropriately focus on maternal glycemia, which demonstrably improves pregnancy outcomes for mother and infant. However, we may be reaching the boundaries of obtainable glycemic control for many women. It has been acknowledged that maternal lipids are important in pregnancies complicated by diabetes. Elevated maternal lipids are associated with preeclampsia, preterm delivery, and large-forgestational-age infants. Despite this understanding, assessment of management strategies targeting maternal lipids has been neglected to date. Consideration needs to be given to whether normalizing maternal lipids would further improve pregnancy outcomes. This review examines the dyslipidemia associated with pregnancy complicated by diabetes, reviews possible therapies, and considers whether it is time to start actively managing this aspect of maternal metabolism.Although rates of adverse outcomes in pregnancies complicated by preexisting diabetes (type 1 and type 2) and gestational diabetes mellitus (GDM) have improved, there is still excess maternal and fetal morbidity compared with normal pregnancy. Current management strategies focus on maternal glycemic control, which demonstrably improves pregnancy outcomes for mother and infant. Truly "normal" glucose levels in pregnancy appear lower than previously thought (1) and achieving currently recommended glucose targets in pregnancy carries a risk of hypoglycemia (2). The challenges in reaching glycemic targets before and after conception raise the question of whether other aspects of maternal metabolism could potentially be addressed to provide benefit to mother and infant.Multiple maternal metabolic, hormonal, and inflammatory factors other than maternal glucose are associated with maternal and fetal outcomes and are altered in pregnancies complicated by prepregnancy diabetes and GDM. These include maternal amino acids, glycerol, ketones, and lipids (3). Lipid management in diabetes is acknowledged as a key therapeutic target in the nonpregnant setting. However, it has not been accorded the same attention in pregnancy. Abnormal maternal lipids in pregnancy have been associated with preeclampsia (4,5), preterm delivery (6), and large-forgestational-age (LGA) infants (7). This review examines the dyslipidemia associated with pregnancy complicated by diabetes, reviews possible therapies, and considers whether there is sufficient evidence to start actively managing lipids in pregnancy. LIPID METABOLISM IN PREGNANCYMaternal metabolism is designed to provide adequate nutrition for fetal growth, in the form of glucose, ketones, lipids, and other fuels. In early pregnancy, maternal

A distinct bacterial signature of the placenta was reported, providing evidence that the fetus does not develop in a sterile environment. The oral microbiome was suggested as a possible source of the bacterial DNA present in the placenta based on similarities to the oral non-pregnant microbiome. Here, the possible origin of the placental microbiome was assessed, examining the gut, oral and placental microbiomes from the same pregnant women. Microbiome profiles from 37 overweight and obese pregnant women were examined by 16SrRNA sequencing. Fecal and oral contributions to the establishment of the placental microbiome were evaluated. Core phylotypes between body sites and metagenome predictive functionality were determined. The placental microbiome showed a higher resemblance and phylogenetic proximity with the pregnant oral microbiome. However, similarity decreased at lower taxonomic levels and microbiomes clustered based on tissue origin. Core genera: Prevotella, Streptococcus and Veillonella were shared between all body compartments. Pathways encoding tryptophan, fatty-acid metabolism and benzoate degradation were highly enriched specifically in the placenta. Findings demonstrate that the placental microbiome exhibits a higher resemblance with the pregnant oral microbiome. Both oral and gut microbiomes contribute to the microbial seeding of the placenta, suggesting that placental colonization may have multiple niche sources.

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