Introduction
There are more than 1000 species microbiota residing in human gut.1 It is the largest and most complex microbial community in human. The types and numbers of gut microbiota are relatively stable, but they are also changed by diet, endocrine, hygienic habits, age, and hygienic conditions. The total number of microbes is nearly 10 times the number of cells in a human body.1 The most recent estimate of the ratio of bacteria to human cells in the adult body is approximately 1:1.2 The genes of the microbiome are 150-fold greater than those of individual human genome.3 Gut microbiota are abundant and widely involved in human physiological activities, which have a very important impact on human health. The gut microbiome could provide lots of functions, including assimilating nutrition, detoxifying xenobiotics, and renewaling and maintaining the intestinal integrity.4 Gut microbiota are thought to play a role in the maintenance of a healthy pregnancy by involving the process of human metabolism and immunity.
During pregnancy, the gastrointestinal function and the gut microbiome change greatly to meet the needs of pregnancy. Ovarian hormones, including estrogen and progesterone, can affect the peripheral and central regulatory mechanisms of the brain-gut axis and regulate intestinal barrier function and immune activation (IA) of intestinal mucosa.5 In addition, ovarian hormones can impact the composition of the gut microbiome through their effect on bacterial metabolism and growth and virulence of pathogenic bacteria.6
Gut microbiota of human has been the extensive subject in scientific research, and gut microbiome has been identified as a key factor in maintaining health during pregnancy. The goal of this review is to summarize the current knowledge on that the changes of gut microbiota in women during pregnancy, and the relationship between gut microbiome and pregnancy complications including metabolic disease, acquired immune deficiency syndrome, and premature labor.
Changes of gut microbiome in normal pregnant women
During pregnancy, the gastrointestinal function of pregnant women changes obviously to meet the needs of pregnancy, and the gut microbiome also makes a difference due to the changes in hormones, immunity, and metabolism.7 In earlier years, characterization of the gut microbiome among 91 pregnant women revealed that the composition of gut microbiota changed significantly during pregnancy, and the number of gut microbiome increased significantly from first to third trimesters, although the species of gut microbiome decreased in the third trimesters stage, the number of Proteus and Actinomycetes increased substantially. It can be inferred that gut microbiota may play a role in pregnancy.8 Smid et al.9 collected fecal samples from mothers by rectal swabs and analyzed them by 16s rRNA sequencing. The results showed that the number of Proteus and Clostridium increased significantly during pregnancy, and the increase in early pregnancy was greater than that of the third trimester. A study by 16s rRNA gene sequencing of 169 female gut microbiome samples at 4 days postpartum showed the number of Proteus and Bacteroides increasing significantly.6
However, Jost et al.10 showed that the gut microbiome remained relatively stable throughout the perinatal period by analyzing the fecal microbiota of pregnant women during pregnancy and 30 days postpartum. The results of Avershina et al.11 studies also showed that gut microbiota remained relatively stable during pregnancy. This distinct finding may be caused by factors that independently affect the maternal gut microbiome, such as maternal diet, body mass index (BMI), metabolism, and the use of antibiotic.
Changes of gut microbiome in pregnant women with metabolic disorders
The normal endocrine and metabolic functions of the mother are the key to the success of pregnancy, and these functions ensure that the mother and the developing fetus have enough energy supply. The prevalence of metabolic diseases during pregnancy is on the rise in the world. Gestational diabetes mellitus (GDM) and obesity have become a major public health problem. Gut microbiome plays an important role in obesity and some other metabolic disorders or diseases. The interaction between gut microbiome and metabolic diseases during pregnancy has become a hot research topic.
Gut microbiota can greatly impact host metabolism via microbiome metabolites. Undigested complex carbohydrates are substrates of intestinal bacterial fermentation. Main metabolites of intestinal flora are short-chain fatty acids (SCFAs) including butyric acid acetate and propionic acid, which plays an important role in regulating host metabolism, immune system, and cell proliferation.12 Butyrate can prevent obesity caused by a high-fat diet, protect beta cell function of the pancreas, and reduce metabolic disorders during pregnancy.13 Meanwhile, sodium butyrate can prevent hypertension by suppressing angiotensin II and renin-angiotensin system.14 Gomez-Arango et al.15 found the inverse relation of maternal blood pressure with the abundance of bacteria in Odoribacter and Clostridiaceae, which are important butyrate producing bacteria. At 16 weeks’ gestation, the abundance of butyrate bacteria in gut microbiota of overweight and obese pregnant women was negatively correlated with blood pressure and plasminogen activator inhibitor-1, and the abundance of butyrate-producing bacteria decreased significantly. From what has been discussed above, gut microbiome is closely related to metabolism in pregnant women and regulation of microbiome metabolites helps to control the metabolic function of pregnant women.
Gut microbiome and obesity in pregnancy
Obesity is the most common metabolic disorder in pregnancy and is closely related to the occurrence of other metabolic disorders or diseases. Obesity is related to imbalance of gut microbiota. Most gut microbiota belongs to one of the two phyla: Bacteroidetes and Firmicutes. Firmicutes produce more energy than Bacteroidetes, and obese people have more Firmicutes.16 The abundance of Firmicutes, Fecal coccus, Streptococcus, and Actinomycetes increased, and the proportion of intestinal Firmicutes and Bacteroides increased in obese mothers.17 There has been controversy on the report of intestinal Bacteroides and changes of gestational BMI.18 Whether the increase in Bacteroides is related to obesity needs further study.
Overweight and obesity are both associated with inflammation in pregnant women and the composition of their gut microbiota. Houttu et al.19 found that obese pregnant women had higher levels of low inflammatory markers high-sensitivity C-reactive protein (hsCRP) and glycoprotein acetyls than normal pregnant women. Glycoprotein acetyls has been shown to be associated with obesity and insulin resistance.20 This has been important in understanding the increased risk of gestational diabetes in obese pregnant women. In overweight and obese pregnant women, inflammatory biomarkers including haptoglobin and hsCRP in the third trimester were positively correlated with BMI in the first trimester.17 Meanwhile, the higher the haptoglobin and hsCRP level, the lower the diversity of intestinal microbiota. In summary, obesity is related to microbial disorders, metabolism, and systemic inflammation. It is of great significance that further research is needed on biomarkers of inflammation as a potential tool for predicting pregnancy complications and offspring health.
Gut microbiome and GDM
GDM is one of the most common complications of pregnancy. The incidence of GDM is on the rise worldwide, and GDM is associated with increased risk of adverse perinatal outcomes such as obesity, metabolic syndrome, and type 2 diabetes.15,21,22 Gut microbiota respond to neuroendocrine and immunobiochemical information and participate in the regulation of human blood glucose.23 Gut microbiota can regulate metabolic health and affect insulin resistance, which may play an important role in the etiology of GDM.
A study using 16S amplification sequencing of fecal microbiome of pregnant women with GDM at 24 to 28 weeks and 38 weeks of gestation showed that the abundance of Firmicutes increased from the second trimester to the third trimester, while the abundance of Bacteroidetes and Actinomycetes decrease.24 Crusell et al.25 reported that Collinsella, Rothia, and Desulfovibrio had higher abundance in GDM with Actinomycetes increased. About 8 months after delivery, microbiome in prior gestational diabetes mellitus (pGDM) still have unusual components, including Bavariicoccus, Clostridium sensu stricto, Bacteroides, and Veillonella were enriched postpartum in women with gestational diabetes. Furthermore, analyzing bacterial communities of fecal samples from 42 pGDM and 35 control subjects 3 to 16 months after delivery by high-throughput 16S rRNA gene sequencing, Fugmann et al.26 reported that the relative abundance of Prevotella in pGDM was obviously high but the relative abundance of Firmicutes in pGDM group was significantly lower. This result indicates that there occurred a unique change for the postpartum gut microbiome in pregnant women with GDM, suggesting an important research significance for the mechanism that can explain how GDM could develop into type 2 diabetes mellitus. The gut microbiome and related intermediate metabolic characteristics of GDM women were similar to type 2 diabetic patients, and Collinsella was associated with the increase in fasting insulin and homeostasis model assessment of insulin resistance levels in normal pregnancy, which is abundant in non-pregnant patients with type 2 diabetes and women with a history of GDM.25 It can be seen that the bacterial genus may be a potential alternative bacterium for screening type 2 diabetes in the future.
Kuang et al.27 reported a study of fecal sample from 43 patients with GDM and 81 healthy pregnant women at 21 to 29 weeks of gestation by whole metagenomic sequencing showed that Bacteroides and Klebsiella variola were enriched in GDM pregnant woman, while Methanobrevibacter smithii, Alistipes, Bifidobacterium, and Eubacterium were enriched in controls. The study identified 154,837 genes which aggregate into 129 metagenome linkage groups (MLGs), and the total abundance ratio of MLGs in GDM group and control group was positively correlated with blood glucose level. This study found a new relationship between gut microbiome and GDM that Fecal metagenomic linkage group has a good predictive ability for the occurrence of GDM and suggested that changes in microbial composition can be used to identify pregnant women at risk for GDM.
Obese pregnant women have higher risk of GDM. Gut microbiota regulate metabolism and affect insulin resistance and lipid metabolism. Gomez-Arango et al.28 reported that the correlation of changes in metabolic hormone and fecal microorganism in 29 overweight and 41 obese pregnant women, and the results showed that the high abundance of Verrucomicrobia in early pregnancy may be related to the poor metabolic condition, Rhizoma could be used as a markerofimpaired glucose metabolism, and thehigh abundance of Spirillaceae, Prevoidae, and Bacteroidae is related to maternal energy metabolism. Studies have shown that the proportion and diversity of certain microbiome may be used as potential markers of insulin resistance and abnormal lipids metabolism, which is of great significance for the study of metabolic disorders in obese pregnant women.
These studies suggest that gut microbiome has a significant effect on metabolic disorders during pregnancy, and it can be inferred that the strategy of regulating gut microbiota may be a potential and effective way to affect the metabolic health of pregnant women.
Maternal metabolic disorders related to gut microbiome in offspring
Early reproductive science have been that the fetus resides in a sterile environment, but recent studies have shown that infants have an initial microbiome before birth.29 Fetal gut contains microbiome during pregnancy which derived from the mother and closely related to the mother microbiota.30 The offspring gut microbiome has been gradually formed before delivery and will be affected by the maternal pregnancy.
Recent evidence suggests that obesity during pregnancy is associated with changes in gut microbes in offspring and their health.31–35 The gut microbiota of newborns born to overweight or obese mothers delivered via vagina was significantly different from that of babies born to normal-weight mothers. The most significant difference was the relative abundance of gram-negative bacilli, including the increase in Bacteroides and the decrease in Acinetobacter, Enterococcus, Pseudomonas and Hydrophila.31 The changes in gut microbiome in offspring show a significant effect on the development of metabolic diseases. Studies have shown that the maternal nutrition status is associated with the offspring obesity, and high fat diet during pregnancy and lactation can consistently change the gut microbiome in the offspring, resulting in weight gain and elevated blood lipid levels that may persist into adulthood.32 Owing to epigenetic mechanisms are regulated by environmental factors, maternal diet, and early nutrition intervention may have important effects on early epigenetic inheritance. Epigenetic changes may affect early microbial colonization and gut development, and the changes of maternal diet habits to gut microbiome and metabolism in offspring are related to epigenetic inheritance such as DNA methylation.33,34 Therefore, maternal diet plays an important role in the occurrence of obesity in offspring through the regulation of epigenetics. Probiotics supplementation during pregnancy may affect the DNA methylation status of some promoters of obesity-related genes in mothers and their children, thereby providing a potential mechanism for controlling obesity in offspring.35
Newborn disorders of gut microbiota may be related to GDM. The number of Proteobacteria and Actinobacteria in newborn of GDM pregnant women increased, but the Bacteroidetes obviously reduced.36 Wang et al.37 found that the uniformity of fecal flora of neonates associated with GDM was decreased, and the abundance of herpesvirus, poxvirus, and mammary adenovirus were high. Furthermore, metabolic pathways of neonates associated with GDM decreased, which may have adverse effects on newborn nutrition absorption or some metabolic capacity. These studies are of great significance in understanding the potential effects of GDM on gut microbiome and metabolism in neonates. It is reported that hyperglycemia in pregnancy confers a significant increase in risk in the offspring of developing diabetes or obesity in the future.38Anaerotruncus genus has been positively associated with both glucose intolerance and gut permeability.39 The Anaerotruncus genus was more abundant in the children of women with a history of GDM compared to those whose mothers did not have GDM.35 This finding is helpful to determine the role of Anaerotruncus genus in GDM and to investigate whether children with high Anaerotruncus levels are at greater risk of developing diabetes or becoming obese when they mature.
The establishment of neonatal gut microbiome has a great impact on the metabolism and immune development of infants, and its composition overlaps with maternal gut microbiome and breast milk.40 This indicates that the changes of maternal gut microbiota may affect neonatal gut microbiome and play an important role in the study of metabolism and immune diseases related to neonatal gut microbiome. The above results indicate that maternal metabolism is associated with gut microbiota and health of offspring, but further studies are needed to confirm whether such an association is related to changes in maternal gut microbiota. Bhagavata et al.41 found that changes in maternal gut microbiota due to diet or obesity can be transmitted to offspring by animal model studies. Another animal model study showed that maternal gut microbiota affected gut microbiota colonization and innate immunity of offspring.42 So far, there is also a lack of data on microbiota in the human intestine.
Gut microbiome and preeclampsia (PE)
PE is a pregnancy-specific disease characterized by elevated blood pressure and proteinuria after 20 weeks of gestation. It is one of the main causes of maternal and perinatal mortality.43 The pathogenesis of PE has not yet been elucidated, but immune dysfunction, oxidative stress, and vascular endothelial injury are all related to the occurrence of PE.44 PE is closely related to metabolic syndrome, which can lead to disorders of glucose and lipid metabolism, insulin resistance and vascular endothelial injury. Therefore, PE is also considered as one of the metabolic disorders associated with pregnancy.45 The pathophysiological process of PE includes abnormal elevated blood pressure in the middle and third trimester of pregnancy accompanied by multiple organ or system damage. SCFAs, a metabolite of gut microbiome, is closely related to blood pressure.46 SCFAs have anti-inflammatory and histone deacetylation inhibitory effects, which can improve renal injury by regulating inflammatory processes.47 Butyrate, one of a group of short-chain fatty acids, has obvious effect on lowering blood pressure during pregnancy.15 Butyrate may inhibit the production of plasminogen activator inhibitor-1, thereby reducing the vasoconstriction and vascular endothelial function damage caused by endothelial nitric oxide synthase inhibition, thus reducing the occurrence of PE.10 Pregnant women with PE may experience obvious changes in gut microbiota during pregnancy. A study of gut microbiota by 16S rDNA gene sequencing from 26 women with PE in the third trimester and 74 healthy pregnant women showed that the pathogenic bacteria, Clostridium perfringens and Bulleidia moorei increased in women with PE but the probiotic bacteria Coprococcus catus decreased.45 Using the same methods, Lv et al.48 found that Blautia, Ruminococcus2, Bilophila, and Fusobacterium were significantly enriched in the antepartum samples of PE patients, but Faecalibacterium, Gemmiger, Akkermansia, Dialister, and Methanobrevibacter were significantly depleted. These study suggest that gut microbiota in women with PE are significantly different from normal pregnant women (Table 1), which may be related to the occurrence and development of PE. It is rarely reported that the effects of gut microbiome on PE, and further research is needed to understand the underlying mechanism of different gut microbiome in the development of PE.
Table 1 -
Changes of gut microbiome in metabolic disorders during pregnancy.
| Author |
Year |
Disease |
Gut microbiome |
| Increase |
Decrease |
| ZacarÃas MF, et al.
17
|
2018 |
Obesity |
Firmicutes, Fecal coccus, Streptococcus and Actinomycetes |
None |
| Gomez-Arango LF, et al.
28
|
2016 |
Obesity and overweight |
Verrucomicrobia, Rhizoma, Spirillaceae, Prevoidae and Bacteroidae |
None |
| Ferrocino I, et al.
24
|
2018 |
GDM |
Firmicutes |
Bacteroidetes and Actinomycetes |
| Crusell MKW, et al.
25
|
2018 |
GDM |
Actinomycetes, Collinsella, Rothia and Desulfovibrio |
None |
| Crusell MKW, et al.
25
|
2018 |
pGDM |
Bavariicoccus, Clostridium sensu stricto, Bacteroides and Veillonella |
None |
| Kuang YS, et al.
27
|
2017 |
GDM |
Bacteroides and Klebsiella variola |
Methanobrevibacter smithii, Alistipes, Bifidobacterium, and Eubacterium |
| Mueller NT, et al.
31
|
2016 |
Newborn of obesity |
Bacteroides |
Acinetobacter Enterococcus Pseudomonas and Hydrophila |
| Guo Y, et al.
32
|
2018 |
Newborn of GDM |
Proteobacteria and Actinobacteria |
Bacteroidetes |
| Liu J, et al.
45
|
2017 |
PE |
Clostridium perfringens and Bulleidia moorei |
Coprococcus catus |
| Lv LJ, et al.
48
|
2019 |
PE |
Blautia, Ruminococcus2, Bilophila, and Fusobacterium |
Faecalibacterium, Gemmiger, Akkermansia, Dialister, and Methanobrevibacte |
PE: Preeclampsia; pGDM: Prior gestational diabetes mellitus; GDM: Gestational diabetes mellitus.
Gut microbiome and premature rupture of membranes
Preterm birth is one of the most important complications associated with pregnancy, and the most important risk factor for neonatal morbidity and mortality worldwide. Premature rupture of membranes (PPROM) is an important clinical phenotype of premature birth. Bacterial infection and subsequent inflammatory responses are considered to be an important cause of premature rupture of membranes.49 Studies have shown that microorganism exists in amniotic cavity during pregnancy.50 Aagaard et al.51 found that the placenta has a unique microbiome, mainly composed of non-pathogenic common microbiota, including firmicutes, Tenericutes, proteobacteria, bacteroidetes, and clostridium. Jiménez et al.52 isolated Enterococcus, Streptococcus, Staphylococcus or Propionibacterium from umbilical cord blood of healthy newborns after cesarean section. A large number of researchers analyzed meconium and found the presence of microorganisms.53,54 In the amniotic fluid of women who experienced PPROM, the results showed that the gut microbiome play a role in intrauterine infections.55 After the discovery of gut microbiota in amniotic fluid, gut microbiome is also considered a possible source of intrauterine infection and 56 intestinal flora can settle in the vagina and rise.56 A study suggests that change in gut microbiome may lead to changes in the vaginal flora, and changes in vaginal flora may increase the incidence of preterm birth. Gut microbiome of pregnant women may be translocated to the vagina, leading to changes in the structure of vaginal microbiome and inducing preterm births. Vaginal microbiome in women with PPROM was complex and abnormal.58 During the second trimester, the vaginal microflora in women with PPROM shifted to higher diversity.59 The microflora is characterized by an increase in the relative abundance of potentially pathogenic species. Vaginal microbiome can climb the cervical canal, on the placenta tissue colonization, resulting in chorionic amnionitis, and eventually inducing PPROM.49
Gut microbiome in human immunodeficiency virus (HIV) infection and pregnancy with preterm birth
Intestinal epithelium is an important protective barrier of internal aseptic environment and external environment. The tight epithelial junction and gastrointestinal immune system protect the host from pathogen invasion. Gastrointestinal tract is rich in acquired immune deficiency syndrome target cells, mainly CD4+ T cells. Therefore, the gastrointestinal tract is the main site of HIV infection.60 HIV infection destroys the intestinal epithelial immune system and related immune cells, leading to changes in the frequencies and types of gut microbiota and microbial translocation (MT), and further to the activation of the whole body immune system.61 The changes in the immune function in pregnant women after HIV infection are complex. A study about biomarkers of IA and MT in both pregnant and nonpregnant HIV-1 infected women showed that there was no significant difference in intestinal MT and continuous IA between pregnant and nonpregnant HIV-1 infected women.62
A study shows that preterm delivery is associated with HIV-infected pregnant women, and incidence of premature delivery in HIV-infected pregnant women is higher than that in normal pregnant women.63 Maternal inflammation has been identified to be closely related to premature delivery. Inflammatory markers soluble cluster of differentiation 14 (sCD14) and soluble cluster of differentiation 163 (sCD163) are associated with the levels of plasma lipopolysaccharide (LPS) (representative marker of MT), which have been widely used as markers for MT and for monocyte/macrophage activation.64 Analysis of plasma samples from pregnant women infected with HIV-1 showed higher levels of intestinal fatty acid binding protein (makers of intestinal barrier dysfunction), sCD14 levels and sCD163 levels in maternal plasma. It is possible that intestinal barrier dysfunction and monocyte activation are associated with premature delivery, and it suggests that intestinal barrier integrity and MT may affect preterm birth. A prospective cohort study by López et al.65 showed that the plasma levels of sCD14 and lipopolysaccharide binding protein in early pregnancy and sCD14 in late pregnancy significantly increased in HIV-infected pregnant women. This study further suggests that intestinal MT may be an important factor in the preterm delivery of HIV-infected pregnant women. Zhou et al.66 found that plasma LPS level increased in preterm pregnant women infected with HIV, and progesterone level significantly decreased in subjects infected with HIV in early pregnancy and middle pregnancy. It indicated a significant negative correlation between plasma LPS and progesterone. It can be seen from the result (Fig. 1) that intestinal MT and the reduction of plasma progesterone levels may increase preterm birth rate in infected pregnant women. MT is an important risk factor for preterm birth, and interventions toward intestinal integrity and MT are needed to reduce the incidence of preterm birth.
;)
Figure 1: The possible mechanism of preterm caused by gut microbiota in HIV-infected pregnant. Women. HIV: Human immunodeficiency virus; LPS: Lipopolysaccharide; LBP: Lipopolysaccharide binding protein; sCD14: Soluble cluster of differentiation 14; sCD163: Soluble cluster of differentiation 163.
The above studies indicated that MT may be an important factor for preterm delivery in HIV-infected pregnant women, and the gut microbiome translocation from intestinal cavity to blood and finally to amniotic cavity in HIV-infected pregnant women may be a pathogenic factor. To explore the influence of gut microbiota changes on pregnancy has a certain effect on the pathogenesis of pregnancy status of HIV-infected pregnant women. And the studies are of significant importance to reduce preterm birth and other adverse pregnancy outcomes of HIV-infected pregnant women.
Pregnant women infected with HIV are at high risk of pregnancy. Changes in gut microbiota have a significant impact on pregnancy complications and pregnancy outcomes. However, at present, there are few studies on the pregnancy complications caused by changes in gut microbiome in HIV-infected patients, and the impact of changes in gut microbiome on pregnancy complications needs to be further studied.
The effect of diet on gut microbiota in pregnancy-related conditions
The dietary habits of pregnant women during pregnancy can influence the composition of gut microbiota.67 Our diets feed gut microbiome, so we should also consider the impact of food and nutrition on the composition of gut microbiota. Early studies have shown that organic vegetables in the diet can affect the composition of intestinal microflora and reduce the risk of PE.68 There are a number of reports that high-fat diets can increase total anaerobic microorganisms, particularly bacteroides, and low-fat diets can increase the abundance of bifidobacteria while reducing fasting glucose and total cholesterol.69 During pregnancy, a high-fat diet leads to an unfavorable microbial pattern that reduces bacterial richness.22 Low dietary fiber can increase the abundance of Collinsella in the gut of obese pregnant women, regulate circulating insulin, and has a certain significance in regulating gestational blood glucose.70 The recommended nutrient intake of dietary fiber and fat was related to the higher abundance of intestinal flora and the lower richness of Bacteroidaceae, and the intake of nutrients was related to the diversity of gut microbiota and low-grade inflammation during pregnancy.22 These discoveries prove to be a strategy for improving metabolic and inflammation in pregnant women.
Intestinal probiotics are bacteria implanted in the human gastrointestinal tract, improve the host intestinal microenvironment and can help the human body improve intestinal function and immune function. It has long been reported that probiotic lactofructose regulates gut microbiome by stimulating the growth of bifidobacteria and lactobacillus.71 Probiotics can control pregnancy weight gain and reduce pregnancy complications by inducing changes in gut microbiome during pregnancy. Nordqvist et al.72 found in cohort studies that pregnant women drinking milk containing specific probiotics could significantly reduce the incidence of preterm at early pregnancy, and could significantly reduce the incidence of PE in third trimester. Pregnant women who take orally probiotics containing streptococcus faecalis, clostridium butyrate and bacillus mesenteri from 12 weeks of gestation until delivery, have shown that intestinal probiotics significantly inhibited premature delivery before 32 weeks of gestation, and also presented the tendency of inhibiting chorionic amnionitis and fungal inflammation.73 A meta-analysis showed that probiotics supplementation at to 8 weeks of gestation significantly reduced insulin resistance in pregnant women with GDM, which has been considered as a potential therapy for GDM.74 Probiotics can also significantly reduce the blood pressure of GDM patients, which has potential application value for pregnant women with diabetes mellitus and hypertension.75 These studies indicate that probiotics supplementation during pregnancy may have a protective effect on pregnancy complications and adverse outcomes. However, recent studies have reported that probiotics administered from the second trimester cannot prevent GDM or improve secondary outcomes of pregnancy in overweight and obese pregnant women.76 Probiotics appear to be safe and easy to take without any obvious maternal or infant side effects. However, the efficacy of probiotics for pregnancy-related complications has not been determined. The prevention and treatment of pregnancy-related diseases by probiotics need to be further studied. At present, our understanding of complications from gut microbiome during pregnancy is limited. We are still far from finding personalized dietary control and therapy for pregnancy-related complications. However, Diet regulation of host-microbial interactions may be a promising method for pregnancy-related complications.
Conclusions
Pregnancy is a special physiological period for women of child-bearing age. The gut microbiome in pregnant women changes significantly in order to adapt the changing metabolism and immunity, which plays an important role in maintaining maternal health and fetal development. In this review, we have discussed the known associations between gut microbiome and metabolic diseases, PE, infectious diseases, and neonatal diseases. Evidence focused on the effect of gut microbiome on metabolic diseases during pregnancy is rapidly mounting in current studies. However, there are few studies on other aspects. Furthermore, most studies on the relationship between gut microbiota and newborn health have been focused on the gut microbiome of infants, while few studies on the effect of maternal gut microbiota are available. Research on the relationship of gut microbiota with pregnancy complications and adverse outcomes can play an important role in healthy fetal development, and prevention from adverse conditions and future diseases originated in pregnancy. Due to the lack of research reports, the summary of gut microbiome and pregnancy related complications in this paper is also relatively simple, which needs further supplement from other scholars. In the near future, an important research direction is required to study the relationship between gut microbiota and adverse pregnancy outcomes.
Funding
This work was supported by the National Natural Science Foundation of China (No. 81760273), Projects in Yunnan Science and Technology Plan (No. 2017FB107), and Medical Reserve Talents of Yunnan Health and Family Planning Commission (No. H-201628).
Author Contributions
All authors contributed to the manuscript and approved the final version.
Conflicts of Interest
None.
References
1. Ehrlich SD. The human gut microbiome impacts health and disease. C R Biol 2016;339(7-8):319–323. doi:10.1016/j.crvi.2016.04.008.
2. Sender R, Fuchs S, Milo R. Are we really vastly outnumbered?Revisiting the ratio of bacterial to host cells in humans. Cell 2016;164(3):337–340. doi:10.1016/j.cell.2016.01.013.
3. Power SE, O’Toole PW, Stanton C., et al. Intestinal microbiota, diet and health. Br J Nutr 2014;111(3):387–402. doi:10.1017/S0007114513002560.
4. Mayer EA, Savidge T, Shulman RJ. Brain-gut microbiome interactions and functional bowel disorders. Gastroenterology 2014;146(6):1500–1512. doi:10.1053/j.gastro.2014.02.037.
5. Mulak A, Taché Y, Larauche M. Sex hormones in the modulation of irritable bowel syndrome. World J Gastroenterol 2014;20(10):2433–2448. doi:10.3748/wjg.v20.i10.2433.
6. Stanislawski MA, Dabelea D, Wagner BD, et al. Pre-pregnancy weight, gestational weight gain, and the gut microbiota of mothers and their infants. Microbiome 2017;5(1):113. doi:10.1186/s40168-017-0332-0.
7. Edwards SM, Cunningham SA, Dunlop AL, et al. The maternal gut microbiome during pregnancy. MCN Am J Matern Child Nurs 2017;42(6):E22–E23. doi:10.1097/NMC.0000000000000398.
8. Koren O, Goodrich JK, Cullender TC, et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012;150(3):470–480. doi:10.1016/j.cell.2012.07.008.
9. Smid MC, Ricks NM, Panzer A, et al. Maternal gut microbiome biodiversity in pregnancy. Am J Perinatol 2018;35(1):24–30. doi:10.1055/s-0037-1604412.
10. Jost T, Lacroix C, Braegger C, et al. Stability of the maternal gut microbiota during late pregnancy and early lactation. Curr Microbiol 2014;68(4):419–427. doi:10.1007/s00284-013-0491-6.
11. Avershina E, Storro O, Oien T, et al. Major faecal microbiota shifts in composition and diversity with age in a geographically restricted cohort ofmothers and their children. FEMS Microbiol Ecol 2014;87(1):280–290. doi:10.1111/1574-6941.12223.
12. Koh A, De Vadder F, Kovatcheva-Datchary P, et al. From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites. Cell 2016;165(6):1332–1345. doi:10.1016/j.cell.2016.05.041.
13. Li HP, Chen X, Li MQ. Butyrate alleviates metabolic impairments and protects pancreatic ß cell function in pregnant mice with obesity. Int J Clin Exp Pathol 2013;6(8):1574–1584.
14. Wang L, Zhu Q, Lu A, et al. Sodium butyrate suppresses angiotensin II-induced hypertension by inhibition of renal (pro) renin receptor and intrarenal renin-angiotensin system. J Hypertens 2017;35(9):1899–1908. doi:10.1097/HJH.0000000000001378.
15. Gomez-Arango LF, Barrett HL, McIntyre HD, et al. Increased systolic and diastolic blood pressure is associated with altered gut microbiota composition and butyrate production in early pregnancy. Hypertension 2016;68(4):974–981. doi:10.1161/HYPERTEN-SIONAHA.116.07910.
16. Komaroff AL. The microbiome and risk for obesity and diabetes. JAMA 2017;317(4):355–356. doi:10.1001/jama.2016.20099.
17. ZacarÃas MF, Collado MC, Gómez-Gallego C, et al. Pregestational overweight and obesity are associated with differences in gut microbiota composition and systemic inflammation in the third trimester. PLoS One 2018;13(7):e0200305. doi:10.1371/journal.pone.0200305.
18. Aatsinki AK, Uusitupa HM, Munukka E, et al. Gut microbiota composition in mid-pregnancy is associated with gestational weight gain but not prepregnancy body mass index. J Womens Health (Larchmt) 2018;27(10):1293–1301. doi:10.1089/jwh.2017.6488.
19. Houttu N, Mokkala K, Laitinen K. Overweight and obesity status in pregnant women are related to intestinal microbiota and serum metabolic and inflammatory profiles. Clin Nutr 2018;37(6 Pt A):1955–1966. doi:10.1016/j.clnu.2017.12.013.
20. Bao W, Dar S, Zhu Y, et al. Plasma concentrations of lipids during pregnancy and the risk of gestational diabetes mellitus: a longitudinal study. J Diabetes 2018;10(6):487–495. doi:10.1111/1753-0407.12563.
21. Hod M, Kapur A, Sacks DA, et al. The International Federation of Gynecology and Obstetrics (FIGO) initiative on gestational diabetes mellitus: a pragmatic guide for diagnosis, management, and care. Int J Gynaecol Obstet 2015;131(Suppl 3):S173–S211. doi:10.1016/S0020-7292(15)30033-3.
22. Röytiö H, Mokkala K, Vahlberg T, et al. Dietary intake of fat and fibre according to reference values relates to higher gut microbiota richness in overweight pregnant women [published correction appearsinBrJNutr.2018Sep;120(5):599-600]. Br J Nutr 2017;118(5):343–352. doi:10.1017/S0007114517002100.
23. Stefanaki C, Peppa M, Mastorakos G, et al. Examining the gut bacteriome, virome, and mycobiome in glucose metabolism disorders: are we on the right track?Metabolism 2017;73:52–66. doi:10.1016/j.metabol.2017.04.014.
24. Ferrocino I, Ponzo V, Gambino R, et al. Changes in the gut microbiota composition during pregnancy in patients with gestational diabetes mellitus (GDM). Sci Rep 2018;8(1):12216. doi:10.1038/s41598-018-30735-9.
25. Crusell MKW, Hansen TH, Nielsen T, et al. Gestational diabetes is associated with change in the gut microbiota composition in third trimester of pregnancy and postpartum. Microbiome 2018;6(1):89. doi:10.1186/s40168-018-0472-x.
26. Fugmann M, Breier M, Rottenkolber M, et al. The stool microbiota of insulin resistant women with recent gestational diabetes, a high risk group for type 2 diabetes. Sci Rep 2015;5:13212. doi:10.1038/srep13212.
27. Kuang YS, Lu JH, Li SH, et al. Connections between the human gut microbiome and gestational diabetes mellitus. Gigascience 2017;6(8):1–12. doi:10.1093/gigascience/gix058.
28. Gomez-Arango LF, Barrett HL, McIntyre HD, et al. Connections between the gut microbiome and metabolic hormones in early pregnancy in overweight and obese women. Diabetes 2016;65(8):2214–2223. doi:10.2337/db16-0278.
29. Funkhouser LJ, Bordenstein SR. Mom knows best: the universality of maternal microbial transmission. PLoS Biol 2013;11(8): e1001631. doi:10.1371/journal.pbio.1001631.
30. WilczyiÃska P, SkarZynska E, Lisowska-Myjak B. Meconium microbiome as a new source of information about long-term health and disease: questions and answers. J Matern Fetal Neonatal Med 2019;32(4):681–686. doi:10.1080/14767058.2017.1387888.
31. Mueller NT, Shin H, Pizoni A, et al. Birth mode-dependent association between pre-pregnancy maternal weight status and the neonatal intestinal microbiome. Sci Rep 2016;6:23133. doi:10.1038/srep23133.
32. Guo Y, Wang Z, Chen L, et al. Diet induced maternal obesity affects offspring gut microbiota and persists into young adulthood. Food Funct 2018;9(8):4317–4327. doi:10.1039/c8fo00444g.
33. Wankhade UD, Zhong Y, Kang P, et al. Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations. PLoS One 2017;12(4):e0175675. doi:10.1371/journal.pone.0175675.
34. Cortese R, Lu L, Yu Y, et al. Epigenome-microbiome crosstalk: a potential new paradigm influencing neonatal susceptibility to disease. Epigenetics 2016;11(3):205–215. doi:10.1080/15592294.2016.1155011.
35. Hasan S, Aho V, Pereira P, et al. Gut microbiome in gestational diabetes: a cross-sectional study of mothers and offspring 5 years postpartum. Acta Obstet Gynecol Scand 2018;97(1):38–46. doi:10.1111/aogs.13252.
36. Su M, Nie Y, Shao R, et al. Diversified gut microbiota in newborns of mothers with gestational diabetes mellitus. PLoS One 2018;13(10): e0205695. doi:10.1371/journal.pone.0205695.
37. Wang J, Zheng J, Shi W, et al. Dysbiosis of maternal and neonatal microbiota associated with gestational diabetes mellitus. Gut 2018;67(9):1614–1625. doi:10.1136/gutjnl-2018-315988.
38. Kim SY, Sharma AJ, Callaghan WM. Gestational diabetes and childhood obesity: what is the link?Curr Opin Obstet Gynecol 2012;24(6):376–381. doi:10.1097/GCO.0b013e328359f0f4.
39. Everard A, Lazarevic V, Derrien M, et al. Responses of gut microbiota and glucose and lipid metabolism to prebiotics in genetic obese and diet-induced leptin-resistant mice [published correction appears in Diabetes. 2011 Dec;60(12):3307. Muccioli, Giulio M [corrected to Muccioli, Giulio G]]. Diabetes 2011;60(11):2775–2786. doi:10.2337/db11-0227.
40. Schanche M, Avershina E, Dotterud C, et al. High-resolution analyses of overlap in the microbiota between mothers and their children. Curr Microbiol 2015;71(2):283–290. doi:10.1007/s00284-015-0843-5.
41. Bhagavata Srinivasan SP, Raipuria M, Bahari H, et al. Impacts of diet and exercise on maternal gut microbiota are transferred to offspring. Front Endocrinol (Lausanne) 2018;9:716. doi:10.3389/fendo.2018.00716.
42. Nyangahu DD, Lennard KS, Brown BP, et al. Disruption of maternal gut microbiota during gestation alters offspring microbiota and immunity. Microbiome 2018;6(1):124. doi:10.1186/s40168-018-0511-7.
43. Hod T, Cerdeira AS, Karumanchi SA. Molecular mechanisms of preeclampsia. Cold Spring Harb Perspect Med 2015;5(10): a023473. doi:10.1101/cshperspect.a023473.
44. Ahmed A, Rezai H, Broadway-Stringer S. Evidence-based revised view of the pathophysiology of preeclampsia. Adv Exp Med Biol 2017;956:355–374. doi:10.1007/5584_2016_168.
45. Liu J, Yang H, Yin Z, et al. Remodeling of the gut microbiota and structural shifts in preeclampsia patients in South China. Eur J Clin Microbiol Infect Dis 2017;36(4):713–719. doi:10.1007/s10096-016-2853-z.
46. Bier A, Braun T, Khasbab R, et al. A high salt diet modulates the gut microbiota and short chain fatty acids production in a salt-sensitive hypertension rat model. Nutrients 2018;10(9):1154. doi:10.3390/nu10091154.
47. Andrade-Oliveira V, Amano MT, Correa-Costa M, et al. Gut bacteria products prevent AKI induced by ischemia-reperfusion. J Am Soc Nephrol 2015;26(8):1877–1888. doi:10.1681/ASN.2014030288.
48. Lv LJ, Li SH, Li SC, et al. Early-onset preeclampsia is associated with gut microbial alterations in antepartum and postpartum women. Front Cell Infect Microbiol 2019;9:224. doi:10.3389/fcimb.2019.00224.
49. Doyle RM, Harris K, Kamiza S, et al. Bacterial communities found in placental tissues are associated with severe chorioamnionitis and adverse birth outcomes. PLoS One 2017;12(7):e0180167. doi:10.1371/journal.pone.0180167.
50. Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 2016;6:23129. doi:10.1038/srep23129.
51. Aagaard K, Ma J, Antony KM, et al. The placenta harbors a unique microbiome. Sci Transl Med 2014;6(237):237ra65. doi:10.1126/scitranslmed.3008599.
52. Jiménez E, Fernández L, MarÃn ML, et al. Isolation of commensal bacteria from umbilical cord blood of healthy neonates born by cesarean section. Curr Microbiol 2005;51(4):270–274. doi:10.1007/s00284-005-0020-3.
53. Dominguez-Bello MG, Costello EK, Contreras M, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A 2010;107(26):11971–11975. doi:10.1073/pnas.1002601107.
54. Gosalbes MJ, Llop S, Vallès Y, et al. Meconium microbiota types dominated by lactic acid or enteric bacteria are differentially associated with maternal eczema and respiratory problems in infants. Clin Exp Allergy 2013;43(2):198–211. doi:10.1111/cea.12063.
55. DiGiulio DB, Romero R, Kusanovic JP, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and pregnancy outcome in women with preterm pre-labor rupture of membranes. Am J Reprod Immunol 2010;64(1):38–57. doi:10.1111/j.1600-0897.2010.00830.x.
56. Dunlop AL, Mulle JG, Ferranti EP, et al. Maternal microbiome and pregnancy outcomes that impact infant health: a review. Adv Neonatal Care 2015;15(6):377–385. doi:10.1097/ANC.0000000000000218.
57. Haque MM, Merchant M, Kumar PN, et al. First-trimester vaginal microbiome diversity: a potential indicator of preterm delivery risk. Sci Rep 2017;7(1):16145. doi:10.1038/s41598-017-16352-y.
58. Paramel Jayaprakash T, Wagner EC, van Schalkwyk J, et al. High diversity and variability in the vaginal microbiome in women following preterm premature rupture of membranes (PPROM): a prospective cohort study. PLoS One 2016;11(11):e0166794. doi:10.1371/journal.pone.0166794.
59. Brown RG, Al-Memar M, Marchesi JR, et al. Establishment of vaginal microbiota composition in early pregnancy and its association with subsequent preterm prelabor rupture of the fetal membranes. Transl Res 2019;207:30–43. doi:10.1016/j.trsl.2018.12.005.
60. Guo L, Xu XQ, Zhou L, et al. Human intestinal epithelial cells release antiviral factors that inhibit HIV infection of macrophages. Front Immunol 2018;9:247. doi:10.3389/fimmu.2018.00247.
61. Villanueva-Millán MJ, Pérez-Matute P, Recio-Fernández E, et al. Differential effects of antiretrovirals on microbial translocation and gut microbiota composition of HIV-infected patients. J Int AIDS Soc 2017;20(1):21526. doi:10.7448/IAS.20.1.21526.
62. Mitchell CD, Dominguez S, Roach M, et al. Microbial translocation and immune activation in HIV-1 infected pregnant women. Curr HIV Res 2018;16(3):208–215. doi:10.2174/1570162X16666180731145011.
63. Dos Reis HL, Araujo Kda S, Ribeiro LP, et al. Preterm birth and fetal growth restriction in HIV-infected Brazilian pregnant women. Rev Inst Med Trop Sao Paulo 2015;57(2):111–120. doi:10.1590/S0036-46652015000200003.
64. Shivakoti R, Gupte N, Kumar NP, et al. Intestinal barrier dysfunction and microbial translocation in human immunodeficiency virus-infected pregnant women are associated with preterm birth. Clin Infect Dis 2018;67(7):1103–1109. doi:10.1093/cid/ciy253.
65. López M, Figueras F, Coll O, et al. Inflammatory markers related to microbial translocation among HIV-infected pregnant women: a risk factor of preterm delivery. J Infect Dis 2016;213(3):343–350. doi:10.1093/infdis/jiv416.
66. Zhou Z, Powell AM, Ramakrishnan V, et al. Elevated systemic microbial translocation in pregnant HIV-infected women compared to HIV-uninfected women, and its inverse correlations with plasma progesterone levels. J Reprod Immunol 2018;127:16–18. doi:10.1016/j.jri.2018.04.001.
67. Gohir W, Whelan FJ, Surette MG, et al. Pregnancy-related changes in the maternal gut microbiota are dependent upon the mother’s periconceptional diet. Gut Microbes 2015;6(5):310–320. doi:10.1080/19490976.2015.1086056.
68. Torjusen H, Brantsæter AL, Haugen M, et al. Reduced risk of preeclampsia with organic vegetable consumption: results from the prospective Norwegian Mother and Child Cohort Study. BMJ Open 2014;4(9):e006143. doi:10.1136/bmjopen-2014-006143.
69. Singh RK, Chang HW, Yan D, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med 2017;15(1):73. doi:10.1186/s12967-017-1175-y.
70. Gomez-Arango LF, Barrett HL, Wilkinson SA, et al. Low dietary fiber intake increases Collinsella abundance in the gut microbiota of overweight and obese pregnant women. Gut Microbes 2018;9(3):189–201. doi:10.1080/19490976.2017.1406584.
71. Vanhoutte T, De Preter V, De Brandt E, et al. Molecular monitoring of the fecal microbiota of healthy human subjects during administration of lactulose and Saccharomyces boulardii. Appl Environ Microbiol 2006;72(9):5990–5997. doi:10.1128/AEM.00233-06.
72. Nordqvist M, Jacobsson B, Brantsæter AL, et al. Timing of probiotic milk consumption during pregnancy and effects on the incidence of preeclampsia and preterm delivery: a prospective observational cohort study in Norway. BMJ Open 2018;8(1):e018021. doi:10.1136/bmjopen-2017-018021.
73. Kirihara N, Kamitomo M, Tabira T, et al. Effect of
probiotics on perinatal outcome in patients at high risk of preterm birth. J Obstet Gynaecol Res 2018;44(2):241–247. doi:10.1111/jog.13497.
74. Taylor BL, Woodfall GE, Sheedy KE, et al. Effect of
probiotics on metabolic outcomes in pregnant women with gestational diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutrients 2017;9(5):461. doi:10.3390/nu9050461.
75. Nabhani Z, Hezaveh SJG, Razmpoosh E, et al. The effects of synbiotic supplementation on insulin resistance/sensitivity, lipid profile and total antioxidant capacity in women with gestational diabetes mellitus: a randomized double blind placebo controlled clinical trial. Diabetes Res Clin Pract 2018;138:149–157. doi:10.1016/j.diabres.2018.02.008.
76. Callaway LK, McIntyre HD, Barrett HL, et al.
Probiotics for the prevention of gestational diabetes mellitus in overweight and obese women: findings from the SPRING double-blind randomized controlled trial. Diabetes Care 2019;42(3):364–371. doi:10.2337/dc18-2248.
