Articles••

Early-life gut microbiota development from maternal vertical transmission

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Abstract

The gut microbiota of early life is crucial for childhood growth and development. Maternal gut microbiota directly or indirectly affects the colonization and development of early-life gut microbiota. Factors such as delivery mode, feeding mode, gestational age at birth, diet, and antibiotic use, can influence the vertical transmission of maternal gut microbiota to infants and affect the development of metabolic, endocrine, neural, and immune pathways in the early life. In this review, we summarize the latest knowledge of factors affecting early-life gut microbiota from maternal vertical transmission.

In recent years, authors of emerging studies have found that changes in maternal microecological community, particularly those of gut microbiota, are closely related to complications in pregnancy and could affect the colonization and development of early-life gut microbiome. The first 1000 days – that is, the period from conception to two years of age – is critical for early childhood growth and development. This paper includes a review of the factors influencing the vertical transmission of maternal gut microbiota to the colonization and development of early-life gut microbiota.

1 Gut microbiota

Human microorganisms tend to be distributed in the intestine, mouth, respiratory tract, urogenital tract, and skin, most of which are colonized in the intestine. There are many gut microorganisms that inhabit more than 100 trillion microorganisms. These mainly include bacteria, archaea, fungi, and viruses, of which more than 99% are bacteria.¹ Humans have symbiotically co-evolved with these microorganisms. More than 99% of bacteria belong to five major phyla²: Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia.

The gut microbial community is both complex and diverse, as is essential for maintaining the physiological dynamic balance of the human body. Its genome is known as the ‘second genome’ of human beings.³ The gut microbiome is closely related to human metabolism and can regulate the expression of approximately 10% of host transcription genes, especially those related to cell proliferation, immunity, and metabolism.⁴ Gut microbiota can regulate the absorption of food energy, as well as decomposing lactic acid, hydrogen sulfide, and other toxic and harmful substances in the human body. It can also provide various essential amino acids and vitamins, as well as some antibiotics and peptides for the human body, and can regulate host gene expression, intestinal peptide hormone secretion, choline, and bile acid metabolism, and other mechanisms for maintaining the body’s stability. Rastelli et al.⁵ suggested that gut microbiota was an important endocrine organ that could communicate with human organs in a variety of ways, such as by stimulating key receptors or specific hormones through nutrients or metabolites (for example, 5-hydroxytryptamine), and produce regulatory effects. Authors of recent studies have found that the metabolites of gut microbiota play a vital role in organs other than the gastrointestinal tract, through the gut-brain axis, gut-liver axis, gut-kidney axis, gut-lung axis, and gut-heart axis.⁶ Gut microbiome dysbiosis could lead to a variety of diseases including kidney diseases, hypertension, diabetes mellitus, obesity, lipid metabolism disorders, and so on. Additionally, disordered gut microbiota is related to cystic fibrosis, inflammatory bowel disease, colon cancer, nervous system diseases (including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis), musculoskeletal and autoimmune diseases (including rheumatoid arthritis, systemic lupus erythematosus, and so on) as well as other diseases.⁷

2 Maternal gut microbiota during pregnancy

Many physiological changes to glucose and lipid metabolism might occur during pregnancy. Throughout a typical, healthy pregnancy, women experience immunological, hormonal, and metabolic changes. To ensure sufficient energy intake for the nutritional needs of both fetal and the women’s own development, the body will increase fat and decrease insulin sensitivity, both of which are related to the self-regulation of the gut microbiome in pregnant women. Koren et al.⁸ suggested that during early pregnancy, numbers of butyrate-producing bacteria, such as Faecalibacterium and Eubacterium, increased, while butyrate, which has anti-inflammatory and immune regulation functions, could prevent maternal immune responses toward the fetal allograft. Such changes may be related to maternal endocrine and immune regulation to adapt to pregnancy. From early to late pregnancy, gut microbiota diversity decreased, while Proteobacteria and Actinobacteria increased. During late pregnancy, the α diversity of gut microbiota decreased while the β diversity of gut microbiota increased. Additionally, the increase of Lactobacillus species related to lactic acid fermentation in the intestinal tract may be related to gut microbiota colonization in the infants as well as the digestion and absorption of lactose in mother’s milk.

3 Early-life gut microbiota

An infant’s gut microbiota typically includes four phyla; that is, Actinobacteria, Proteobacteria, Firmicutes, and Bacteroidetes.⁹ A key source of infant gut microbiota is the mother; microbiota can be transmitted vertically from the maternal gut microbiota, vaginal microbiota, and breast milk. In a cohort of 25 Italian infants, it was found that more than half of the bacterial species in the infants’ gut originated from the guts, vaginas, mouths, and skin of their mothers.¹⁰

The construction of healthy newborns’ gut microbiota tends to be derived from maternal gut microbial community. Additionally, the establishment of gut microbiota during early life is a continuous process, beginning in the uterus and continuing until two to three years after birth. This is important for the development of immune and digestive systems in both infants and young children.¹¹

Whether the placenta is sterile remains controversial.¹²^,¹³ Many authors cite the existence of microbiota in human placental tissues and amniotic fluid, supporting the mother-to-infant microbiota transmission. Theis et al.¹⁴ used electron microscopy to find granular and bacteria-like structures in the intestinal tract of the fetus. Combined with culture omics, these were regarded as a type of active bacteria with low abundance which impacted the intestinal development and immunity of newborns. Thus, it was found that newborns interacted with microorganisms before birth. Dong et al.¹⁵ carried out a paired study and found a similar microbial composition in the placenta, amniotic fluid, and neonatal feces.

Following birth, facultative bacteria and aerotolerant microorganisms such as Proteobacteria appear immediately, leading to oxygen depletion in the gut and subsequent colonization by strict anaerobes.⁹ Authors of a recent study found that, by day seven after birth, the microbiota of vaginal-born infants was mainly facultative anaerobic bacteria; that is, Bifidobacterium, Escherichia, Bacteroides, and Parabacteroides.¹⁶

Weaning and intake of solid food are important for the development of an infant’s gut microbiota. In a longitudinal study of 43 US infants from birth to 2–3 years, solid food intake resulted in a decrease of Bifidobacterium, Bacteroides, and Clostridium, and an increase in a diverse mixture of Clostridiales from six to 24 months after birth.¹⁷ With age, alpha diversity increases, in particular between one and two years after birth.¹⁸ The infant gut microbiota from birth to two years old is affected by many factors. The microbiome could be targeted to optimize healthy composition with successful interventions in this period. However, after two years, the gut microbiota is almost fixed and stabilized, as it is in adults.¹⁹ This means that different unique gut microbiota and microbiota-targeted interventions during this period may be less effective for growth.²⁰

There is emerging evidence to suggest that the colonization of microbes during early life is critical for early childhood growth and development. Authors of numerous studies have found that infant gut microbiota plays a key role in allergies such as atopic eczema and asthma, obesity and obesity-related disorders, and other chronic disorders such as irritable bowel syndrome, and type 1 diabetes mellitus, and so on.²⁰

The establishment, development, and maturation of gut microbiota in early life are affected by many factors, such as delivery mode, feeding mode, gestational age, complications in pregnancy, diet, antibiotics, and so on.⁹

3.1 Delivery mode

Researchers have found that, during the first few weeks after birth, delivery mode is a major determinant of gut microbiota.²¹ Differences in infants’ microbiota as a result of birth mode have been observed. Many more strains are transmitted to vaginal-born babies than those delivered by cesarean section. Strains of Bacteroides and Actinomycetes (especially Bacteroides and Bifidobacterium) are only passed on during vaginal delivery. The gut microbiota of 98 Swedish mothers was analyzed days after delivery, while those of their full-term infants were analyzed in the first week after birth as well as at four and 12 months of age. The researchers observed a 72% correspondence in meta OTUs in mother-newborn pairs following vaginal delivery, compared to 41% after cesarean-section, indicating vertical transmission. The guts of naturally delivered newborns are initially colonized by relatively aerobic bacteria (Enterococcus, Escherichia/Shigella, Streptococcus, and Rothia), as well as by the anaerobic bacteria (Bifidobacterium, Lactobacillus, Collinsella, Granulicatella, and Veillonella) which is involved in lactate metabolism during lactation, fiber and carbohydrate degradation, and SCFAs (short chain fatty acids) production, resembling maternal microbiota.²¹

The gut microbiota of infants born vaginally is closer to maternal vaginal microbiota and is composed of Bifidobacterium, Escherichia, Bacteroides, and Parabacteroides. In contrast, that of cesarean-section infants is unstable, more like the external environment (since the first major microorganism to be exposed by cesarean section infants is the mother’s skin and/or the surrounding environment of major genera including Enterococcus, Enterobacter, and Klebsiella species), more likely to carry potential pathogens, and easier to change.¹⁶

In October 2020, a study into fecal microbiota transplantation of maternal diluted feces mixed with colostrum in cesarean-born infants was conducted.²² It was found that the microbial composition of these infants at three months was closer to that of natural delivery infants and differed significantly from other infants born by cesarean-section who did not receive their mothers’ feces. It is, therefore, suggested that newborn microbiome after cesarean-section can be remodeled by fecal transplantation.²²

3.2 Feeding mode

Human breastmilk contains 10²-10⁴ viable bacteria per mL, which directly affects the neonatal microbiota establishment. Additionally, Lactobacillus, Staphylococcus, Enterococcus, and Bifidobacterium can be transferred via lactation.²³ Differences in gut microbiota between breastfeeding and formula feeding are large, greatly impacting newborns’ immunity.²⁴ The source of bacteria in breast milk remains controversial. Some believe that human milk bacteria are derived from the mother’s skin, as there are some common bacteria in human milk.²⁵ However, most authors suggest that the transport of bacteria from the mother’s gut to the mammary gland is the main pathway.²⁵ Breast-fed newborns may have more beneficial bacterial strains, such as Bifidobacteria and Lactobacillus, while proportions of potentially pathogenic bacteria such as Clostridium are lower. Compared with formula-fed children, the absolute concentration of SCFAs in the feces of breast-fed infants was lower. This may be due to lower microbial diversity and higher lactic acid concentration. However, there was a higher proportion of acetate in breast-fed children.²⁶

Antimicrobial factors in breast milk may affect microbiota. Breast milk is the primary source of lactoferrin in infants, protecting against bacterial invasion by isolating iron from bacterial pathogens as well as interacting directly with bacteria.²⁷ The development of beneficial microbiota relies on the ability to protect infants from pathogenic microorganisms.²⁷

3.3 Full-term and premature infants

In vaginally term-born infants, facultative anaerobic microbiota such as Proteobacteria are gradually replaced by anaerobes such as Bifidobacterium and Clostridium.²⁸ Compared to full-term infants, preterm infants have less bacterial diversity and more potential pathogens. They tend to have a high abundance of Enterobacteriaceae, Staphylococcaceae, and Enterococcaceae as well as low and delayed colonization of Bifidobacterium.²⁹

Gilson et al.³⁰ found that six bacteria species (Enterococcus faecalis, Enterobacter cloacae, Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, and Klebsiella oxytoca) were abundant in preterm infants’ gut microbiota, increases in proportions of potential pathogens including Clostridium difficile and Klebsiella pneumoniae have been observed in preterm infants. Additionally, compared to full-term, preterm infants had fewer bacterial species, with reduced Bifidobacterium, Bacteroides, and Atopobium, as well as increased facultative anaerobes, which may delay immune system maturation in these infants.³¹

Milk feeding helps efficient digestion and absorption of nutrients by structural and functional maturation of the gastrointestinal tract.²⁷ During preterm births, infants suffered from immature digestion and motility. Lactase activity, which is key for milk lactose degradation, increases progressively from 24 to 40 weeks of gestation.³² An immature gastrointestinal barrier and nutrient absorption affect the abnormal colonization of gut microbiota in preterm infants.

3.4 Complications in pregnancy

Significantly altered gut microbiota has been found in pregnant women with gestational diabetes mellitus (GDM), gestational hypertension, and other metabolic diseases during pregnancy. Kuang et al.³³ found that, compared with healthy pregnant women, Parabacteroides distasonis, Klebsiella variicola, and so on were enriched in GDM patients, while Methanobrevibacter smithii, Alistipes spp., Bifidobacterium spp., and Eubacterium spp. were enriched in the control group. Wang et al.³⁴ found consistent changes in the microbiota of GDM pregnant women and their newborns in multiple specimens. The metabolic capacity of neonatal intestinal bacteria in pregnant women with GDM decreased. These crucial breakthroughs emphasize the key role of healthy gut microbiota in shaping newborns’ initial gut microbiome. The discovery of some high abundance bacteria related to GDM as well as oral glucose tolerance tests may provide markers for clinical testing of GDM. It is suggested that maternal gut microbiota dysbiosis may affect the gut microbiome of newborns.

Additionally, women who are obese before pregnancy and/or during pregnancy as well as excessive gestational weight gain (GWG) are associated with maternal gut microbiota dysbiosis, such as a higher abundance of Bacteroides, Clostridium, and Staphylococcus.³⁵ Furthermore, GWG is strongly associated with the metabolic pathways of the infant microbiota for the first eight months, indicating that GWG may influence specific gut microbiota transmission into infants.³⁶

3.5 Maternal diet

The maternal microbiota which is altered by diet could affect transmission to the offspring. In one cohort, based on a dietary questionnaire, infants born to a maternal high-fat (>40%) gestational diet had enriched Lactococcus, Enterococcus, and Granulicatella, and a decrease of Bacteroides, Parabacteroides, Sutterella, and Comamonas. This influence could persist to six weeks of age.³⁷

It has also been found that a higher maternal intake of saturated fatty acids (SFA) is significantly associated with higher Firmicutes and lower Proteobacteria, while higher maternal intakes of fiber and vegetable protein are associated with lower Bacteroidetes in neonatal gut microbiota.³⁸ In a nested cross-sectional study with the longitudinal MAMI cohort, it was found that the existing association between maternal diet, intestinal producers, and neonatal gut microbiota is mostly influenced by the intake of SFA and monounsaturated fatty acids. Members of Firmicutes in the neonatal microbiota were positively associated with maternal fat intake and negatively correlated to fiber, vegetable proteins, and vitamins.³⁹

Maternal diet may be an important factor for modulating a mother’s colostrum HMO (Human milk oligosaccharides) levels. A large, double-blind, placebo-controlled randomized clinical trial of probiotic supplementation study was carried out with 1223 pregnant mothers from Finland.⁴⁰ It was found that concentrations of HMO such as 3-fucosyllactose and 3′-sialyllactose were significantly higher in colostrum from the mothers in the probiotic supplementation group compared to those in the non-supplemented group. HMO is a major substrate for infants’ gut microbiota which affects the maturation of the intestinal mucosal immune system. Maternal probiotic supplementation during the third trimester of pregnancy may change HMO composition in human milk, thus affecting infants’ gut microbiota.⁴⁰

3.6 Antibiotics

Neonatal gut microbiota is influenced by maternally administered antibiotics. These antibiotics have a prophylactic use during childbirth, following guidelines, or non-prophylactic use during pregnancy and before delivery. Zimmermann et al.⁴¹ conducted a study on 272 infants and found that, compared to non-exposed infants, infants who were exposed to GBS (group B streptococcus) IAP (intrapartum antibiotic prophylaxis) had a lower bacterial diversity, a lower relative abundance of Actinobacteria, especially Bifidobacteriaceae, and a larger relative abundance of Proteobacteria in their gut microbiota. Antibiotics may reduce the stability, diversity, and richness of intestinal microbiota in infants, with increased Proteobacteria, including Enterobacteriaceae and drug resistance genes,⁴² decreased proportions in Actinobacteria, Firmicutes, and Bacteriodetes as well as decreased diversity.⁴³

Antibiotics may affect the early colonization of microorganisms in several ways. Firstly, antibiotics administered maternally reach newborns’ blood stream through the umbilical cord and remain in place for at least 10 h following administration. They may also affect early colonization of gut microbiota.⁴⁴ Secondly, antibiotics administered maternally can change mothers’ vaginal and gut microbiota, thus affecting the vertical microbial transmission process.⁴⁵ Thirdly, antibiotic therapy independently affects the composition of breast milk microbiota following delivery.⁴⁶

In conclusion, maternal gut microbiota directly or indirectly affects the colonization and development of early-life gut microbiota. Factors including delivery and feeding mode, gestational age at birth, diet, and antibiotic use can influence the maternal vertical transmission of gut microbiota to infants as well as affecting the development of metabolic, endocrine, neural, and immune pathways in early life. Thus, in the future, systematic and prospective research should be carried out to investigate maternal and infant gut microbiota, providing opportunities to improve maternal and infant health.

Funding

This work was supported by Peking University International Hospital Research Funds (No.YN2020QN02).

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.