The impact of maternal exposure to antibiotics on the development of child gut microbiome

Abstract

Antibiotics are widely prescribed for mothers in the peripartum period today. Approximately 40% of pregnant women at term are exposed to antibiotics. Antibiotics are useful against infectious conditions such as chorioamnionitis; however, they alter the maternal microbiome. The maternal microbiome, particularly the gut microbiome, is transmitted to their neonates and is one of the major sources that shape the child's gut microbiome. The gut microbiome early in life plays a crucial role in the development of the gut microbiome itself as well as the host health over the entire life. Microbes structure the commensal ecosystem in the host. Simultaneously, microbial components and metabolites influence the host organ functions including the immune system, and vice versa, the various factors of the host impact the microbiome. The alterations of the gut microbiome induced by antibiotics in mothers can lead to gut dysbiosis in children eventually resulting in chronic disease conditions including immune disorders. Knowledge of the lasting impacts of maternal peripartum exposure to antibiotics on the gut microbiome and health in offspring and reconsideration of the adequate use of antibiotics in clinical practice are needed. Avoiding and restoring neonatal dysbiosis following maternal antibiotics-induced dysbiosis could be a new preventive strategy for various diseases.

Keywords:

• Gut microbiome
• dysbiosis
• peripartum period
• antibiotics
• developmental period

1. Introduction

The progress of genome sequencing technology, bioinformatics, and multi-omic technologies has extended our understanding of the human gut microbiome. These advances have revealed that the gut microbiome plays an important role in human health and its imbalance, dysbiosis, is associated with diseases [1]. Interactions between the host and the gut microbiome are crucial for the healthy development of the host. The gut microbiome early in life plays critical roles in the development of host immune systems [2,3] as well as metabolism and other organ functions [4,5] and is thought to influence the host health over the entire life [6]. Recent epidemiological studies have shown the association between the use of antibiotics early in life with the increased risk of various diseases such as obesity [7–10], food allergy [11], atopic disorders [11], asthma [12], inflammatory bowel disease [13–15], celiac disease [16], juvenile idiopathic arthritis [17]. Given that antibiotics can alter the gut microbiome, these findings suggest that dysbiosis early in life may have causative effects in the development of the diseases later in life.

The human gut microbiome develops early in life. This development process is affected by various factors, such as maternal microbiome [18], mode of delivery [19–21], feeding practice/diet [22,23], diet supplements [22,24], probiotics [25], antibiotics [26], environmental factors (e.g. living area, hygiene, lifestyle, and so on) [26,27], and genetic background [28,29]. Peripartum maternal microbiome is one of the key factors that shape the gut microbiome in children. Antibiotics are widely used for women in the peripartum period, especially in developed countries [30]. Peripartum antibiotics for mothers can influence the development of the child’s gut microbiome via antibiotics-induced alterations of the maternal vaginal and gut microbiome. This antibiotic-perturbed microbiome in a child, in turn, could have unfavorable health effects in the future.

Here we review the contribution of the maternal microbiome to the development of the child gut microbiome and the impact of maternal exposure to antibiotics on the microbiome development process of neonates and health later in life.

2. Maternal exposure to antibiotics during peripartum period in the current clinical setting

Antibiotics are needed for infectious diseases, particularly bacterial infections, including during pregnancy. Today, antibiotics are widely prescribed for mothers and neonates during the peripartum period, especially in the developed countries. There are data that approximately 40% of pregnant women at term and more than 30% of neonates are exposed to antibiotics [31,32]. During pregnancy, broad-spectrum antibiotics, such as cephalosporins, have become prescribed more frequently in the developed countries [33,34]. During pregnancy and labor, obstetrical antibiotic indications include chorioamnionitis, prevention of maternal infections after cesarean section, prevention of preterm birth, and prevention of Group B streptococcus (GBS) diseases in neonates [30]. However, while maternal infections and inflammation lead to the increased risk of preterm birth, it has not been established whether antibiotic therapy can prevent it [35]. A randomized trial showed that antibiotic treatment for the prevention of preterm birth might be even harmful leading to functional impairments and increased risk of [36]. GBS is one of the leading causes of neonatal infections [30]. Maternal intrapartum GBS colonization is the primary risk factor for neonatal GBS early-onset disease that occurs within the first week after birth. Intrapartum antibiotic prophylaxis (IAP) for GBS-colonized women decreases the risk of GBS transmission to their neonates and the risk of neonatal GBS infections [37]. Meanwhile, it remains an important challenge to establish a risk-based strategy for screening subjects for IAP to avoid unnecessary prescriptions [38,39].

3. Transmission of the maternal microbiome to neonates and its impacts on the infant gut microbiome

The maternal microbiome is vertically transmitted from mothers to their children [18]. With metagenomic shotgun sequencing and advanced bioinformatics technologies, now this process is confirmed at the strain level [20,40]. The maternal microbiome in the gut as well as other body sites influences the child microbiome. Ferretti et al. reported that the maternal microbiome of the gut, vagina, oral cavity, and skin contribute to structuring the infant gut microbiome accounting for 22.1%, 16.3%, 7.2%, and 5.0%, respectively [41]. Although it remains controversial, several recent studies describe that the maternal microbiome starts to transmit to the fetus in the uterus [42–45]. The difference in the mode of delivery impacts this vertical microbiome transmission process. The gut microbiome is different between vaginal-delivered neonates and those delivered by cesarean section [19–21]. Meanwhile, when cesarean-born infants were exposed to maternal vaginal fluids, their microbiome became partially similar with vaginal-delivered infants [46]. The transmitted maternal microbiome is thought to be dominant in neonates particularly during the first few days. Ferretti et al. reported that 50.7% of the bacterial species in the child gut microbiome on the day of birth were derived from their mothers [41]. Bäckhed et al. showed that the vaginal-delivered infants shared up to 72% of species with their mothers within 2-5 days after birth [47].

After birth, neonates are exposed to various environmental factors which may influence the microbiome [26,27]. Feeding practice is one of these factors that influence the gut microbiome development. It has been reported that the microbiome of exclusively breast-fed infants is different from those with non-exclusive breastfeeding [48]. The infant gut microbe develops dynamically early in life while being influenced by internal (e.g. genetics) and external (e.g. growing environment) factors and is thought to be almost completely established by around 3 years old [49,50] (Figure 1). The microbes derived from mothers are relatively stable in the infant's gut over months [41]. Microbes in the gut share the niche and biological resources and the timing and order of colonization can be crucial for establishing the microbial community. In an animal model, it has been shown that the microbes colonize early in life contributes to determining the eventual gut microbiome structure [51,52]. These findings suggest that maternal antibiotics-induced dysbiosis can transmit to their children and maternal dysbiosis has lasting impacts on the development and establishment of the gut microbiome in children.

Figure 1. Development of the gut microbiome in children. The maternal microbiome is one of the significant factors that shape the neonatal gut microbiome. Various internal and external factors influence the development process of the microbial community. The gut microbiome reaches the adult-like structure at around three years old.

Several studies demonstrated that IAP affects the neonatal gut microbiome structure [53–59]. Aloisio et al. compared the abundance of Lactobacillus spp., Bifidobacterium spp., Bacteroides fragilis group, Clostridiodis difficile, and Escherichia coli using real-time PCR between newborns at 6–7th days after birth from GBS-negative mothers and those from mothers treated with ampicillin as IAP. They showed that Bifidobacterium was significantly decreased [53]. They performed another study employing 16S rRNA gene amplicon sequencing analysis and demonstrated a reduced bacterial diversity with a predominance of Enterobacteriaceae and a significant decrease of Bifidobacterium in infants from mothers with IAP for GBS compared to the healthy control [54]. Corvaglia et al. employed real-time PCR and showed that Bifidobacterium significantly decreased in infants from mothers who received ampicillin as IAP for GBS on the 7th day after birth but there was no difference between the IAP group and the control at 30th day [55]. In another Italian cohort, Mazzola et al. performed 16S rRNA gene amplicon sequencing and reported that infants from mothers with IAP of ampicillin for GBS presented a lower relative abundance of Bifidobacterium and higher relative abundance of Enterobacteriaceae compared to the control at 7th day after birth, while the Bifidobacterium recovered in the IAP group by 30th day. Nogacka et al. analyzed infants from mothers who received penicillin as IAP for GBS with 16S rRNA and demonstrated that the IAP group showed the different gut bacterial compositions from the control within the first weeks of life, with the lower relative abundance of Actinobacteria and Bacteroidetes and higher relative abundance of Proteobacteria and Firmicutes. The differences almost disappeared by 90 days of age. Interestingly, they also showed that IAP affected the levels of short-chain fatty acids (SCFA) in the infant feces [57]. This finding suggests that IAP impacts on the gut microbiome structure as well as metabolic functions. Stearns et al. showed less bacterial diversity, a lower relative abundance of Bifidobacterium, and a higher abundance of Escherichia and Clostridium in infants from mothers with IAP of penicillin for GBS over the first 12 weeks, while the differences became less apparent by 12 weeks of age. Meanwhile, in the infants from mothers with IAP due to cesarean section, the alterations were evident persistently [58]. The differences in the delivery mode, as well as the type of antibiotics, need to be taken into account when interpreting this result. In a large cohort study in Canada, Azad et al. analyzed the gut microbiome of 198 infants with 16S rRNA amplicon sequencing [59]. The indications of IAP included GBS, the pre-labor rupture of membrane, and cesarean section in the cohort. They demonstrated that compositions of the gut microbiome in children with IAP were different from the control at 3 months after birth; less diversity, fewer Bacteroides and Parabacteroides, and more Enterococcus and Clostridium in the IAP group. The difference in the gut microbiome structure persisted up to 12 months, particularly in children with IAP for emergency cesarean section.

These studies support the notion that the influence of antibiotics administration in peripartum period on the neonatal microbiome needs to be recognized.

4. Maternal antibiotics exposure can increase the risk of diseases in children later in life

The gut microbiome early in life is now thought to have a crucial, lasting impact on human immune system health throughout life [60,61]. Various studies using animal models support this notion. For example, colonization of E. coli during pregnancy impacts on the intestinal mucosal innate immunity in offspring via aryl hydrocarbon receptor (AhR) leading to the increase of intestinal group 3 innate lymphoid (ILC3) cells and F4/80⁺ CD11c⁺ mononuclear cells in offspring [62]. Glycosphingolipids of B. fragilis early in life play an important role in establishing the homeostasis of host invariant natural killer T (iNKT) cells [63]. SCFA plays a role in regulating Tregs through the inhibition of histone deacetylases (HDAC) [64,65]. Thorburn et al. demonstrated that maternal consumption of a high-fiber diet alters the gut microbiome and promotes intestinal SCFA production, such as acetate, leading to an increased potential to induce regulatory T cells (Tregs) in the pups of a murine asthma model [66]. A recent study by Al Nabhani et al. demonstrated the interactions between the host and gut microbiome in the weaning period are essential for the development of RORγt + Tregs and this process is crucial for host health in adulthood [67]. Thus, the gut microbiome early in life plays an important role in the healthy development of both innate and adaptive immunity of the host. Missing the appropriate immunological education due to gut dysbiosis in the critical window period early in life could lead to aberrant immune development eventually resulting in immunological disorders later in life. Given maternal dysbiosis can be transmitted to children as mentioned above, maternal antibiotics-induced dysbiosis could lead to diseases in offspring.

Recent human epidemiological studies have demonstrated the association between maternal exposure to antibiotics in the peripartum period and the increased risk of diseases in children. A study in Denmark demonstrated that maternal exposure to antibiotics during pregnancy increased the risk of asthma in children [68]. The analysis in a European birth cohort study showed that antibiotic exposure in utero was associated with atopic dermatitis and food allergy of children [11]. A cohort study in Sweden reported the increased risk of inflammatory bowel diseases (IBD) in children with exposure to antibiotics during pregnancy [15]. Clinical studies are limited in their ability to establish a causal link between maternal antibiotics-induced dysbiosis and diseases in children due to large differences in the inter-individual gut microbiome, challenges in controlling for confounding variables, and constraints of the observational clinical design. It is crucial to determine if maternal exposure to antibiotics during the peripartum period has a causative effect in the diseases via the child's gut dysbiosis for understanding the underlying pathophysiology and for developing preventive and therapeutic strategies. For this purpose, translational research using animal models can provide scientific merits. Alhasan et al. [69] developed a mouse asthma model in which maternal antibiotic exposure during pregnancy increases the susceptibility to asthma in offspring. They showed that the antibiotic treatment caused gut dysbiosis and decreased levels of SCFA in offspring. These observations support the findings in human subjects [70]. This animal model would be helpful to obtain further mechanistic insights on the changes in the immune profile of the offspring and the development of asthma caused by maternal exposure to antibiotics during pregnancy. Miyoshi et al. [71] reported a mouse model that presents gut dysbiosis, the aberrant immune development, and the development of colitis in offspring with maternal peripartum antibiotic exposure. They demonstrated that the maternal antibiotic-induced dysbiosis was transmitted to their pups and showed a causal link between gut dysbiosis and the pro-inflammatory immune development in offspring. Schulfer et al. also reported that maternal perturbed microbiome by the antibiotic exposure promotes susceptibility to colitis in offspring [72]. These models would be useful to investigate pathoetiology of IBD.

5. Conclusions

The maternal dysbiosis induced by peripartum exposure to antibiotics is transmitted to their children and has lasting impacts on the development of the child's gut microbiome. This process eventually can influence the health condition of children later in life. While antibiotics administration is crucial for some medical situations, recent evidence underscores the importance to carefully consider the use of antibiotics. It also suggests that the interventions approaching gut dysbiosis early in life can be future preventive strategies for various diseases.

Acknowledgment

The authors thank Dr. Mark W. Musch for his English proofreading.

Disclosure statement

The authors declare no conflict of interest.