In healthy individuals, there is a diverse microbial community present in the gut with numerous bacterial species, defined as the microbiota (Harmsen and de Goffau, 2016). Research has shown that the human gut microbiota likely contains 1,000–1,500 bacterial species; nevertheless, each person has only approximately 160 bacterial species (Lee and Mazmanian, 2010; Shi et al., 2017). Tierney et al. (2019) made an effort to sequence the bacterial genomes of the microbiota, indicating that our gut microbiota contains about 22.2 million genes, which is over 700 times the length of the human genome. The GI microbiota of healthy individuals was primarily composed of four phyla of bacteria: Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria (Wright et al., 2015). Furthermore, most of the microbiota was composed of the phyla Firmicutes and Bacteroidetes, and the class Clostridia dominated the Firmicutes sequences (Cai et al., 2021). Of note, the microbiome includes not only bacteria, but also viruses, phage, fungi, archaea and so on (Gong et al., 2021).

In the past decades, numerous studies on the GI microbiota have been restricted to the point of view that fetuses, considered microbiologically sterile, would not be exposed to bacteria until they come into contact with the vaginal and intestinal microbiota of the mother or with other environmental microorganisms at birth (Satokari et al., 2009). Nevertheless, this traditional view has been challenged by a new view that microbial colonization of the healthy new-born intestinal tract may begin in utero rather than during or after birth (Milani et al., 2017). Studies have found that the placenta harbors a unique microbiota composed of non-pathogenic commensal microbiota, which is similar to the oral microbiota of the mother, indicating that the placental microbiota may be established by the hematogenous spread of oral microbiota (Aagaard, 2014; Prince et al., 2016; Theis et al., 2019). Jimenez et al. (2008) detected microbial DNA in meconium (Mshvildadze et al., 2010). An additional study has found a high degree of similarity between microbes in meconium and those in amniotic fluid; presumably, this is due to the high likelihood that fetuses swallow plentiful amounts of amniotic fluid during the later stages of pregnancy, and meconium microbes are derived from the amniotic fluid that is swallowed (Nanthakumar et al., 2000; Ardissone et al., 2014; Cereta et al., 2021). Taken together, these finding show that microbial colonization of the healthy new-born GI tract may begin in utero.

While there is good evidence that prenatal exposure to maternal gut microbes may occur, the mechanisms by which microbes may be transported from the maternal GI to the developing fetus have yet to be identified. At present, the most likely hypothesis is that microbes are transferred from the intestinal epithelium to the bloodstream and then transported to the placenta. Normally, an epithelial barrier prevents bacteria from entering the bloodstream; however, dendritic cells (DCs) have been shown to actively penetrate intestinal epithelial cells and absorb bacteria from the intestinal lumen. Studies have shown that DCs can isolate living symbiotic bacteria here for a few days. Once attached to dendritic cells and transferred to the lymphatic system, the bacteria can spread to other parts of the body (Laubereau et al., 2004). These bacteria-loaded dendritic cells can be transported to mesenteric lymph nodes through GI lymphatic vessels (Jimenez et al., 2008). GI microbiota are also found in breast milk, and the same transport mechanism has been theorized (Forsberg et al., 2013).

However, it is of importance to be mindful that the above-mentioned source may not be the only one, that may vary between pregnancies and that fetal seeding may be a dynamic, gestational age-dependent process. And by determining the origins of the fetal microbiome, we might find chances for pre- and post-natal health interventions to prevent dysbiosis and minimize the incidence and impact of non-communicable diseases.

Neonates demonstrate a complex microbiota in the gut within the week immediately following birth, with dynamic fluctuations in the composition of the gut microbiota until a stable adult microbiota composition is reached at the age of 2–2.5 years. Research suggests that facultative and aerotolerant bacteria such as lactic acid bacteria, Enterobacteria, and streptococci dominate the initial flora in the neonatal gut, followed by an increasing number of strict anaerobes, including Bifidobacterium, Clostridium, Bacteroides (Bottacini et al., 2017; Milani et al., 2017; Brosseau et al., 2021).

The delivery mode is thought to be a vital driver of the early GI tract composition in full-term infants (Dominguez-Bello et al., 2010). A large number of studies have reported differences in full-term infants gut microbiota diversity and/or composition between caesarean delivery (CD) and vaginal delivery (VD) delivered infants. And consistent among many of these researches are findings of lower overall microbial diversity and decreased abundance of Bifidobacterium, Bacteroides, and Lactobacillus in infants born by CD compared to those VD (Dominguez-Bello et al., 2010; Jakobsson et al., 2014; Brumbaugh et al., 2016; Francino, 2018). For example, Lee et al. (2016) collected fecal samples and performed 16S rRNA gene analysis via 454 pyrosequencing of the V1–V3 regions. Unsurprisingly, they found that during the neonatal period, infants born by caesarean delivery (CD) showed a lower richness and diversity of the GI microbiota than those born by vaginal delivery (VD; Lee et al., 2016).

Differences in microbial colonization patterns are of importance, not only because of their potential impact on the eventual composition of the microbiota, but also because they affect the concomitant development of the infant’s immune system. The maturation of intestinal mucosa and its associated lymphoid tissue depends on intestinal colonization. The GI-associated lymphoid tissue Peyer’s patches, mesenteric lymph nodes, and isolated lymphoid follicles require signals from the GI microbiota to fully develop and/or recruit mature immune cell complement (Maynard et al., 2012). In addition, microbiota shape the immune phenotype in early infancy by binding to molecular receptors in various intestinal immune cells and initiating cascades of signals that indicate cell differentiation and control inflammatory states (Romagnani, 2006). In conclusion, under the influence of the GI microbiota, the immune cell pool established during this critical period will influence the host’s lifetime immunity and susceptibility to disease (Maynard et al., 2012; Francino, 2014; Brugman et al., 2015). Thus, the disruption of colonization caused by CD may be reflected in altered immune system development with potential long-term consequences. Several studies have addressed the impact of CD on T-cell response development and production of different cytokines. The study by Jakobsson et al. (2014) identified limited evidence that CD is thought to be linked with lowered cyclic dynamic levels of Th1-associated chemokines in infancy (Jakobsson et al., 2014). And the study by Jakobsson et al. (2014) showed that Bacteroides can exert strong effects on the immune system. In the case of Bacteroides fragilis, a surface polysaccharide is recognized by toll-like receptor 2 (TLR2) in Treg cells and induces production of IL-10 and other cytokines that affect the Th1/Th2 balance and promote immune tolerance (Round and Mazmanian, 2010). So the absence of Bacteroides may be related to the reduction of Th1 responses detected in CD infants. And poor immune system can result in remarkably lower levels of Th1-associated chemokines, such as CXL10 and CXL11, which are associated with immune responses (Munyaka et al., 2014). Here, it is conjectured that birth via CD is related to adverse effects on immune development and allergies.

The type of infant feeding is another profound element affecting the composition and function of the GI microbiota (Cerdo et al., 2019). Human milk oligosaccharides (HMOs) are important components of breast milk and can regulate the proliferation and maturity of GI cells and benefit the growth and development of babies. In addition, HMOs tend to provide nutrients, probiotics, and IgAs, which protect infants from exogenous infections and makes the immune system work more efficiently. Research on the transcription of enterocytes by Praveen et al. (2015) suggests that the infant diet also has a great influence on the expression of host genes and that breastfeeding can lead to the promotion of gene transcription related to immunity and metabolism (Praveen et al., 2015). Furthermore, it is well documented that the GI microbiota of formula-fed infants shows higher diversity than that of breastfed babies (Bezirtzoglou et al., 2011). The GI microbiota of breastfed infants tends to be dominated by Bifidobacteria during the first week of life, with members of the Enterobacteriaceae family concomitantly decreasing (Cerdo et al., 2019). Therefore, for the first 6 months of life, babies can benefit from exclusively being fed breast milk.

Antibiotics are the most frequently used drugs in pediatric therapy, nonetheless, excess antimicrobial use and long-term use of antibiotics can not only clear pathogenic microorganisms from the host but can also kill beneficial gut bacteria, induce the alteration of intestinal flora and affect gene expression in the intestine via immunoreactions (Chai et al., 2012; Cox et al., 2014; McArdle et al., 2021). Gasparrini et al. (2019) used 16S rDNA community analysis to study the GI microbiota of 437 infant stools that had taken antibiotics and concluded that these newborns, including 41 preterm infants, had a greater abundance of Enterobacter, Escherichia, and Enterococcus, and a lower relative abundance of Bifidobacterium during the course of antibiotic use. Furthermore, animal models have demonstrated that antibiotic use can destroy the GI microbiota and subsequently slow the growth of the immune system, which results in airway hyper-responsiveness in susceptible children and thereby increases the risk of allergic diseases such as asthma and allergic rhinitis (Korpela et al., 2016). As mentioned above, even short-term use, especially during the first 2 years of childhood, may lead to long-term changes in the GI microbiota that alter host interactions (Vangay et al., 2015). Gut dysbiosis promotes the horizontal transfer of resistance genes and fuels the evolution of drug-resistant pathogens and the spread of antibiotic resistance (Stecher et al., 2013).

Environment, which mostly includes family lifestyle, family members, close siblings, family size and structure, birth order and geographical location, has also been considered a correlative factor that may affect the infant GI microbiota. Some recent studies defined the “sibling effect,” namely, that the anaerobe-to-facultative anaerobe ratio and the abundance of Bifidobacteria, in infants with older siblings are higher than those in infants without siblings (Rodriguez et al., 2015). An analysis comparing American children in an upper-middle-class community and Bangladeshi children living in an urban slum of the same age living in poorer conditions indicated that the American children had a greater abundance of Bacteroides and were depleted in Prevotella than the Bangladeshi children (Lin et al., 2013). These results suggest that differing environmental or genetic factors may shape the microbiota of healthy children in the two countries. Another analysis comparing children from southeastern Africa and northern Europe showed differences in microbiota composition and structure, with the microbiota of African children being enriched in Bifidobacterium, Bacteroides, and Prevotella compared to the microbiota of European children (Lin et al., 2013).

Allergic asthma is a complicated chronic respiratory disease (CRD) characterized by airway hyper-responsiveness (AHR) and airway remodeling. Allergic asthma is a global health issue that has affected over 300 million patients of all age groups and all regions worldwide; over the last few decades, the morbidity of allergic asthma has been increasing (Bousquet et al., 2010; McKenzie et al., 2017). Currently, asthma is commonly treated with inhaled corticosteroids (ICSs) and beta-2 adrenergic receptor agonist (i.e., Salbutamol), which can help control symptoms; unfortunately, this treatment is not a cure. Therefore, there is priority in exploring novel, effective therapeutic methods to combat allergic asthma, and the microbiota and its associated metabolites have been considered as a therapeutic target.

In fact, the colonization of microorganisms in human lung is closely related to its anatomical and physiological functions. Respiratory microbes that enter the mouth travel to the lungs and are suspended in the air or on particles. The upper respiratory tract is layered with cylindrical respiratory epithelium covered by mucous membrane. The constant fluctuation of mucus and airflow determines the balance between microbial migration and elimination. Mucociliary micromotility and coughing support microbial clearance, all of which are influenced by host immune status (Dickson et al., 2014). It has been proposed that the main source of lower respiratory colonization is the resident upper respiratory microbiome. It also seems plausible that bacteria may reach the lower respiratory tract through micro-inhalation of oropharyngeal secretions and, to a lesser extent, direct inhalation (Segal et al., 2013). And in healthy individuals, low density and continuous renewal of the lung microbiome and low bacterial replication rates have been observed. Conditions conducive to the replication and persistence of certain bacterial species may lead to imbalances or disorders in the lung microbiome, which may lead to the development of asthma (Teo et al., 2015). Colonization of the upper respiratory tract began very early, as tracheal aspirations of newborns only a few hours after birth showed that Firmicutes and Proteobacteria were the dominant phyla, in addition to Actinomycetes and Bacteroides. Interestingly, the development of resident respiratory microbiota is largely dependent on exposure in the first few hours, including mode of delivery, and the environment over the next 4–5 months. Many human clinical studies found a relation between alterations in the lung microbiota and asthma. The potential of airway microbes to regulate asthma is readily recognized due to their proximity to sites of allergic inflammation, while the GI microbiota, although anatomically isolated, are now recognized to play a vital role in asthma. The roles and dysfunction of the GI microbiota are considered to have indirect physiological effects on distal anatomical sites, including the lungs. The communication between the colonization of GI tract and the mechanism of asthma, termed the gut-lung axis, is highly complex, which stresses the interaction between the GI tract and the lung. The gut-lung axis, which in asthma mainly involves changes in the immune differentiation of cells and partial production of metabolites impacted by the mechanisms of the GI microbiota, has been confirmed. Namely, a disrupted connection within the axis or a disruption to the composition of the gut microbiota can lead to negative effects on the immunological equilibrium mechanism; in turn, this may result in allergic reactions (Durack et al., 2018; Chatenoud et al., 2020). In fact, we do not fully understand the mechanisms underlying this axis, but the GI microbiota is considered to play a crucial role in the gut-lung axis, and several contributing pathways have been confirmed (see Figure 3). Based on the existing mechanisms, we summarized the important cells in these pathways and stated their effects in Table 2 (Choy et al., 2015; Kumar et al., 2017; Cait et al., 2018).

New models for the diagnosis, phenotyping and prediction of asthma treatment responses are the result of our growing understanding of the role of symbiotic microbiota in asthma; as a result, microbial ecology can lead to new therapeutic approaches to prevent and treat asthma. Some clinical studies have shown that the main mechanism in treating allergic asthma with probiotics involves regulating the composition of the GI microbiota, binding to the receptor competitively, preventing bacterial invasion and producing bacteriocins to prevent the growth of pathogens. A meta-analysis by Lin et al. (2013) suggested that probiotics can significantly reduce episodes of asthma; nevertheless, no significant differences were obtained regarding FEV1 (i.e., forced expiratory volume in the first second), Childhood Asthma Control Test (CACT) scores, PEF (i.e., peak expiratory flow) and quality of life (Zuccotti et al., 2015). Of note, the severity of the airflow limitation, as measured by percent predicted FEV1; PEF can evaluate the degree of airway blockage and make an effective judgment on the diagnosis or recovery of asthma and the severity of the disease; and the CACT is a test questionnaire to assess asthma control in children aged 4–11 years and can be used at home for long-term monitoring of the condition. As underlined in two recent reviews, the specific effects of probiotics in children who suffer from asthma need to be further confirmed based randomized-controlled trials (RCTs) with larger sample sizes (Zuccotti et al., 2015; Huang et al., 2019). In our opinion, pharmacodynamic alteration of the GI microbiota to change its composition or to target specific host pathways impacted by the GI microbiota in asthma patients remain promising therapeutic options.

Food allergy, a severe health issue, has aroused public concern, especially in developed countries. About 5% of children in the United States who are 5 years old or younger suffer from FA, and evidence shows that SCFAs produced by the GI microbiota, dietary elements and the GI microbiota seriously affect immune tolerance (Kim et al., 2016).

This first studies to use germiculture showed that babies who were allergic to milk had a higher total bacterial and anoxybiotic microbe count. In addition, there is evidence that the dysbiosis of the GI microbiota prior to FA subsequently impacts the progression of FA. An investigation by Goldberg et al. (2020) discovered that babies with food allergies showed a lower abundance of Prevotella copri than babies without food allergies, with the concomitant increase in SCFAs, which may destroy intestinal homeostasis and barrier function. Currently, microbiota-directed therapy has been a new focus for the treatment of food allergies, and studies with larger sample sizes are needed to clarify the specific effects (Schuijs et al., 2015).

Eczema is a common chronic disease of the skin that commonly begins in infancy (Biagini Myers and Khurana Hershey, 2010). Reduced diversity of the GI microbiota has been proven by several prospective studies to be related to the morbidity of eczema. In 2012, a prospective study by Abrahamsson et al. (2012) discovered that babies who suffered from eczema at the age of one-and-a-half had a lower diversity of the GI microbiota than healthy babies. Additionally, a lower abundance of Lactobacillus, Bifidobacterium and SCFAs was detected in children with eczema at the age of one than in healthy babies (Song et al., 2016). Interestingly, several probiotics that mainly contain the genera Lactobacillus and Bifidobacterium can be used as therapy for eczema because they decrease IgE levels (Toh et al., 2012; Abrahamsson et al., 2014). Nevertheless, the literature on the effectiveness of probiotic use for treating eczema is limited and hampered because studies fail to address important confounding factors. In fact, more rigorous experiments and long-term follow-up are needed to prove the efficacy of this type of treatment.

Compared to other allergic diseases, there is markedly less literature specifically discussing the effect of the GI microbiota on the development of allergic rhinitis, and many of the studies that do exist are based on mouse models. A study by Flach and Diefenbach (2015). found a fixed relation between lifetime antibiotic administration and the eventual development of allergic rhinitis (OR 1.06; 95% CI 1.04–1.09) (Flach and Diefenbach, 2015). For allergic rhinitis, the GI microbiota is considered a new target for early intervention, but its mechanism and therapeutic effect need to be further studied. While there are few significant experimental results and studies correlated with allergic diseases, it is well documented that a correlation can be drawn between the GI microbiota and asthma (Bousquet et al., 2010; Suzuki et al., 2010; Shi et al., 2017; van den Elsen et al., 2017), which is frequently associated with allergic rhinitis. Thus, further research in this direction is needed.