The first important microbiologic exposure of a newborn is at the time of delivery, with microbial growth in and on the infant being facilitated by immunological tolerance [25].

The route of delivery has a major and persistent effects on the composition of the intestinal microbiota early in life [26]. In a study of the intestinal microbiome of infants at six months of age, those delivered vaginally had healthier and more diverse bifidogenic microbiota (Table 1) than infants delivered via cesarean section, who were shown to suffer from a greater number of respiratory infections [27].

Studies in a mouse model also found that vaginal delivery was more important in early shaping of the infant microbiome than exposure to the environment [28]. After birth, the timing of bacterial colonization of the gut while essential for health and development was shown to be time-dependent and variable for each infant [29].

While it is logical to assume that microbiota from the vagina are the critical early strains that help form a newborn’s microbiome during vaginal delivery, there are other pathways via which maternal microbiota reach the newborn, skin, tongue, and feces. There is growing evidence that taxa from the mother’s rectum and fecally-contaminated perineal surface are a more important sources of engrafting bacteria of the intestine of newborns during vaginal birth than the vagina [30,31]. In a supportive study, maternal vaginal organisms given orally to their respective infants born via cesarean section showed no modification of the infants’ intestinal microbiome compared with a placebo group [32]. In a second study, a pregnant woman with recurrent Clostridioides difficile infection (CDI) treated with fecal microbiota transplantation (FMT) lead to engraftment of FMT donor microbiota in the mother that were later transferred to her infant during vaginal delivery [33].

In the US, the C-section rate remained at 22% from 2016 to 2019 and then rose an additional 4% from 2019 to 2021 [56]. In a study of 9350 deliveries carried out in 2001, 11.6% underwent a non-medically indicated cesarean delivery, providing indirect evidence that many cesarean deliveries are medically unnecessary [57].

Cesarean delivery excludes the newborn from vaginal and pelvic microbiota, leading to acquisition of a less diverse intestinal microbiome [58], which may explain why the intestinal microbiome of newborns born via C-section less resemble the gut microbiome of their mothers when compared with infants born vaginally [59]. In one study, microbiota acquired during cesarean delivery were acquired from the general environment in the hospital [60]. In a systematic review of infants, the gut microbiota for the first 3 months of life were affected by mode of delivery [61], with environmentally acquired organisms common constituents of the intestinal microbiome in newborns born via cesarean delivery [62]. The microbiomes of babies born via cesarean delivery begin to resemble breast-fed babies between 4 and 12 months of age [59], but by then, the health benefits exerted by a diverse microbiome early in life have been lost. Babies born via cesarean delivery suffer more frequently from immune-mediated and allergic disorders, including asthma [63,64,65], inflammatory bowel disease, celiac disease, obesity [64] and type 1 diabetes [66] than those born by vaginal delivery.

The practice of giving mothers undergoing C-sections antibiotics to reduce infections further impairs the microbiome of both the mother and newborn. In one study of cesarean delivery, the findings of an increased ratio of Proteobacteria/Bacteroidetes and fecal colonization of C. difficile at 12 months after cesarean delivery were markers of unhealthy microbiome and a predictor of later childhood obesity and atopy [67].

A study of monozygotic and dizygotic twins was carried out to determine the relative importance of genetics versus environmental factors in the formation of the early microbiome [68]. At month one, the monozygotic pair showed common patterns in their fecal microbiomes distinctly different from those of a fraternal sibling, but by one year of age they showed a similar microbiome pattern. The authors hypothesize that genetic factors are important in early infant life. Abundance of two core organisms acquired early in life, Bifidobacterium and Ruminococcus [69], was shown to be dependent on the presence of two human genes [70]. Genetic factors are less important in influencing constituents of the microbiome of older children and adults [71,72].

The immune system undergoes a programming and maturation process early in life [2], facilitated by the immunological tolerance of newborns that occurs as a response to regulatory T lymphocytes from their mothers [62], allowing colonization by organisms encountered early in life. In experimental studies in a germ-free mouse model, the exposure to microbes was essential to the development of a complete functioning immune system, but the exposure had to occur at an early age [73]. The microbiome participates in both pro-inflammatory and regulatory responses of the immune system [74]. Most young children’s microbiome diversity pattern matures into that seen in older children and adults after 2 to 3 years of age [75], or it may take up to 5 years of age or even longer [76]. The infant’s microbiome begins to participate in the regulation of the immune function via interphase with intestinal intraepithelial lymphocytes and the gut immune system [77] leading to IgA-coating of a proportion of gut bacteria, first from breast milk [78] and then, after a few weeks, from the infants’ own immune system [79], providing a homeostatic effect in a setting of microbiome health, or in the setting of dysbiosis, coating of proinflammatory bacteria in attempting to attenuate microbial virulence [80].

Engraftment of a healthy diverse microbiota is important to development of early infant health, and its absence, together with reduced microbiome diversity (dysbiosis), can lead to alteration of the immune system and development of atopic disorders and food allergies [81,82]. Infant immune training and maturation during early life can prevent later immunologic disorders [83]. Studies in pathogen-free vs. germ-free mice have demonstrated that age-specific exposure to microbes during childhood is associated with protection from immune associated disorders via reduction of natural killer T cells that, when present, predispose those affected to asthma and inflammatory bowel disease. A healthy microbiome is important in immune response to an infecting organism, to response to vaccines [3] and to response to cancer chemotherapy in children [84].

Breast feeding has become accepted by most pregnant women in Western cultures. In a very large survey of different ethnic groups in the United States, 88% of mothers delivering infants decided to start breast feeding [85]. Reasons not to start included “didn’t want to”, “didn’t like it” or “taking care of other kids”. At 10 weeks, 70% were still breast feeding. The mothers who stopped indicated they had “trouble with baby latching”, “breast milk was insufficient” or they had “nipple pain”.

There are multiple reasons why future mothers should be encouraged to breast feed their newborn infants. A study of 107 mother infant pairs found that bacteria in the mother’s milk engrafted in the colon of their infants became an important source of the infants’ microbiome [86]. Breast milk is a complex biofluid that contains a number of active ingredients that exert immunomodulatory effects [87], such as hormones [88], with perhaps the principal effect on gut microbiome exerted by the different indigestible oligosaccharides contained in human milk [89]. Finally, breast milk provides excellent nutrition to infants. Breast feeding brings macronutrients and micronutrients and other well-defined factors to the infant, which contribute to a newborn’s microbiome formation, which is additionally influenced by the mother’s diet [90,91]. The diet of an overweight mother can affect her infant’s weight, causing metabolic dysfunction, and is one of several factors that can lead to obesity and type 2 diabetes in infants [92]. Undernutrition in childhood leading to dysbiosis was shown in one study to increase risk of later development of coronary artery disease [93].

Complementary food can be added to the infants’ diet at about 4 months of age, when the microbiome of the infant shows major differences from the mother’s microbiome [59], contributing to the expansion and complexity of the infant’s microbiome. Cessation of breast feeding sometime around six months of age was shown to correlate more with the establishment of an adult-type microbiome than introduction of solid food in a Swedish study [59]. It is particularly important to delay feeding from the tabletop in the rural developing world to prevent enteric infection from contaminated foods [94].

While physical interaction between mother and infant contributes the greatest to the early development of infant microbiomes, direct exposure to microbiota because of hygienic factors or unique environments, such as exposure to soil, animals and other people all contribute to the evolution of the microbiome and the general health of young children [95].

A setting where environmental contamination may help establish microbiome diversity with programming of the immune system leading to improved health during later years is on farms with exposure to animals. Children growing up on farms show reduced frequency of later asthma [96], other allergies and inflammatory bowel disease [97,98]. In a study of 82 mothers, cord blood obtained from the 22 farming mothers showed higher levels of T regulatory cells and lower cytokine levels and lymphocyte proliferation than non-farming mothers, indicating differences in immune development in the two study groups [99]. In another study, early exposure to a microbial world seen with farming and exposure to cats and dogs in infants was shown to lead to development of an IFN-γ immune responses during the first 3 months of life [100].

Day care centers (DCCs) housing young children, typically beginning at about 3 months of age, put infants together with other non-toilet-trained infants, contributing to fecal contamination of the environment [101]. In the early weeks of first attending large day care centers, children often experience increased rates of upper respiratory infections and bouts of infectious diarrhea which lesson in frequency with continued presence in the facilities [102,103]. Unique microbiome engraftment was seen in children attending one of four DCCs compared with age-matched children living at home [55]. The DCC effect on a child’s microbiome may relate to size of the center and exposure to areas in the DCCs where there is a greater likelihood of fecal contamination [104].

In one study, the frequency of attending day care centers or having close interactions with other children during early years of life was shown to inversely relate to the frequency of diabetes [105,106]. In large families, young siblings were shown to have reduced rates of atopic disorders compared to young children from smaller families [107,108].

Early microbial exposures from the environment have been postulated to train the immune system not to overreact to immune stimuli [55]. The “hygiene hypothesis” that focuses on the importance of exposure to a microbial world to improve health should not be abandoned [109], as it represents important pathways for microbiome development in infancy and childhood. Two important environmental sources of microbiota in early life that contribute to the diversity of the microbiome are exposure to dirt and other children, who lack hygienic standards. Soil and the human intestinal microbiome were shown to contain similar concentration of microbiota and specific taxa [110].

A rich and diverse microbiome was shown to be present in African hunter–gatherers with limited hygienic practices, who have near-constant exposure to environmental microbes from the ground, animals and people and rarely receive antibiotics [111]. From this close-to-earth population, the research team found a richer microbiome with more than two times the number of bacterial species than in their U.S. control population and with organisms shown to be less prone to oxidative damage.

It has been estimated that between 2% and 5% of newborns are exposed to parenteral antibiotics for presumed sepsis [112]. A prospective controlled study of 100 term newborns delivered via the vaginal route were studied for exposure to pre-natal and post-partum antibiotics to determine the effects on the fecal microbiota at one year of age in study conducted in Finland [113]. Perinatal antibiotics severely damaged the intestinal microbiome, which persisted for at least until one year of age, a critical duration of time for immune system development. Microbiome damage was shown to be far greater in infants than when antibiotics were given to older children. Dysbiosis from early infant exposure to antibiotics in other studies found the impaired microbiome was still present at 2–3 years of life when studied, a critical time for microbiome health [39,114]. Persistent damage to the microbiome in young children can result in future allergic and metabolic consequences [115], including asthma, atopic disorders, obesity, type 1 diabetes and inflammatory bowel disease [116]. Additionally, prior antibiotic exposure in early life can encourage development of antibiotic resistant gene reservoirs in their microbiome that make them more susceptible to difficult-to-treat infections [117].

With the National Ambulatory Medical Care Survey 2010–2011, it was found that 30% of outpatient antibiotic prescriptions were inappropriate, with the largest number being directed to children with respiratory infections not meeting standard criteria for treatment [118]. An effective national and local antibiotic stewardship program should be developed to minimize inappropriate use of antimicrobials targeting infants [119]. Greater efforts to document infection via laboratory testing rather than giving empiric treatment and using the narrowest spectrum antibiotics when this treatment is needed should be followed.