Elements in the Immune System of a Newborn: Comparison
View Latest Version
Please note this is a comparison between Version 2 by Jessie Wu and Version 1 by Herbert L. DuPont.

The initial exposure to a microbial world for an infant born vaginally is from the mother’s microbiota, influenced by maternal diet, level of stress, smoking history and living conditions. The intestinal microbiome in the first 2–3 years of life participates in the programming and development of the gut immune system, important to immune reactivity and general health as well as to response to infectious organisms and vaccines resulting in protective immunity. The intestinal microbiome and the immune system early in life can put infants on a long-term path to health or lead to medical and allergic disorders that can persist into adulthood.

  • microbiome in pregnancy
  • microbiome in infants
  • prebiotics
  • probiotics
  • vaginal seeding
  • fecal microbiota transplantation

1. Introduction

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][1].

2. Natural Birth, Vaginal Delivery

The route of delivery has a major and persistent effects on the composition of the intestinal microbiota early in life [26][2]. 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][3].
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][4]. 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][5].
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][6][7]. 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][8]. 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][9].
Table 1.
Vaginal and Intestinal Microbiome Changes in Pregnancy and Intestinal Microbiome of Newborns.
Comparative Group Microbiota Findings during Pregnancy Reference
Pregnancy, Vaginal Microbiome
  • The vaginal microbiome influences pregnancy outcomes.
  • During pregnancy, the vaginal microbiome was shown to undergo a reduction in α-diversity with reduced numbers of vagitypes of lactobacilli and lower prevalence of G. vaginalis and other microbiome profiles.
  • Post-partum, the Lactobacillus spp. changed type and became less prevalent, and strains of Clostridia, Bacteroidia and Actinomycetia classes increased.
  • Women who delivered preterm infants showed lower vaginal levels of Lactobacillus spp., higher levels of bacterial vaginosis-associated bacterium 1 (BVAB1), Sneathia amnii and Prevotella spp. and increases in proinflammatory cytokines in vaginal fluid.
 [18,19,34,[11][1235][10]][13]
Maternal Intestinal Microbiome During Pregnancy
  • Microbiota diversity was shown to decrease in the 3rd trimester with an increase in strains of Proteobacteria and Actinobacteria and decrease in strains of butyrate-producing, anti-inflammatory Fecalibacterium.
 [10][14]
Intestinal Microbiome During Pregnancy with Obesity
  • Dysbiosis was seen with an increase in strains of Firmicutes and an increased in Staphylococcus and Enterobacteriaceae
  • Decrease in Bifidobacterium and Bacteroides.
 [36,37][15][16]
Pregnant Women Given Antibiotics
  • Antibiotics significantly altered the gut and vaginal microbiome but more importantly reduced the α-diversity in the gut and vagina of pregnant women, leading to a sustained drop in abundance of Bifidobacterium and Bacteroidetes in newborn.
 [38][17]
  Infant Microbiome Findings  
Vaginal Birth
  • The most abundant phyla in the first-pass meconium, reflecting the in utero transfer of microbes to a newborn, were shown to be strains within the phyla, Firmicutes, Proteobacteria and Bacteroidetes.
  • During the first few days of life, the intestinal microbiome of newborns delivered vaginally showed high proportions of Bacteroides, including Prevotella spp., Bifidobacterium and Lactobacillus.
 [16,39][18][19]
Cesarean Delivery
  • In infants born via cesarean delivery, α-diversity of fecal microbiota was reduced with colonization by environmental bacteria, Staphylococcus spp. and Propionibacterium, without vaginal organisms such as Lactobacillus, Bacteroides (including Prevotella spp.), and Bifidobacterium spp., which were only found later.
  • Cesarean delivery also influenced infant microbiome with breast feeding early on when compared with vaginal delivery, which may have implications for infant health.
 [26,40,41][2][20][21]
Perinatal Exposure to Antibiotics
  • Perinatal exposure to antibiotics led to reduced fecal α-diversity and reduced maturity of the microbiome with depletion of health-promoting Bifidobacterium spp., Lactobacillus spp. Lachnospiraceae and Bacteroidetes spp. and with increase in proportion of proinflammatory Proteobacteria.
  • Some species were found to be dominated by a single strain, and antibiotic resistance genes carried on microbial chromosomes decreased sharply, while those on mobile elements were shown to persist long after antibiotic therapy was stopped.
 [39,42,43][19][22][23]
Preterm Birth
  • Preterm infants show reduced microbiome diversity and colonization by facultative anerobic bacteria, Enterobacter, Enterococcus, Escherichia and Klebsiella and showed a higher frequency of antibiotic resistance if antibiotics were administered.
  • Factors that negatively influenced microbiome development with preterm births included prolonged hospitalization, postnatal medications and formula feeding.
 [44,45,46,47,48][24][25][26][27][28]
Breast feed infants
  • Breast feeding was shown in one study to be the major factor determining the composition of infant microbiomes.
  • The most abundant bacterial species in exclusively breastfed infants were Bifidobacterium spp., Lactobacillus spp. and Bacteroides spp. with lower fecal α-diversity compared with formula fed infants.
 [36,49,50][15][29][30]
Formula Fed Infants
  • Despite the efforts of manufacturers to make formula preparations as close to breast milk as possible, the microbiome findings show there remain differences.
  • Common strains found in formula-fed infants were members of Streptococcus, Enterococcus, Lachnospiraceae, Enterobacteriaceae, Staphyloccoccaceae and C. difficile with low levels of Bifidobacterium.
  • Antibiotic-resistance genes were found to be present in one study.
 [49,51][29][31]
Changes After Weaning
  • As infants begin solid foods after weaning from breast feeding or infant formula, they are exposed to dietary carbohydrates (glycans) that alter the gut microbiome.
  • The introduction of solid foods alters the gut microbiota moving toward a more mature microbiome seen in older children, with the most prevalent strains from the phyla Firmicutes and Bacteroidetes and with an increase in Atopobium, Clostridium, Akkermansia, Lachnospiraceae and Ruminococcus and a decrease in facultative anaerobes.
 [52,53,54][32][33][34]
Changes when attending a Day Care Center
  • While home care infants and young children commonly were found to be colonized by Bifidobacterium spp. and Lactobacillus spp., infants attending DCCs had microbiomes more closely resembling those of older children in age-match studies with increased abundance of species within the Firmicute phylum (including species of Lachnospiraceae and Ruminocccus), and Bacteroides (including Prevotella spp).
 [55][35]

3. Cesarean Delivery

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][36]. 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][37].
Cesarean delivery excludes the newborn from vaginal and pelvic microbiota, leading to acquisition of a less diverse intestinal microbiome [58][38], 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][39]. In one study, microbiota acquired during cesarean delivery were acquired from the general environment in the hospital [60][40]. In a systematic review of infants, the gut microbiota for the first 3 months of life were affected by mode of delivery [61][41], with environmentally acquired organisms common constituents of the intestinal microbiome in newborns born via cesarean delivery [62][42]. The microbiomes of babies born via cesarean delivery begin to resemble breast-fed babies between 4 and 12 months of age [59][39], 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[43][44][45],64,65], inflammatory bowel disease, celiac disease, obesity [64][44] and type 1 diabetes [66][46] 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][47].

4. The Role of Host Genetics in Shaping the Infant Microbiome

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][48]. 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][49], was shown to be dependent on the presence of two human genes [70][50]. Genetic factors are less important in influencing constituents of the microbiome of older children and adults [71,72][51][52].

5. Formation of the Infant Immune System

The immune system undergoes a programming and maturation process early in life [2][53], facilitated by the immunological tolerance of newborns that occurs as a response to regulatory T lymphocytes from their mothers [62][42], 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][54]. The microbiome participates in both pro-inflammatory and regulatory responses of the immune system [74][55]. Most young children’s microbiome diversity pattern matures into that seen in older children and adults after 2 to 3 years of age [75][56], or it may take up to 5 years of age or even longer [76][57]. 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][58] leading to IgA-coating of a proportion of gut bacteria, first from breast milk [78][59] and then, after a few weeks, from the infants’ own immune system [79][60], 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][61].
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][62][63]. Infant immune training and maturation during early life can prevent later immunologic disorders [83][64]. 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][65] and to response to cancer chemotherapy in children [84][66].

6. Breast Feeding and Infant Diet in Microbiome Development

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][67]. 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][68]. Breast milk is a complex biofluid that contains a number of active ingredients that exert immunomodulatory effects [87][69], such as hormones [88][70], with perhaps the principal effect on gut microbiome exerted by the different indigestible oligosaccharides contained in human milk [89][71]. 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][72][73]. 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][74]. Undernutrition in childhood leading to dysbiosis was shown in one study to increase risk of later development of coronary artery disease [93][75].
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][39], 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][39]. It is particularly important to delay feeding from the tabletop in the rural developing world to prevent enteric infection from contaminated foods [94][76].

7. Hygiene and the Environmental

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][77].
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][78], other allergies and inflammatory bowel disease [97,98][79][80]. 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][81]. 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][82].
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][83]. 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][84][85]. Unique microbiome engraftment was seen in children attending one of four DCCs compared with age-matched children living at home [55][35]. 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][86].
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][87][88]. In large families, young siblings were shown to have reduced rates of atopic disorders compared to young children from smaller families [107,108][89][90].
Early microbial exposures from the environment have been postulated to train the immune system not to overreact to immune stimuli [55][35]. The “hygiene hypothesis” that focuses on the importance of exposure to a microbial world to improve health should not be abandoned [109][91], 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][92].
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][93]. 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.

8. Perinatal Antibiotics

It has been estimated that between 2% and 5% of newborns are exposed to parenteral antibiotics for presumed sepsis [112][94]. 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][95]. 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][19][96]. Persistent damage to the microbiome in young children can result in future allergic and metabolic consequences [115][97], including asthma, atopic disorders, obesity, type 1 diabetes and inflammatory bowel disease [116][98]. 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][99].
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][100]. An effective national and local antibiotic stewardship program should be developed to minimize inappropriate use of antimicrobials targeting infants [119][101]. 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.

References

  1. Mold, J.E.; Michaelsson, J.; Burt, T.D.; Muench, M.O.; Beckerman, K.P.; Busch, M.P.; Lee, T.H.; Nixon, D.F.; McCune, J.M. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 2008, 322, 1562–1565.
  2. Biasucci, G.; Benenati, B.; Morelli, L.; Bessi, E.; Boehm, G. Cesarean delivery may affect the early biodiversity of intestinal bacteria. J. Nutr. 2008, 138, 1796S–1800S.
  3. Liu, Y.; Ma, J.; Zhu, B.; Liu, F.; Qin, S.; Lv, N.; Feng, Y.; Wang, S.; Yang, H. A health-promoting role of exclusive breastfeeding on infants through restoring delivery mode-induced gut microbiota perturbations. Front. Microbiol. 2023, 14, 1163269.
  4. Tasnim, N.; Quin, C.; Gill, S.; Dai, C.; Hart, M.; Gibson, D.L. Early life environmental exposures have a minor impact on the gut ecosystem following a natural birth. Gut Microbes 2021, 13, 1875797.
  5. Beller, L.; Deboutte, W.; Falony, G.; Vieira-Silva, S.; Tito, R.Y.; Valles-Colomer, M.; Rymenans, L.; Jansen, D.; Van Espen, L.; Papadaki, M.I.; et al. Successional Stages in Infant Gut Microbiota Maturation. mBio 2021, 12, e0185721.
  6. Ferretti, P.; Pasolli, E.; Tett, A.; Asnicar, F.; Gorfer, V.; Fedi, S.; Armanini, F.; Truong, D.T.; Manara, S.; Zolfo, M.; et al. Mother-to-Infant Microbial Transmission from Different Body Sites Shapes the Developing Infant Gut Microbiome. Cell Host Microbe 2018, 24, 133–145.e5.
  7. Mitchell, C.M.; Mazzoni, C.; Hogstrom, L.; Bryant, A.; Bergerat, A.; Cher, A.; Pochan, S.; Herman, P.; Carrigan, M.; Sharp, K.; et al. Delivery Mode Affects Stability of Early Infant Gut Microbiota. Cell Rep. Med. 2020, 1, 100156.
  8. Wilson, B.C.; Butler, E.M.; Grigg, C.P.; Derraik, J.G.B.; Chiavaroli, V.; Walker, N.; Thampi, S.; Creagh, C.; Reynolds, A.J.; Vatanen, T.; et al. Oral administration of maternal vaginal microbes at birth to restore gut microbiome development in infants born by caesarean section: A pilot randomised placebo-controlled trial. EBioMedicine 2021, 69, 103443.
  9. Wei, S.; Jespersen, M.L.; Baunwall, S.M.D.; Myers, P.N.; Smith, E.M.; Dahlerup, J.F.; Rasmussen, S.; Nielsen, H.B.; Licht, T.R.; Bahl, M.I.; et al. Cross-generational bacterial strain transfer to an infant after fecal microbiota transplantation to a pregnant patient: A case report. Microbiome 2022, 10, 193.
  10. Romero, R.; Hassan, S.S.; Gajer, P.; Tarca, A.L.; Fadrosh, D.W.; Nikita, L.; Galuppi, M.; Lamont, R.F.; Chaemsaithong, P.; Miranda, J.; et al. The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. Microbiome 2014, 2, 4.
  11. Fettweis, J.M.; Serrano, M.G.; Brooks, J.P.; Edwards, D.J.; Girerd, P.H.; Parikh, H.I.; Huang, B.; Arodz, T.J.; Edupuganti, L.; Glascock, A.L.; et al. The vaginal microbiome and preterm birth. Nat. Med. 2019, 25, 1012–1021.
  12. MacIntyre, D.A.; Chandiramani, M.; Lee, Y.S.; Kindinger, L.; Smith, A.; Angelopoulos, N.; Lehne, B.; Arulkumaran, S.; Brown, R.; Teoh, T.G.; et al. The vaginal microbiome during pregnancy and the postpartum period in a European population. Sci. Rep. 2015, 5, 8988.
  13. Serrano, M.G.; Parikh, H.I.; Brooks, J.P.; Edwards, D.J.; Arodz, T.J.; Edupuganti, L.; Huang, B.; Girerd, P.H.; Bokhari, Y.A.; Bradley, S.P.; et al. Racioethnic diversity in the dynamics of the vaginal microbiome during pregnancy. Nat. Med. 2019, 25, 1001–1011.
  14. Koren, O.; Goodrich, J.K.; Cullender, T.C.; Spor, A.; Laitinen, K.; Backhed, H.K.; Gonzalez, A.; Werner, J.J.; Angenent, L.T.; Knight, R.; et al. Host remodeling of the gut microbiome and metabolic changes during pregnancy. Cell 2012, 150, 470–480.
  15. Laursen, M.F.; Andersen, L.B.; Michaelsen, K.F.; Molgaard, C.; Trolle, E.; Bahl, M.I.; Licht, T.R. Infant Gut Microbiota Development Is Driven by Transition to Family Foods Independent of Maternal Obesity. mSphere 2016, 1, e00069-15.
  16. Santacruz, A.; Collado, M.C.; Garcia-Valdes, L.; Segura, M.T.; Martin-Lagos, J.A.; Anjos, T.; Marti-Romero, M.; Lopez, R.M.; Florido, J.; Campoy, C.; et al. Gut microbiota composition is associated with body weight, weight gain and biochemical parameters in pregnant women. Br. J. Nutr. 2010, 104, 83–92.
  17. Azad, M.B.; Konya, T.; Persaud, R.R.; Guttman, D.S.; Chari, R.S.; Field, C.J.; Sears, M.R.; Mandhane, P.J.; Turvey, S.E.; Subbarao, P.; et al. Impact of maternal intrapartum antibiotics, method of birth and breastfeeding on gut microbiota during the first year of life: A prospective cohort study. BJOG Int. J. Obstet. Gynaecol. 2016, 123, 983–993.
  18. Tapiainen, T.; Paalanne, N.; Tejesvi, M.V.; Koivusaari, P.; Korpela, K.; Pokka, T.; Salo, J.; Kaukola, T.; Pirttila, A.M.; Uhari, M.; et al. Maternal influence on the fetal microbiome in a population-based study of the first-pass meconium. Pediatr. Res. 2018, 84, 371–379.
  19. Yassour, M.; Vatanen, T.; Siljander, H.; Hamalainen, A.M.; Harkonen, T.; Ryhanen, S.J.; Franzosa, E.A.; Vlamakis, H.; Huttenhower, C.; Gevers, D.; et al. Natural history of the infant gut microbiome and impact of antibiotic treatment on bacterial strain diversity and stability. Sci. Transl. Med. 2016, 8, 343ra81.
  20. Harrison, I.S.; Monir, R.L.; Neu, J.; Schoch, J.J. Neonatal sepsis and the skin microbiome. J. Perinatol. 2022, 42, 1429–1433.
  21. Hermansson, H.; Kumar, H.; Collado, M.C.; Salminen, S.; Isolauri, E.; Rautava, S. Breast Milk Microbiota Is Shaped by Mode of Delivery and Intrapartum Antibiotic Exposure. Front. Nutr. 2019, 6, 4.
  22. Gopalakrishnan, V.; Spencer, C.N.; Nezi, L.; Reuben, A.; Andrews, M.C.; Karpinets, T.V.; Prieto, P.A.; Vicente, D.; Hoffman, K.; Wei, S.C.; et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 2018, 359, 97–103.
  23. Tanaka, S.; Kobayashi, T.; Songjinda, P.; Tateyama, A.; Tsubouchi, M.; Kiyohara, C.; Shirakawa, T.; Sonomoto, K.; Nakayama, J. Influence of antibiotic exposure in the early postnatal period on the development of intestinal microbiota. FEMS Immunol. Med. Microbiol. 2009, 56, 80–87.
  24. Bargheet, A.; Klingenberg, C.; Esaiassen, E.; Hjerde, E.; Cavanagh, J.P.; Bengtsson-Palme, J.; Pettersen, V.K. Development of early life gut resistome and mobilome across gestational ages and microbiota-modifying treatments. EBioMedicine 2023, 92, 104613.
  25. Greenwood, C.; Morrow, A.L.; Lagomarcino, A.J.; Altaye, M.; Taft, D.H.; Yu, Z.; Newburg, D.S.; Ward, D.V.; Schibler, K.R. Early empiric antibiotic use in preterm infants is associated with lower bacterial diversity and higher relative abundance of Enterobacter. J. Pediatr. 2014, 165, 23–29.
  26. Grier, A.; Qiu, X.; Bandyopadhyay, S.; Holden-Wiltse, J.; Kessler, H.A.; Gill, A.L.; Hamilton, B.; Huyck, H.; Misra, S.; Mariani, T.J.; et al. Impact of prematurity and nutrition on the developing gut microbiome and preterm infant growth. Microbiome 2017, 5, 158.
  27. Schwiertz, A.; Gruhl, B.; Lobnitz, M.; Michel, P.; Radke, M.; Blaut, M. Development of the intestinal bacterial composition in hospitalized preterm infants in comparison with breast-fed, full-term infants. Pediatr. Res. 2003, 54, 393–399.
  28. Zwittink, R.D.; van Zoeren-Grobben, D.; Martin, R.; van Lingen, R.A.; Groot Jebbink, L.J.; Boeren, S.; Renes, I.B.; van Elburg, R.M.; Belzer, C.; Knol, J. Metaproteomics reveals functional differences in intestinal microbiota development of preterm infants. Mol. Cell. Proteom. 2017, 16, 1610–1620.
  29. Ma, J.; Li, Z.; Zhang, W.; Zhang, C.; Zhang, Y.; Mei, H.; Zhuo, N.; Wang, H.; Wang, L.; Wu, D. Comparison of gut microbiota in exclusively breast-fed and formula-fed babies: A study of 91 term infants. Sci. Rep. 2020, 10, 15792.
  30. van den Elsen, L.W.J.; Garssen, J.; Burcelin, R.; Verhasselt, V. Shaping the Gut Microbiota by Breastfeeding: The Gateway to Allergy Prevention? Front. Pediatr. 2019, 7, 47.
  31. Parnanen, K.M.M.; Hultman, J.; Markkanen, M.; Satokari, R.; Rautava, S.; Lamendella, R.; Wright, J.; McLimans, C.J.; Kelleher, S.L.; Virta, M.P. Early-life formula feeding is associated with infant gut microbiota alterations and an increased antibiotic resistance load. Am. J. Clin. Nutr. 2022, 115, 407–421.
  32. Al Nabhani, Z.; Dulauroy, S.; Marques, R.; Cousu, C.; Al Bounny, S.; Dejardin, F.; Sparwasser, T.; Berard, M.; Cerf-Bensussan, N.; Eberl, G. A Weaning Reaction to Microbiota Is Required for Resistance to Immunopathologies in the Adult. Immunity 2019, 50, 1276–1288.e5.
  33. Laursen, M.F.; Bahl, M.I.; Michaelsen, K.F.; Licht, T.R. First Foods and Gut Microbes. Front. Microbiol. 2017, 8, 356.
  34. McKeen, S.; Young, W.; Fraser, K.; Roy, N.C.; McNabb, W.C. Glycan Utilisation and Function in the Microbiome of Weaning Infants. Microorganisms 2019, 7, 190.
  35. Amir, A.; Erez-Granat, O.; Braun, T.; Sosnovski, K.; Hadar, R.; BenShoshan, M.; Heiman, S.; Abbas-Egbariya, H.; Glick Saar, E.; Efroni, G.; et al. Gut microbiome development in early childhood is affected by day care attendance. NPJ Biofilms Microbiomes 2022, 8, 2.
  36. Osterman, M. Changes in Primary and Repeat Cesarean Delivery US, 2016–2021. NVSS Vital Statistics Rapid Release; No. 21; 2022. Available online: https://stacks.cdc.gov/view/cdc/117432 (accessed on 21 October 2023).
  37. Witt, W.P.; Wisk, L.E.; Cheng, E.R.; Mandell, K.; Chatterjee, D.; Wakeel, F.; Godecker, A.L.; Zarak, D. Determinants of cesarean delivery in the US: A lifecourse approach. Matern. Child Health J. 2015, 19, 84–93.
  38. Gronlund, M.M.; Lehtonen, O.P.; Eerola, E.; Kero, P. Fecal microflora in healthy infants born by different methods of delivery: Permanent changes in intestinal flora after cesarean delivery. J. Pediatr. Gastroenterol. Nutr. 1999, 28, 19–25.
  39. Backhed, F.; Roswall, J.; Peng, Y.; Feng, Q.; Jia, H.; Kovatcheva-Datchary, P.; Li, Y.; Xia, Y.; Xie, H.; Zhong, H.; et al. Dynamics and Stabilization of the Human Gut Microbiome during the First Year of Life. Cell Host Microbe 2015, 17, 690–703.
  40. Shin, H.; Pei, Z.; Martinez, K.A., 2nd; Rivera-Vinas, J.I.; Mendez, K.; Cavallin, H.; Dominguez-Bello, M.G. The first microbial environment of infants born by C-section: The operating room microbes. Microbiome 2015, 3, 59.
  41. Rutayisire, E.; Huang, K.; Liu, Y.; Tao, F. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants’ life: A systematic review. BMC Gastroenterol. 2016, 16, 86.
  42. Dominguez-Bello, M.G.; Costello, E.K.; Contreras, M.; Magris, M.; Hidalgo, G.; Fierer, N.; Knight, R. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc. Natl. Acad. Sci. USA 2010, 107, 11971–11975.
  43. Bager, P.; Wohlfahrt, J.; Westergaard, T. Caesarean delivery and risk of atopy and allergic disease: Meta-analyses. Clin. Exp. Allergy 2008, 38, 634–642.
  44. Sevelsted, A.; Stokholm, J.; Bonnelykke, K.; Bisgaard, H. Cesarean section and chronic immune disorders. Pediatrics 2015, 135, e92–e98.
  45. Thavagnanam, S.; Fleming, J.; Bromley, A.; Shields, M.D.; Cardwell, C.R. A meta-analysis of the association between Caesarean section and childhood asthma. Clin. Exp. Allergy 2008, 38, 629–633.
  46. Cardwell, C.R.; Stene, L.C.; Joner, G.; Cinek, O.; Svensson, J.; Goldacre, M.J.; Parslow, R.C.; Pozzilli, P.; Brigis, G.; Stoyanov, D.; et al. Caesarean section is associated with an increased risk of childhood-onset type 1 diabetes mellitus: A meta-analysis of observational studies. Diabetologia 2008, 51, 726–735.
  47. Vu, K.; Lou, W.; Tun, H.M.; Konya, T.B.; Morales-Lizcano, N.; Chari, R.S.; Field, C.J.; Guttman, D.S.; Mandal, R.; Wishart, D.S.; et al. From Birth to Overweight and Atopic Disease: Multiple and Common Pathways of the Infant Gut Microbiome. Gastroenterology 2021, 160, 128–144.e10.
  48. Murphy, K.; CA, O.S.; Ryan, C.A.; Dempsey, E.M.; PW, O.T.; Stanton, C.; Ross, R.P. The gut microbiota composition in dichorionic triplet sets suggests a role for host genetic factors. PLoS ONE 2015, 10, e0122561.
  49. Sagheddu, V.; Patrone, V.; Miragoli, F.; Puglisi, E.; Morelli, L. Infant Early Gut Colonization by Lachnospiraceae: High Frequency of Ruminococcus gnavus. Front. Pediatr. 2016, 4, 57.
  50. Kurilshikov, A.; Medina-Gomez, C.; Bacigalupe, R.; Radjabzadeh, D.; Wang, J.; Demirkan, A.; Le Roy, C.I.; Raygoza Garay, J.A.; Finnicum, C.T.; Liu, X.; et al. Large-scale association analyses identify host factors influencing human gut microbiome composition. Nat. Genet. 2021, 53, 156–165.
  51. Goodrich, J.K.; Davenport, E.R.; Beaumont, M.; Jackson, M.A.; Knight, R.; Ober, C.; Spector, T.D.; Bell, J.T.; Clark, A.G.; Ley, R.E. Genetic Determinants of the Gut Microbiome in UK Twins. Cell Host Microbe 2016, 19, 731–743.
  52. Rothschild, D.; Weissbrod, O.; Barkan, E.; Kurilshikov, A.; Korem, T.; Zeevi, D.; Costea, P.I.; Godneva, A.; Kalka, I.N.; Bar, N.; et al. Environment dominates over host genetics in shaping human gut microbiota. Nature 2018, 555, 210–215.
  53. Ganal-Vonarburg, S.C.; Hornef, M.W.; Macpherson, A.J. Microbial-host molecular exchange and its functional consequences in early mammalian life. Science 2020, 368, 604–607.
  54. Olszak, T.; An, D.; Zeissig, S.; Vera, M.P.; Richter, J.; Franke, A.; Glickman, J.N.; Siebert, R.; Baron, R.M.; Kasper, D.L.; et al. Microbial exposure during early life has persistent effects on natural killer T cell function. Science 2012, 336, 489–493.
  55. Cerf-Bensussan, N.; Gaboriau-Routhiau, V. The immune system and the gut microbiota: Friends or foes? Nat. Rev. Immunol. 2010, 10, 735–744.
  56. Stewart, C.J.; Ajami, N.J.; O’Brien, J.L.; Hutchinson, D.S.; Smith, D.P.; Wong, M.C.; Ross, M.C.; Lloyd, R.E.; Doddapaneni, H.; Metcalf, G.A.; et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 2018, 562, 583–588.
  57. Roswall, J.; Olsson, L.M.; Kovatcheva-Datchary, P.; Nilsson, S.; Tremaroli, V.; Simon, M.C.; Kiilerich, P.; Akrami, R.; Kramer, M.; Uhlen, M.; et al. Developmental trajectory of the healthy human gut microbiota during the first 5 years of life. Cell Host Microbe 2021, 29, 765–776.e3.
  58. Hoytema van Konijnenburg, D.P.; Reis, B.S.; Pedicord, V.A.; Farache, J.; Victora, G.D.; Mucida, D. Intestinal Epithelial and Intraepithelial T Cell Crosstalk Mediates a Dynamic Response to Infection. Cell 2017, 171, 783–794.e13.
  59. Guo, J.; Ren, C.; Han, X.; Huang, W.; You, Y.; Zhan, J. Role of IgA in the early-life establishment of the gut microbiota and immunity: Implications for constructing a healthy start. Gut Microbes 2021, 13, 1908101.
  60. Janzon, A.; Goodrich, J.K.; Koren, O.; Group, T.S.; Waters, J.L.; Ley, R.E. Interactions between the Gut Microbiome and Mucosal Immunoglobulins A, M, and G in the Developing Infant Gut. mSystems 2019, 4, 6.
  61. DuPont, H.L.; Jiang, Z.D.; Alexander, A.S.; DuPont, A.W.; Brown, E.L. Intestinal IgA-Coated Bacteria in Healthy- and Altered-Microbiomes (Dysbiosis) and Predictive Value in Successful Fecal Microbiota Transplantation. Microorganisms 2022, 11, 93.
  62. Mousa, W.K.; Chehadeh, F.; Husband, S. Microbial dysbiosis in the gut drives systemic autoimmune diseases. Front. Immunol. 2022, 13, 906258.
  63. Sandin, A.; Braback, L.; Norin, E.; Bjorksten, B. Faecal short chain fatty acid pattern and allergy in early childhood. Acta Paediatr. 2009, 98, 823–827.
  64. Cereta, A.D.; Oliveira, V.R.; Costa, I.P.; Guimaraes, L.L.; Afonso, J.P.R.; Fonseca, A.L.; de Sousa, A.R.T.; Silva, G.A.M.; Mello, D.; de Oliveira, L.V.F.; et al. Early Life Microbial Exposure and Immunity Training Effects on Asthma Development and Progression. Front. Med. 2021, 8, 662262.
  65. Collins, N.; Belkaid, Y. Do the Microbiota Influence Vaccines and Protective Immunity to Pathogens? Engaging Our Endogenous Adjuvants. Cold Spring Harb. Perspect. Biol. 2018, 10, a028860.
  66. Rotz, S.J.; Dandoy, C.E. The microbiome in pediatric oncology. Cancer 2020, 126, 3629–3637.
  67. Quintero, S.M.; Strassle, P.D.; Londono Tobon, A.; Ponce, S.; Alhomsi, A.; Maldonado, A.I.; Ko, J.S.; Wilkerson, M.J.; Napoles, A.M. Race/ethnicity-specific associations between breastfeeding information source and breastfeeding rates among U.S. women. BMC Public Health 2023, 23, 520.
  68. Pannaraj, P.S.; Li, F.; Cerini, C.; Bender, J.M.; Yang, S.; Rollie, A.; Adisetiyo, H.; Zabih, S.; Lincez, P.J.; Bittinger, K.; et al. Association between Breast Milk Bacterial Communities and Establishment and Development of the Infant Gut Microbiome. JAMA Pediatr. 2017, 171, 647–654.
  69. Lonnerdal, B. Human Milk: Bioactive Proteins/Peptides and Functional Properties. Nestle Nutr. Inst. Workshop Ser. 2016, 86, 97–107.
  70. Hamosh, M. Bioactive factors in human milk. Pediatr. Clin. N. Am. 2001, 48, 69–86.
  71. Walsh, C.; Lane, J.A.; van Sinderen, D.; Hickey, R.M. Human milk oligosaccharides: Shaping the infant gut microbiota and supporting health. J. Funct. Foods 2020, 72, 104074.
  72. Boudry, G.; Charton, E.; Le Huerou-Luron, I.; Ferret-Bernard, S.; Le Gall, S.; Even, S.; Blat, S. The Relationship between Breast Milk Components and the Infant Gut Microbiota. Front. Nutr. 2021, 8, 629740.
  73. Cortes-Macias, E.; Selma-Royo, M.; Garcia-Mantrana, I.; Calatayud, M.; Gonzalez, S.; Martinez-Costa, C.; Collado, M.C. Maternal Diet Shapes the Breast Milk Microbiota Composition and Diversity: Impact of Mode of Delivery and Antibiotic Exposure. J. Nutr. 2021, 151, 330–340.
  74. Barlow, G.M.; Yu, A.; Mathur, R. Role of the Gut Microbiome in Obesity and Diabetes Mellitus. Nutr. Clin. Pract. 2015, 30, 787–797.
  75. Barker, D.J.; Osmond, C. Infant mortality, childhood nutrition, and ischaemic heart disease in England and Wales. Lancet 1986, 1, 1077–1081.
  76. Hossain, M.M.; Reves, R.R.; Radwan, M.M.; Arafa, S.A.; Habib, M.; DuPont, H.L. Breast-feeding in Egypt. J. R. Soc. Health 1994, 114, 290–296.
  77. Tasnim, N.; Abulizi, N.; Pither, J.; Hart, M.M.; Gibson, D.L. Linking the Gut Microbial Ecosystem with the Environment: Does Gut Health Depend on Where We Live? Front. Microbiol. 2017, 8, 1935.
  78. Stein, M.M.; Hrusch, C.L.; Gozdz, J.; Igartua, C.; Pivniouk, V.; Murray, S.E.; Ledford, J.G.; Marques Dos Santos, M.; Anderson, R.L.; Metwali, N.; et al. Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. N. Engl. J. Med. 2016, 375, 411–421.
  79. Ananthakrishnan, A.N. Epidemiology and risk factors for IBD. Nat. Rev. Gastroenterol. Hepatol. 2015, 12, 205–217.
  80. Piovani, D.; Danese, S.; Peyrin-Biroulet, L.; Nikolopoulos, G.K.; Lytras, T.; Bonovas, S. Environmental Risk Factors for Inflammatory Bowel Diseases: An Umbrella Review of Meta-analyses. Gastroenterology 2019, 157, 647–659.e4.
  81. Schaub, B.; Liu, J.; Hoppler, S.; Schleich, I.; Huehn, J.; Olek, S.; Wieczorek, G.; Illi, S.; von Mutius, E. Maternal farm exposure modulates neonatal immune mechanisms through regulatory T cells. J. Allergy Clin. Immunol. 2009, 123, 774–782.e5.
  82. Roponen, M.; Hyvarinen, A.; Hirvonen, M.R.; Keski-Nisula, L.; Pekkanen, J. Change in IFN-gamma-producing capacity in early life and exposure to environmental microbes. J. Allergy Clin. Immunol. 2005, 116, 1048–1052.
  83. Ekanem, E.E.; DuPont, H.L.; Pickering, L.K.; Selwyn, B.J.; Hawkins, C.M. Transmission dynamics of enteric bacteria in day-care centers. Am. J. Epidemiol. 1983, 118, 562–572.
  84. Ball, T.M.; Holberg, C.J.; Aldous, M.B.; Martinez, F.D.; Wright, A.L. Influence of attendance at day care on the common cold from birth through 13 years of age. Arch. Pediatr. Adolesc. Med. 2002, 156, 121–126.
  85. Sullivan, P.; Woodward, W.E.; Pickering, L.K.; DuPont, H.L. Longitudinal study of occurrence of diarrheal disease in day care centers. Am. J. Public. Health 1984, 74, 987–991.
  86. Lemp, G.F.; Woodward, W.E.; Pickering, L.K.; Sullivan, P.S.; DuPont, H.L. The relationship of staff to the incidence of diarrhea in day-care centers. Am. J. Epidemiol. 1984, 120, 750–758.
  87. McKinney, P.A.; Okasha, M.; Parslow, R.C.; Law, G.R.; Gurney, K.A.; Williams, R.; Bodansky, H.J. Early social mixing and childhood Type 1 diabetes mellitus: A case-control study in Yorkshire, UK. Diabet. Med. 2000, 17, 236–242.
  88. Parslow, R.C.; McKinney, P.A.; Law, G.R.; Bodansky, H.J. Population mixing and childhood diabetes. Int. J. Epidemiol. 2001, 30, 533–538; discussion 538–539.
  89. Bremner, S.A.; Carey, I.M.; DeWilde, S.; Richards, N.; Maier, W.C.; Hilton, S.R.; Strachan, D.P.; Cook, D.G. Infections presenting for clinical care in early life and later risk of hay fever in two UK birth cohorts. Allergy 2008, 63, 274–283.
  90. Strachan, D.P. Hay fever, hygiene, and household size. BMJ 1989, 299, 1259–1260.
  91. Bloomfield, S.F.; Rook, G.A.; Scott, E.A.; Shanahan, F.; Stanwell-Smith, R.; Turner, P. Time to abandon the hygiene hypothesis: New perspectives on allergic disease, the human microbiome, infectious disease prevention and the role of targeted hygiene. Perspect. Public. Health 2016, 136, 213–224.
  92. Blum, W.E.H.; Zechmeister-Boltenstern, S.; Keiblinger, K.M. Does Soil Contribute to the Human Gut Microbiome? Microorganisms 2019, 7, 287.
  93. Conroy, G. Hunter-gatherer lifestyle fosters thriving gut microbiome. Nature 2023.
  94. Fjalstad, J.W.; Stensvold, H.J.; Bergseng, H.; Simonsen, G.S.; Salvesen, B.; Ronnestad, A.E.; Klingenberg, C. Early-onset Sepsis and Antibiotic Exposure in Term Infants: A Nationwide Population-based Study in Norway. Pediatr. Infect. Dis. J. 2016, 35, 1–6.
  95. Ainonen, S.; Tejesvi, M.V.; Mahmud, M.R.; Paalanne, N.; Pokka, T.; Li, W.; Nelson, K.E.; Salo, J.; Renko, M.; Vanni, P.; et al. Antibiotics at birth and later antibiotic courses: Effects on gut microbiota. Pediatr. Res. 2022, 91, 154–162.
  96. Bokulich, N.A.; Chung, J.; Battaglia, T.; Henderson, N.; Jay, M.; Li, H.; Lieber, A.D.; Wu, F.; Perez-Perez, G.I.; Chen, Y.; et al. Antibiotics, birth mode, and diet shape microbiome maturation during early life. Sci. Transl. Med. 2016, 8, 343ra82.
  97. Cox, L.M.; Yamanishi, S.; Sohn, J.; Alekseyenko, A.V.; Leung, J.M.; Cho, I.; Kim, S.G.; Li, H.; Gao, Z.; Mahana, D.; et al. Altering the intestinal microbiota during a critical developmental window has lasting metabolic consequences. Cell 2014, 158, 705–721.
  98. Gaufin, T.; Tobin, N.H.; Aldrovandi, G.M. The importance of the microbiome in pediatrics and pediatric infectious diseases. Curr. Opin. Pediatr. 2018, 30, 117–124.
  99. Gibson, M.K.; Crofts, T.S.; Dantas, G. Antibiotics and the developing infant gut microbiota and resistome. Curr. Opin. Microbiol. 2015, 27, 51–56.
  100. Fleming-Dutra, K.E.; Hersh, A.L.; Shapiro, D.J.; Bartoces, M.; Enns, E.A.; File, T.M., Jr.; Finkelstein, J.A.; Gerber, J.S.; Hyun, D.Y.; Linder, J.A.; et al. Prevalence of Inappropriate Antibiotic Prescriptions among US Ambulatory Care Visits, 2010–2011. JAMA 2016, 315, 1864–1873.
  101. Gerber, J.S.; Jackson, M.A.; Tamma, P.D.; Zaoutis, T.E.; Maldonado, Y.A.; O’leary, S.T.; Banerjee, R.; Barnett, E.D.; Campbell, J.D.; Caserta, M.T.; et al. Antibiotic Stewardship in Pediatrics. Pediatrics 2021, 147, e2020040295.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
Video Production Service
Feedback