The Infant Microbiome: How Environmental & Maternal Factors Influence Its Development

Disturbances in the establishment of the indigenous intestinal microbiome, caused by environmental and maternal factors in early life, have been linked to the risk of immune-mediated and inflammatory conditions such as atopic disorders, inflammatory bowel disease, and obesity later in life.^1-6

The fetal infant microbiome was, until recently, thought to be sterile and only became initially colonized during birth and in the early postpartum period. New research is showing that the initiation of colonization starts in utero, with unique bacterial colonies detectable in the placenta, amniotic fluid, and meconium.⁷ Environmental factors in early life can positively or negatively influence this small, maternally-derived colony, and drive it down inflammatory or anti-inflammatory pathways.

The most influential factors affecting microbial colonization are place of birth, mode of birth, antibiotic use in the perinatal period, infant antibiotic use, and type of infant feeding.⁶

Many of these factors negatively affect the infant microbiome composition and may inextricably alter the natural development and function of a baby’s immune, digestive, and metabolic systems. It is important for a clinician involved in newborn care to discuss with expectant parents the following factors: the role of the microbiome in preventing illness and disease, factors that may disrupt or interfere with early colonization, and the increased risk for inflammatory and non-communicable diseases – in both childhood and adulthood – that are associated with such interference.

Place and Type of Birth

The types of bacterial strains, diversity of strains, and colony numbers are significantly different between infants born at home versus a hospital, and between babies born vaginally versus by cesarean section (C-section). A baby born at home is initially colonized predominantly with “friendly” bacteria from the vaginal tract and from the surrounding environment (eg, dust particles, clothing, bedding, etc), and consequently harbors fewer pathogenic strains than babies born in a hospital and via C-section.^1,2

The predominant bacterial strains in vaginally-born babies are Lactobacillus and bifidobacteria. Cesarean-delivered (CD) babies, however, are colonized with more pathogenic bacteria (eg, Clostridia, Escherichia coli, Staphylococcus), derived from the hospital environment.⁸ This includes pathogens found in the operating room (OR). Shin et al swabbed OR floors, walls, ventilation grids, armrests, and lamps, and found that the bacteria on and in these surfaces corresponded to the predominant strains in surgically-born babies. They concluded that the OR is the first environment for CD newborns and that OR microbes are accordingly seeding the microbiome in these babies.⁹ A small 2016 study of 23 healthy mother-infant pairs supports this finding.¹⁰ Using maternal rectal and vaginal swabs, infant nasal aspirates, and infant stool samples, they found that vaginally-born infants had a higher abundance of Firmicutes bacteria (mainly lactobacilli) in their nasal aspirates compared to those who were surgically born. CD infants, in contrast, were found to be enriched instead in skin bacteria, and had a deficit in Bacteroidetes bacteria. Penders et Al¹¹ studied 1032 infant fecal samples which corroborated these findings, concluding that infants born vaginally at home, and that were exclusively breastfed, harbored the most beneficial gut micobiota (ie, the highest numbers of bifidobacteria and the lowest numbers of E coli and C difficile).¹¹

Research into the effect of mode and place of delivery on the infant microbiome is still in the early stages. The research we do have, however, supports the significant effect the infant’s birth experience may have on the strains and diversity of bacteria initially colonizing the gut.

Perinatal Antibiotic Use

Antibiotic exposure is another significant factor influencing the prenatal and newborn microbiome. The allopathic medical community has acknowledged that over-prescription of unnecessary antibiotics has created antibiotic-resistant bacteria.¹² The misuse of antibiotics has now infiltrated obstetrical care. As primary care clinicians, we should focus on best, evidenced-based practices to support the natural unfolding of the infant microbiota and subsequent digestive-immune system dyad.

The use of an antibiotic will disrupt the structure and function of not only the gastrointestinal (GI) microbiome, but those of the vaginal and urinary tracts as well. These drugs also cross the placenta, remaining elevated in the infant at high levels several hours after birth, preventing further natural seeding.¹ Because antibiotics can enter early life in several ways, it’s important to recognize when this may happen. Antibiotics are often prescribed…

• in pregnancy for any suspected bacterial infection
• prophylactically during labor if positive for Group B Streptococcus in late pregnancy
• in the postpartum period for any suspected bacterial infection (eg, urinary tract infection [UTI], mastitis)
• directly to the infant in the postpartum period for any suspected bacterial infectionMaternal antibiotics alter not only the in-utero colonization, but also the skin and vaginal flora; both are necessary for further sequencing.¹

  Using a mouse model, Gonzalez-Perez et al proved that maternal antibiotic use during pregnancy and lactation profoundly affects the GI microbiota of newborn mice, as well as their immune responses to viral infections, compared to controls.⁴ The antibiotic-treated mother mice had a predominance of Enterococcus fecalis species (rather than bifidobacteria), and exhibited increased mortality following a vaccinia viral infection. The accelerated mortality is postulated to be a result of the disturbed colonization of the GI tract.⁴

  A large prospective study of 136 098 human infant births supports these mouse model findings.¹ The study was designed to assess the additive effects of maternal and infant risk factors on childhood asthma. They found that maternal antibiotic use, maternal UTI, and infant antibiotic use strongly increased the risk of childhood asthma in a dose-dependent manner.¹ For each antibiotic course in pregnancy, the risk of childhood asthma increased by 13%. The authors concluded that these factors, starting in utero, are a result of the disruption in the longitudinal development of the infant microbiome, leading to an upregulation in immune system function. A 2011 review and meta-analysis showed similar effects for asthma and wheezing.¹¹

  A collection of other studies substantiate that, compared to infants not exposed to antibiotics, infants exposed to antibiotics in the intra-partum period have: significantly lower bifidobacteria fecal counts at 7 days of life¹³; significantly different microbiota community structures at 3 months of life (differences persisted to 12 months for infants delivered by emergency C-section)¹⁴; and a reduced microbial richness and biodiversity and an overrepresentation of pathogenic bacteria well into the first year of life, provided there is no pre- or probiotic supplementation or support.^13-15

  Prenatal and early-life exposure to antibiotics is another important factor harming the natural colonization and pattern development of the infant microbiota, and thus should be an area of focus for clinicians to prevent unnecessary antibiotic use and/or to reduce harm by using measures to support a return to GI health during and after antibiotics.

  Infant Feeding Type

  The type of infant milk-feeding immediately after birth continues to build on the microbial foundation set by the internal maternal microbiota, the mode and place of birth, and whether antibiotics were taken. Ie, the choice of breast milk, formula, or a combination of the 2, shapes the continuing early development of the infant microbiota. The type of milk feeding then helps direct further programming of the host immune system.

  Breast milk has the effect of seeding and selecting for particular populations of bacteria in the infant gut. Introduction/supplementation of formula or solid foods early in the postnatal period may upset the colonization and proliferation of the neonatal intestinal microbiota.¹⁶

  The microflora of the breastfed infant is dominated largely by the protective bifidobacteria and lactic acid bacteria. In contrast, the formula-fed infant harbors a greater diversity of strains, and includes more pathogenic bacteria, including E coli, C difficile, and members of the Bacteroides fragilis group.^6,17 These infants still have measurable levels of bifidobacteria, but the colony numbers are reported to be much lower than in an exclusively breastfed infant.⁶ In a study published early this year by Madan et al, stool samples from 102 6-week-old infants were collected.¹⁸ Interestingly, and perhaps surprisingly, the infants receiving combination feeding (ie, both breast milk and formula) were found to have bacterial communities more similar to those associated with exclusive formula feeding than exclusive breastfeeding. If a woman is unable to meet the nutritional needs of her infant, donor milk is thus preferred over formula supplementation. It is safe to conclude that the process of healthy gut and immune system maturation continues after birth with exposure to the pre- and probiotics contained in breast milk. Supporting the initiation of breastfeeding, as well as exclusive breastfeeding, is paramount for optimal GI seeding.

  Conclusion

  Normal colonization of the infant microbiome maintains homeostasis of the immune system. If the intestinal flora in an infant develops differently based on perinatal maternal factors, mode and place of birth, and/or milk feeding, it is reasonable to assume that postnatal development of the immune system may also be different.

  Vaginally-born, home-birthed, and exclusively breastfed infants appear to have the most beneficial gut bacteria and the fewest pathogenic bacteria. Common obstetric and postpartum interventions, such as C-section, antibiotic use, and formula feeding, negatively alter the infant microbiome and may be major factors shaping a new microbiome landscape in human history.

  When presented with an expectant mother-infant pair that may be exposed to the above factors, an informed discussion on the risks to the infant seeding process and its role in lifelong immunity should take place. When such factors are involved, repair and restoration of the microbiome through pre- and probiotic supplementation may be warranted as an initial first step. As clinicians promising to first do no harm, it is our duty to inform expectant parents of the potential for these factors to inextricably alter the natural development of their baby’s immune, digestive, and metabolic systems.

  Carly Wendler, ND, is a licensed naturopathic doctor practicing family medicine in Waterdown, Ontario. After completing an honors degree at the University of Guelph in Applied Human Nutrition, Dr Wendler went on to complete her post-graduate naturopathic medical education at CCNM. Dr Wendler blends her medical knowledge with her practical everyday experiences as a mom to 2 young children, to design practical, effective, and safe treatment plans for women and their families. Her journey into motherhood ignited her passion to care for women during their child-bearing years, and thus her family practice is largely based on fertility, pregnancy, birth, postpartum, and new family care.

  References

  1. Wu P, Feldman A, Rosas-Salazar C, et al. Relative importance and additive effects of maternal and infant risk factors on childhood asthma. PLoS One. 2016;11(3):e0151705.
  2. van Nimwegen FA, Penders J, Stobberingh EE, et al. Mode and place of delivery, gastrointestinal micorbiota, and their influences on asthma and atopy. J Allergy Clin Immunol. 2011;128(5):948-955.
  3. Papathoma E, Triga M, Fouzas S, Dimitriou G. Cesarean delivery and development of food allergy and atopic dermatitis in early childhood. Pediatr Allergy Immunol. 2016;27(4):419-424.
  4. Gonzalez-Perez, G, Hicks AL, Tekieli TM, et al. Maternal antibiotic treatment impacts development of the neonatal microbiome and antiviral immunity. J Immunol. 2016;196(9):3768-3779.
  5. Rutten NB, Rijkers GT, Meijssen CB, et al. Intestinal microbiota composition after antibiotic treatment in early life: the INCA study. BMC Paediatr. 2015;15:204.
  6. Penders J, Thijis C, Vink C, et al. Factors influencing the composition of the intestinal microbiota in early infancy. Pediatrics. 2006;118(2):511-521.
  7. Collado MC, Rautava S, Aakko J, et al. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Scientific Reports. March 22, 2016. Nature.com Web site. http://www.nature.com/articles/srep23129. Accessed March 25, 2016.
  8. Neu J, Rushing J. Cesarean versus vaginal delivery: long term outcomes and the hygeine hypothesis. Clin Perinatol. 2011;38(2):321-331.
  9. Shin H, Pei Z, Martinez KA 2nd, et al. The first microbial environment of infants born by C-section: the operating room microbes. Microbiome. 2015;3:59.
  10. Brumbaugh DE, Arruda J, Robbins K, et al. Mode of Delivery Determines Neonatal Pharyngeal Bacterial Composition and Early Intestinal Colonization. J Pediatr Gastroenterol Nutr. 2016 Mar 28. [Epub ahead of print]
  11. Penders J, Kummeling I, Thijs C. Infant antibiotic use and wheeze and asthma risk: a systemic review and meta-analysis. Eur Respir J. 2011;38(2):295-302.
  12. Centers for Disease Control and Prevention. Get Smart: Know When Antibiotics Work. Last updated April 17, 2015. CDC Web site. http://www.cdc.gov/getsmart/community/index.html. Accessed April 13, 2016.
  13. Corgavlia L, Tonti G, Martini S, et al. Influence of intrapartum antibiotic prophylaxis for Group B Streptococcus on gut microbiota in the first month of life. J Pediatr Gastroenterol Nutr. 2016;62(2):304-308.
  14. Azad MB, Konya T, Persaud RR, 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. 2016;123(6):983-993.
  15. Aloisio I, Quagliariello A, De Fanti S, et al. Evaluation of the effects of intrapartum antibiotic prophylaxis on newborn intestinal microbiota using a sequencing approach targeted to multi hypervariable 16S rDNA regions. Appl Microbiol Biotechnol. 2016;100(12):5537-5546.
  16. Mueller NT, Bakacs E, Combellick J, et al. The infant microbiome development: mom matters. Trends Mol Med. 2015;21(2):109-117.
  17. Praveen P, Jordan F, Priami C, Morine MJ. The role of breast-feeding in infant immune system: a systems perspective on the intestinal microbiome. Microbiome. 2015;3:41.
  18. Madan JC, Hoen AG, Lundgren SN, et al. Association of Cesarean Delivery and Formula Supplementation With the Intestinal Microbiome of 6-Week-Old Infants. JAMA Pediatr. 2016;170(3):212-219.

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