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An Early Start: The Impact of the Microbiome on Pediatric Development in the First Year of Life

A better understanding of early childhood microbiome shifts offers a unique window for detecting disease risk and intervening appropriately.

Janssen: Pharmaceutical Companies of Johnson & Johnson

Dirk Gevers, Ph.D., Global Head, Microbiome Solutions, World Without Disease Accelerator 
Richard Insel, M.D, Global Head, Healthy Baby Initiative, World Without Disease Accelerator

The incidence and prevalence of pediatric immunity-related conditions—from food allergy to type 1 diabetes—has increased over recent decades.1-3 Researchers, clinicians, and policymakers are trying to identify potential underlying causes for this phenomenon to prevent and intercept these diseases. In particular, the World Without Disease Accelerator (WWDA), an R&D group within Janssen Research and Development, LLC, one of the Janssen Pharmaceutical Companies of Johnson & Johnson, is pursuing science related to the infant gut microbiota, which is thought to play a key role in the development of pediatric allergic and autoimmune diseases. 

Starting with a Single Step 

The infant microbiome is shaped by external factors that begin in utero.4 These factors include mode of delivery, maternal and pediatric diet composition (e.g., breast milk vs. cow’s milk formula) and diversity, and antibiotic exposure.5 Societal pressures may also impact microbiome health, as children born in industrialized nations present less species diversity in their gut flora.6 The infant microbiome matures until roughly two to three years of age, after which the gut microbiota takes on adult properties.4 Microbiome disruption or dysfunctional colonization during infancy is linked to immune dysregulation and increased risk of disease. Children born via cesarean section or who are not breast fed, for example, show elevated risks for asthma and allergic disease.4 The WWDA brings together research and external collaborations to discover and develop novel innovations aimed at promoting health and decreasing disease. The WWDA, through its Healthy Baby Initiative (HBI), is targeting three major questions surrounding the potential of pediatric microbiome modulation for preventive purposes. 

How, What, and When? 

The WWDA first aims to determine how certain microbial compositions or microbes of interest interact with the immune system to provide protection against allergic and autoimmune disorders. What specific microbial molecular patterns or metabolites are critical and what particular pathways are being activated? Most importantly, can these mechanisms and phenomena be targeted for decreasing risk of childhood disease, such as atopic dermatitis and food allergy? For example, the introduction of specific beneficial microbes such as Bifidobacterium infantis (B. infantis) and/or glycans7 directs major microbiome shifts at birth and weaning.8 Researchers are investigating whether restoring the disappearing microbe B. infantis7 in infants or replacing synthetic glycans can improve overall health and prevent disease by modulating the gut microbiota. 

The next question is, what are the defining hallmarks of healthy immunoregulatory development in early life?9 The gut microbiome trains the immune system to avoid deleterious responses to stimuli, but it is unclear what a healthy, trained immune system looks like. For example, researchers found that the microbiome promotes protective immune cell phenotypes that drive tolerance of food allergens. However, the precise processes and mechanisms driving protection, along with how and when they function, remains unclear.10,11 Characterizing healthy immunoregulatory development will help identify what could be monitored to determine whether immune training-centered approaches are taking effect. 

Finally, researchers are looking for timepoints in infant microbiome development that might serve as key interventional windows. The infant microbiome undergoes dramatic transformations at major developmental milestones, such as weaning and introduction of complementary food or with exposure to antibiotics.12 A dysbiotic gut microbiome at these pivotal transitions may disproportionally contribute to future susceptibility to the development of allergy or autoimmunity. Researchers have observed this in mice, where inhibiting the typical murine intestinal microbiota-induced immune response upon weaning led to increased susceptibility to colitis, allergic inflammation, and cancer later in life.13 Bestowing a healthy infant gut microbiome at these key windows may have the potential to abrogate the development of childhood disease. 

Prevention, Interception, and Cure 

The WWDA aims to help change healthcare from “diagnose and treat” to “prevention, interception, and cure.” Through initiatives such as the HBI, the WWDA strives to better understand how early childhood offers a unique window for detecting disease risk and intervening appropriately. HBI aims to deliver ways to change the trajectory of pediatric health to ultimately give every child the healthiest start in life and hopefully prevent childhood and even adult disease.

References

  1. O.I. Iweala et al., “Food allergy,” Curr Gastroenterol Rep, 20(5):17, 2018. 
  2. B. G?owi?ska-Olszewska et al., “Increasing co-occurrence of additional autoimmune disorders at diabetes type 1 onset among children and adolescents diagnosed in years 2010-2018-single-center study,” Front Endocrinol (Lausanne), 11:476, 2020.
  3. P.J. Turner et al., “Global trends in anaphylaxis epidemiology and clinical implications,” J Allergy Clin Immunol Pract, 8(4):1169-76, 2020. 
  4. T. Gaufin et al., “The importance of the microbiome in pediatrics and pediatric infectious diseases,” Curr Opin Pediatr, 30(1):117-24, 2018. 
  5. I. Yang et al., “The infant microbiome: Implications for infant health and neurocognitive development,” Nurs Res, 65(1):76-88, 2016. 
  6. E.D. Sonnenburg, J.L. Sonnenburg, “The ancestral and industrialized gut microbiota and implications for human health,” Nat Rev Microbiol, 17(6):383-90, 2019. 
  7. B.M. Henrick et al., “Bifidobacteria-mediated immune system imprinting early in life,” Cell, 184(15):3884-98.e11, 2021. 
  8. S. McKeen et al., “Glycan utilisation and function in the microbiome of weaning infants,” Microorganisms, 7(7):190, 2019. 
  9. A. Olin et al., “Stereotypic immune system development in newborn children,” Cell, 174(5):1277-1292.e14, 2018. 
  10. S. Bunyavanich, M.C. Berin, “Food allergy and the microbiome: Current understandings and future directions,” J Allergy Clin Immunol, 144(6):1468-77, 2019. 
  11. E. Stephen-Victor et al., "Dietary and microbial determinants in food allergy," Immunity, 53(2):277-89, 2020. 
  12. R.C. Robertson et al., “The Human microbiome and child growth - first 1000 days and beyond,” Trends Microbiol, 27(2):131-47, 2019. 
  13. Z. Al Nabhani et al., “A weaning reaction to microbiota is required for resistance to immunopathologies in the adult,” Immunity, 50(5):1276-88.e5, 2019.
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