Factors influencing microbiota development and maturation of the immune system early in life

Immunity

Birth represents the biggest substantial environmental change in life as the newborn is exposed for the first time to a countless variety of microbes which colonize all body surfaces, leading to the establishment of the commensal microbiota in parallel with the immune system. Many factors shape the composition of the gut microbiota and the maturation of the newborn immune system (Fig 3). Discrepancies in the microbiota and immunity crosstalk during each developmental stage can have long-term effects on disease susceptibility.¹³

About this article

Author

Dr Pascal Lavoie, MD, PhD

Associate Professor in the Department of Pediatrics, University of British Columbia, Vancouver, Canada.

He's an expert in infant and newborn development, immune system and disorders.

See the author

Created 19 November 2021

Updated 25 November 2021

Birth impacts gut microbiota composition…

by Dr Travis J. De Wolfe

The mode of delivery impacts what type of bacteria from the mother are transmitted to the neonatal intestine.¹⁴ Babies delivered via the birth canal often carry many gut bacteria that synthesize lipopolysaccharide (LPS), a major membrane component of Gram-negative bacteria that can properly train the human immune system to properly respond to microbial threats.¹⁵ In contrast, children delivered by caesarean section are predisposed to being colonized by opportunistic pathogens that circulate in hospitals.¹⁴

…As well as maturation of immune structure

These differences in initial microbial colonization can affect the subsequent maturation of the local innate lymphoid structures and alter the population of protective regulatory T cells (Treg), resulting in long-term effects on human intestinal physiology. Maturation of T cells and induction of immune factors can protect against, or in some cases, contribute to autoimmune-mediated diseases (diabetes, multiple sclerosis…) that develop later in life.^15,16

Antibiotics impact on immune responses

By Dr Pascal Lavoie

Antibiotics are essential to treat serious bacterial infections, however unnecessary antibiotic exposure can have serious adverse health consequences and should be avoided (ie. when the infection is due to a virus). In older adults, prolonged antibiotic use can lead to the overgrowth of a gut bacterial pathogen called Clostridioides difficile, with potentially life-threatening health consequences, particularly in the elderly.¹⁷ Overusing antibiotics can also promote antimicrobial resistance, which can limit treatment options for future infections.¹⁸ In animal models, antibiotic based perturbation of the gut microbiome alters immune functions and immune response thresholds.¹⁹ Data in humans suggest that unnecessary antibiotic use may increase the risk of developing chronic health problems, like type I diabetes, asthma, allergies or even obesity.²⁰ Prolonged antibiotic use (> 1 week) is known to reduce the diversity of the gut microbiome, with babies born prematurely being the most vulnerable to perturbations in their gut microbiome. Prolonged, broad spectrum antibiotic use in the mother or premature infant reduces gut bacterial diversity, increasing the risk of sepsis and necrotizing enterocolitis.²¹ Overall, the data in humans support the concept that the gut microbiome plays a major role helping babies develop into healthy adults. While the risks of excessive antibiotic exposure in adults are less severe, they may still impact the development of their immune responses, therefore antibiotic usage at any age should be restricted to those cases where they are necessary.

Dysbiosis is not universal and is defined for each individual, according to their state of health. A common definition describes it as a compositional and functional alteration in the microbiota that is driven by a set of environmental and host-related factors that perturb the microbial ecosystem.⁹

FIGURE 3: Environmental factors influencing the development of the newborn microbiota and mucosal immune system.

Adapted from Kalbermatter C et al, 2021¹³

Proof of concept: gut microbiota colonization is essential for immune system development

by Dr Travis J. De Wolfe

Studies with germ-free mice have demonstrated the important role that the microbiota plays in preventing a faulty immune system.²² Germfree mice are impaired in the production of CD4-positive T helper immune cells, whereas selectively colonizing these mice with Clostridia, a commensal bacterial group, can induce the production of these cells that subsequently promote antimicrobial defenses in the gut and protect against pathogen infection.²³ IgA antibodies are another critical component of the immune system, that are deficient in germ-free mice. These antibodies bind to commensal bacteria and prevent them from escaping the GI tract. Selective colonization of germ-free mice with an Escherichia coli strain, or distinct Bacteroides strains trigger a rapid restoration/normalization of IgA.^24,25

Sources

^{13 Kalbermatter C, Fernandez Trigo N, Christensen S, et al. Maternal Microbiota, Early Life Colonization and Breast Milk Drive Immune Development in the Newborn. Front Immunol. 2021 May 13;12:683022.}

^{14 Shao Y, Forster SC, Tsaliki E, et al. Stunted microbiota and opportunistic pathogen colonization in caesarean-section birth. Nature. 2019 Oct;574(7776):117-121.}

^{15 Wampach L, Heintz-Buschart A, Fritz JV, et al. Birth mode is associated with earliest strain-conferred gut microbiome functions and immunostimulatory potential. Nat Commun. 2018 Nov 30;9(1):5091.}

^{16 Vatanen T, Kostic AD, d'Hennezel E, et al. Variation in Microbiome LPS Immunogenicity Contributes to Autoimmunity in Humans. Cell. 2016 May 5;165(4):842-53.}

^{17 Guh AY, Kutty PK. Clostridioides difficile Infection. Ann Intern Med. 2018 Oct 2;169(7):ITC49-ITC64.}

^{18 Costelloe C, Metcalfe C, Lovering A, et al. Effect of antibiotic prescribing in primary care on antimicrobial resistance in individual patients: systematic review and meta-analysis. BMJ. 2010 May 18;340:c2096.}

^{19 Konstantinidis T, Tsigalou C, Karvelas A, et al. Effects of Antibiotics upon the Gut Microbiome: A Review of the Literature. Biomedicines. 2020 Nov 16;8(11):502.}

^{20 Sarkar A, Yoo JY, Valeria Ozorio Dutra S, et al. The Association between Early-Life Gut Microbiota and Long-Term Health and Diseases. J Clin Med. 2021 Jan 25;10(3):459.}

^{21 Walker WA. The importance of appropriate initial bacterial colonization of the intestine in newborn, child, and adult health. Pediatr Res. 2017 Sep;82(3):387-395.}

^{22 Sommer F, Bäckhed F. The gut microbiota--masters of host development and physiology. Nat Rev Microbiol. 2013 Apr;11(4):227-38.}

^{23 Ivanov II, Atarashi K, Manel N, et al. Induction of intestinal Th17 cells by segmented filamentous bacteria. Cell. 2009 Oct 30;139(3):485-98.}