The infant's gut at the heart of immunity

Development of innate immune barriers

Development of the intestinal immune system begins before birth and continues throughout neonatal weaning. In utero, immature lymphoid structures including Peyer’s patches and mesenteric lymph nodes are generated (Fig 1A). Since these structures are not fully functional until later in development, to compensate, antimicrobial peptides (AMP) are produced by the gut epithelium and function as a defense barrier in response to the first bacterial colonizers (Fig 1B).¹ Mucus is another important barrier structure which is produced by goblet cells and secreted at the apical surface of the GI tract. Together, these innate immune barriers play a key role in limiting direct contact of the gut microbiota with host epithelial cells, especially as the microbiota establishes itself within the infant intestine.

Neonatal adaptive immune system is also critical during development 

Immunoglobulin A (IgA) are produced with varying affinity toward members of the microbiota as well as specific food antigens ingested by the neonate. Secreted IgA act to cross-link these targets in the intestinal lumen and limit their ability to adhere to and/or penetrate the gut epithelium (Fig 1B).² Correspondingly, during weaning, the neonatal gut microbiota becomes increasingly diverse and concentrated in response to a changing diet and development of crypt-villous architecture. This requires further protection of the epithelial barrier through maturation of local lymphoid structures. Activated Paneth cells begin to produce host defense proteins (defensins) at the base of small intestinal crypts, allowing other epithelial cells to transition away from producing AMP at baseline. Lastly, proliferation of epithelial cells increases alongside the increased secretion of mucus (Fig 1C).

FIGURE 1: Development of gut microbiota and intestinal immune system before birth (A), before (B) and after weaning (C).

Adapted from Brandtzaeg P, 2017³ and Ximenez C et al, 2017⁶

Importance of intestinal homeostasis

At least 80% of the body’s Ig-producing cells are located in the gut:³ this is the largest effector organ of humoral immunity. Specialized antigen-sampling epithelial cells (M cells) have a gatekeeping function by facilitating the transport of antigens - arising from commensal bacteria, diet or pathogens - from the gut lumen to the underlying lymphoid cells. These antigens will then be digested by dendritic cells (DC) and presented to the adaptive immune system.

Together, the different components of intestinal immunity promote homeostasis through two anti-inflammatory strategies (Fig 1C):

1) Immune exclusion of foreign antigens limits/prevents the gut microbiota from colonizing or penetrating the intestinal mucosa. This is performed by sIgA.³

2) Oral tolerance acts to limit local and peripheral immune responses to innocuous antigens that come in contact with the epithelial barrier.⁴ This depends on Treg cells with regulatory functions (Fig 2).³

When these strategies are operating properly, immune system regulation along with the actions of commensal microbiota in the development and training of this system will lead to the establishment of a durable and homeostatic host-commensal relationship that has long-term implications for human health.⁵

FIGURE 2: Innate and adaptive immune cells and functions.