The Immature Gut Barrier and Its Importance in Establishing Immunity in Newborn Mammals

Abstract

The gut is an efficient barrier which protects against the passage of pathogenic microorganisms and potential harmful macromolecules into the body, in addition to its primary function of nutrient digestion and absorption. Contrary to the restricted macromolecular passage in adulthood, enhanced transfer takes place across the intestines during early life, due to the high endocytic capacity of the immature intestinal epithelial cells during the fetal and/or neonatal periods. The timing and extent of this enhanced endocytic capacity is dependent on animal species, with a prominent non-selective intestinal macromolecular transfer in newborn ungulates, e.g., pigs, during the first few days of life, and a selective transfer of mainly immunoglobulin G (IgG), mediated by the FcRn receptor, in suckling rodents, e.g., rats and mice. In primates, maternal IgG is transferred during fetal life via the placenta, and intestinal macromolecular transfer is largely restricted in human neonates. The period of intestinal macromolecular transmission provides passive immune protection through the transfer of IgG antibodies from an immune competent mother; and may even have extra-immune beneficial effects on organ maturation in the offspring. Moreover, intestinal transfer during the fetal/neonatal periods results in increased exposure to microbial and food antigens which are then presented to the underlying immune system, which is both naïve and immature. This likely stimulates the maturation of the immune system and shifts the response toward tolerance induction instead of activation or inflammation, as usually seen in adulthood. Ingestion of mother's milk and the dietary transition to complex food at weaning, as well as the transient changes in the gut microbiota during the neonatal period, are also involved in the resulting immune response. Any disturbances in timing and/or balance of these parallel processes, i.e., intestinal epithelial maturation, luminal microbial colonization and mucosal immune maturation due to, e.g., preterm birth, infection, antibiotic use or nutrient changes during the neonatal period, might affect the establishment of the immune system in the infant. This review will focus on how differing developmental processes in the intestinal epithelium affect the macromolecular passage in different species and the possible impact of such passage on the establishment of immunity during the critical perinatal period in young mammals.

Keywords: FcRn; fetal; immunity; intestine; permeability; tolerance; transcytosis.

Figure 1

Schematic illustration of the maturational changes taking place in the small intestine, with the replacement of endocytic fetal-type epithelial cells by mature adult-type cells lacking these features during fetal/neonatal development of young mammals. Maternal macromolecules/antigens in amniotic fluid or milk (colostrum), as well as microbial antigens, may pass over the fetal and neonatal epithelial barrier and activate the underlying immature immune system. The transfer of maternal IgG is facilitated by receptor-mediated endocytosis by epithelial FcRn receptors. With maturation, at gut closure, epithelial cell endocytosis ceases and the transepithelial macromolecular passage is largely restricted. In addition to low physiological antigen passage over the adult-type epithelium, a loss of barrier integrity due to e.g., inflammation, can increase the passage of dietary or microbial antigens and impact the immune system.