Neonatal immune adaptation of the gut and its role during infections

Abstract

The intestinal tract is engaged in a relationship with a dense and complex microbial ecosystem, the microbiota. The establishment of this symbiosis is essential for host physiology, metabolism, and immune homeostasis. Because newborns are essentially sterile, the first exposure to microorganisms and environmental endotoxins during the neonatal period is followed by a crucial sequence of active events leading to immune tolerance and homeostasis. Contact with potent immunostimulatory molecules starts immediately at birth, and the discrimination between commensal bacteria and invading pathogens is essential to avoid an inappropriate immune stimulation and/or host infection. The dysregulation of these tight interactions between host and microbiota can be responsible for important health disorders, including inflammation and sepsis. This review summarizes the molecular events leading to the establishment of postnatal immune tolerance and how pathogens can avoid host immunity and induce neonatal infections and sepsis.

Figure 1

Time line of intestinal development in human and mice. Definitive endodermal cells are specified during gastrulation (mouse: embryonic day 6 E6, human: week 3 W3) and initiate the formation of the primitive gut tube, fully formed at E9.5 in mice and W4 in humans. At later stages, the tube is patterned along the anterior-posterior axis. Cytodifferentiation and villus formation take place from E14.5 in mouse and from W9 in human. In mice, crypt formation starts around day 15 after birth (postnatal day 15, P15), whereas in humans, mature crypt-villus architecture is already defined during fetal period from W11.

Figure 2

Factors involved in postnatal intestinal innate immune adaptation. The colonizing microflora and the intestinal mucosa interact in a two-way street to establish life-time tolerance and mutualism between each other. While bacteria activate innate immune pathways in host epithelial and immune cells inducing immune maturation and tolerance, mucosal cells produce factors (antimicrobial peptides AMPs, mucins, immunoglobulin A IgA, etc.) to control the number and the composition of bacteria. Microflora is also influenced by environmental factors (hygiene, lifestyle, etc.). Maternal factors, such as IgA, mucins, oligosaccharides, or other soluble factors, can modulate the microflora, and contribute to improve host immune defense and maturation (maternal immune cells, soluble factors, etc.).

Figure 3

Summary of changes taking place in the intestine during the fetal period, neonatal period, and adult period. Please refer to the text for details. IECs: intestinal epithelial cells: CRAMP: cathelin-related antimicrobial peptide; CRS: cryptdin-related sequence; IgA: immunoglobulin A; TLR: toll-like receptor; IRAK1: interleukin-1 receptor-associated kinase 1; miR-146a: microRNA 146a.