Microecology, intestinal epithelial barrier and necrotizing enterocolitis

Abstract

Soon after birth, the neonatal intestine is confronted with a massive antigenic challenge of microbial colonization. Microbial signals are required for maturation of several physiological, anatomical, and biochemical functions of intestinal epithelial barrier (IEB) after birth. Commensal bacteria regulate intestinal innate and adaptive immunity and provide stimuli for ongoing repair and restitution of IEB. Colonization by pathogenic bacteria and/or dysmature response to microbial stimuli can result in flagrant inflammatory response as seen in necrotizing enterocolitis (NEC). Characterized by inflammation and hemorrhagic-ischemic necrosis, NEC is a devastating complication of prematurity. Although there is evidence that both prematurity and presence of bacteria, are proven contributing factors to the pathogenesis of NEC, the molecular mechanisms involved in IEB dysfunction associated with NEC have begun to emerge only recently. The metagenomic advances in the field of intestinal microecology are providing insight into the factors that are required for establishment of commensal bacteria that appear to provide protection against intestinal inflammation and NEC. Perturbations in achieving colonization by commensal bacteria such as premature birth or hospitalization in intensive care nursery can result in dysfunction of IEB and NEC. In this article, microbial modulation of functions of IEB and its relationship with barrier dysfunction and NEC are described.

Fig. 1

Microbial components such as lipopolysaccharides (LPS), lipoteichoic acid (LTA), formylated peptides, and flagellin serve as microbial-associated molecular patterns (MAMPs) and signal pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), formylated peptide receptors (FPRs), or nucleotide-binding oligomerization domain-like receptors (NODs). Integration of these signals evokes cellular outputs based on the initial perception of the triggering organism. Output can be a protective response to commensal microbiota, an inflammatory response to pathogenic organism(s), or it can trigger apoptosis (reproduced with permission from Sharma et al. [12])

Fig. 2

A schematic illustration of the recognition of microbial-associated molecular patterns (MAMPs), such as lipopolysaccharides (LPS), by pattern recognition receptors (PRRs) on epithelial cells and immune-cell activation or apoptotic response. Transmembrane Toll-like receptors (TLRs) are triggered by MAMPs and stimulate PRRs. Four adaptor proteins for TLRs are involved in propagation of signals and activation of MAP kinases that can result in transcription of proinflammatory cytokines or apoptotic response through activation of NFκB (with permission, adapted from Sharma et al. [12])

Fig. 3

Intestinal immune-cell function can be regulated by microbiota. Microbial recognition by intestinal epithelial cell (IEC) can influence secretion of cytokines such as thymic stromal lymphopoietin (TSLP), transforming growth factor β (TGFβ) and interleukin 10 (IL-10), that can directly activate elaboration of proinflammatory cytokines by dendritic cells (DC) and macrophages in lamina propria and Peyer’s patches. Signals from commensal may influence tissue-specific functions resulting in T-cell regulation and expansion into T helper (Th)-1, Th-2, and Th-3 cells. Modulated by intestinal microbiota, other IEC-derived factors include B-cell activating factor (BAFF), APRIL (a proliferation-inducing ligand), secretory leucocyte peptidase inhibitor (SLP1), prostaglandin E2 and other metabolites. Thus, microbiota regulates functions of both antigen-presenting cells and lymphocytes in the intestinal ecosystem (reproduced with permission from Sharma et al. [4])

Fig. 4

Commensal bacteria block activation of NFκB and thus down-regulate inflammatory cytokine production in mature host. In immature enterocyte, expression of IκB is reduced contributing to exaggerated inflammatory response

Fig. 5

Mircobial–mucosal interactions regulate mucin production. Commensal bacteria induce mucin secretion at basal rate. Conversely, mucin secretion is accelerated upon activation by pathogenic organisms mediated by activation of MAP kinase system and downstream activation of NFκB with increased mucin transcription. In turn, intestinal mucin dictates the composition of bacterial community. Adhesion to specific mucin epitopes is thought to facilitate mucous colonization by commensal bacteria providing them with growth advantage when competing against pathogens (reproduced with permission from Sharma et al. [12])