Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity

Abstract

The intestinal epithelium forms a barrier between the microbiota and the rest of the body. In addition, beyond acting as a physical barrier, the function of intestinal epithelial cells (IECs) in sensing and responding to microbial signals is increasingly appreciated and likely has numerous implications for the vast network of immune cells within and below the intestinal epithelium. IECs also respond to factors produced by immune cells, and these can regulate IEC barrier function, proliferation and differentiation, as well as influence the composition of the microbiota. The mechanisms involved in IEC-microbe-immune interactions, however, are not fully characterized. In this review, we explore the ability of IECs to direct intestinal homeostasis by orchestrating communication between intestinal microbes and mucosal innate and adaptive immune cells during physiological and inflammatory conditions. We focus primarily on the most recent findings and call attention to the numerous remaining unknowns regarding the complex crosstalk between IECs, the microbiota and intestinal immune cells.

Keywords: bacterial; epithelial cell; gut; microbiota; mucosal immunology.

Figure 1

Intestinal epithelial cells (IECs) sense microbial stimuli through a number of different mechanisms that regulate IEC gene transcription and inflammatory responses. For example, tryptophan catabolites and short‐chain fatty acids (SCFAs) produced as a result of microbial metabolism trigger the activation of AhR, PXR, ERK1/2 and p38 that directly regulate the expression of target genes. The inflammasome complexes in IECs reported to respond to microbial stimuli include NLRP3, NAIP‐NLRC4, NLRP6 and NLRP9b, which trigger cell death pathways and the release of inflammatory cytokines and mediators.

Figure 2

In response to microbial stimuli, intestinal epithelial cells (IECs) secrete factors that modulate various immune cell functions. In the small intestine these include interleukin‐15 (IL‐15), required for the recruitment of protective T‐cell receptor (TCR) ‐γδ ⁺ intraepiethlial lymphocytes (IELs) to the epithelial layer, and serum amyloids, which induce the differentiation of IL‐17‐secreting T helper type 17 cells. In the small and large intestine, glucocorticoids and serotonin promote anti‐inflammatory responses by immune cell populations, including lymphocytes and eosinophils, modulating inflammation and the development of disease pathology.

Figure 3

Immune cells contribute to the regulation of intestinal epithelial cell (IEC) differentiation and barrier function. For example, type 3 innate lymphoid cells (ILC3) secretion of interleukin‐22 (IL‐22) regulates IEC secretion of antimicrobial peptides (AMPs) and mucins, tight junction formation, and surface protein glycosylation, assisting in resistance to pathogenic microbes. Tolerance to food antigens is reported to involve IEC responsiveness to IL‐12; however, the subsequent IEC signalling pathways and immune cell types that mediate this response are not currently known.

Figure 4

Microbial modulation of intestinal immune cells is reported to involve both direct interaction of lymphocytes and antigen‐presenting cells (APCs) with microbial stimuli, as well as relatively uncharacterized indirect interactions via intestinal epithelial cells (IECs). These interactions involve many subsets of intraepithelial and lamina propria T cells and microbial metabolites like short‐chain fatty acids, tryptophan catabolites and secondary bile acids, as well as currently undefined microbial antigens.