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Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function

An Erratum to this article was published on 01 March 2010

This article has been updated

Key Points

  • A single layer of intestinal epithelial cells (IECs) provides a physical barrier that separates trillions of commensal bacteria in the intestinal lumen from the underlying lamina propria and deeper intestinal layers. IECs express several Toll-like receptors (TLRs) including TLR1, TLR2, TLR4, TLR5 and TLR9.

  • Polarization of TLRs to the basolateral membrane of the IECs has been described for TLR4, TLR5 and TLR9 and decreases activation in response to luminal commensal bacteria. TLRs are also expressed by specific types of IEC within the crypt to villus axis, such as enteroendocrine cells, which respond to TLR activation by secreting somatostatin and cholecystokinin.

  • Activation of TLRs in IECs results in proliferation, restitution and protection against apoptosis. Following intestinal injury, TLR4 signalling through myeloid differentiation primary-response protein 88 (MYD88) results in the induction of cyclooxygenase 2 (COX2) expression and the production of prostaglandin E2 (PGE2) and amphiregulin, which is an epidermal growth factor family member.

  • TLRs regulate stem cell proliferation during injury by directing the recruitment of COX2-expressing mesenchymal stromal cells and macrophages, which produce trophic factors including PGE2 that stimulate stem cell proliferation.

  • Paneth cells are specialized epithelial cells located at the base of the small intestinal crypts that produce antimicrobial proteins and lectins. MYD88 signalling by Paneth cells is required for the expression of regenerating islet-derived protein 3γ (REG3γ), REG3β, CRP-ductin and resistin-like molecule-β (RELMβ). The absence of these lectins allows dissemination of intestinal pathogens.

  • Secretory IgA produced by lamina propria B cells protects against invasion of both commensal organisms and pathogens. TLR signalling by IECs leads to the production of cytokines such as a proliferation-inducing ligand (APRIL), which induce class switching to IgA2, a protease-resistant, T cell-independent isotype of IgA.

  • TLR signalling promotes the development of APC-dependent colorectal cancers and inflammation-associated colorectal cancers. Manipulating TLR signalling may have a beneficial effect in this setting.

Abstract

A single layer of epithelial cells lines the small and large intestines and functions as a barrier between commensal bacteria and the rest of the body. Ligation of Toll-like receptors (TLRs) on intestinal epithelial cells by bacterial products promotes epithelial cell proliferation, secretion of IgA into the gut lumen and expression of antimicrobial peptides. As described in this Review, this establishes a microorganism-induced programme of epithelial cell homeostasis and repair in the intestine. Dysregulation of this process can result in chronic inflammatory and over-exuberant repair responses, and it is associated with the development of colon cancer. Thus, dysregulated TLR signalling by intestinal epithelial cells may explain how colonic bacteria and inflammation promote colorectal cancer.

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Figure 1: Anatomy of the intestinal immune system.
Figure 2: Polarized expression of Toll-like receptors by intestinal epithelial cells.
Figure 3: Toll-like receptors promote proliferation of intestinal epithelial cells.
Figure 4: The role of Toll-like receptors in epithelial barrier function.

Change history

  • 02 February 2010

    In the version of the article initially published, figure 1 depicted Paneth cells at the base of the crypt in the colon. These cells should have been enterocytes. This has been corrected in the HTML and PDF versions of this article.

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Acknowledgements

I thank L. Hayes for her assistance in the preparation of this review.

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Glossary

Lamina propria

The layer of mucosal tissue directly under the mucosal epithelial cell surface of the gastrointestinal tract, in which mucosal effector immune cells reside.

Goblet cells

Mucus-producing cells found in the epithelial cell lining of the intestine and lungs.

Enteroendocrine cells

Specialized endocrine cells of the gastrointestinal tract that differentiate from pluripotent stem cells. They are characterized by their ability to produce hormones such as serotonin, somatostatin, motilin, cholecystokinin, vasoactive intestinal peptide and enteroglucagon.

Paneth cells

Specialized cells that are generally only found at the base of small intestinal crypts, although they can also be seen in the human colon in chronic inflammatory conditions. Paneth cells produce antimicrobial peptides or lectins, including REG3 proteins and defensins.

Tight junction

A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.

Laser capture microdissection

A method used to isolate specific subpopulations of cells under direct microscopy of the tissue. A laser is used to separate the desired cells from the tissue on a microscope slide and the cells of interest are then captured for subsequent analysis.

Crypts

Tubular invaginations of the intestinal epithelium. At the base of the crypts, there are Paneth cells, which produce bactericidal defensins, and stem cells, which continuously divide and are the source of all intestinal epithelial cells.

CpG-containing oligodeoxynucleotides

Synthetic DNA sequences that include a cytosine–guanosine sequence and certain flanking nucleotides, which have been found to induce innate immune responses through interaction with TLR9.

Crohn's disease

A form of chronic inflammatory bowel disease that can affect the entire gastrointestinal tract but is most common in the colon and terminal ileum. It is characterized by transmural inflammation, strictures and granuloma formation, and is thought to result from an abnormal T cell-mediated immune response to commensal bacteria. Symptoms include abdominal pain, rectal bleeding, diarrhoea and weight loss.

Villi

Projections into the lumen that have an outer layer that mainly consists of mature, absorptive enterocytes and mucus-secreting goblet cells.

Follicle-associated epithelium

(FAE). The epithelium that overlies mucosal lymphoid tissues, such as the Peyer's patches and the isolated lymphoid follicles in the intestine. Lymphoid tissues induce the differentiation of normal intestinal epithelium into FAE, which is specialized in antigen capture and transport.

WNT proteins

Glycoproteins related to the Drosophila melanogaster protein Wingless, a ligand that regulates the temporal and spatial development of the embryo. WNT-mediated signalling has been shown to regulate cell fate determination, proliferation, adhesion, migration and polarity during development. WNT and its downstream signalling molecules also have been implicated in tumorigenesis and have causative roles in human colon cancers.

Cross-tolerance

A state of unresponsiveness in which cells exposed to a TLR ligand show tolerance to subsequent challenge with the same stimulus and also to subsequent challenges with other stimuli that signal through one or more different TLRs.

Septic shock

A systemic response to severe bacterial infections or Gram-negative bacterial endotoxins (such as LPS) that leads to a hyperactive and dysregulated network of inflammatory cytokines, affecting vascular permeability, cardiac function and metabolic balance, which leads to tissue necrosis, multiple-organ failure and death.

Necrotizing enterocolitis

(NEC). A gastrointestinal disease predominantly affecting premature low-birth-weight infants. NEC involves infection and inflammation that causes destruction of the intestine. Although the pathophysiology of NEC is not completely defined, increasing evidence indicates that immaturity of intestinal innate immune function of the premature gut, characterized by over-exuberant IL-8 responses of intestinal epithelial cells to LPS, is a key factor.

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Abreu, M. Toll-like receptor signalling in the intestinal epithelium: how bacterial recognition shapes intestinal function. Nat Rev Immunol 10, 131–144 (2010). https://doi.org/10.1038/nri2707

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