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Intestinal mucosal barrier function in health and disease

Key Points

  • Mucosal barrier function consists of the combined effects of multiple extracellular and cellular processes that may be disrupted globally or in a targeted manner by physiological and pathophysiological stimuli. In the presence of an intact epithelium, mucosal permeability is primarily determined by tight junction barrier function.

  • Intestinal epithelial cells mediate interactions between the mucosal immune system and luminal materials. The mechanisms by which these epithelia regulate and, conversely, are regulated by the immune system are therefore of crucial importance to mucosal homeostasis and disease.

  • In vitro and in vivo studies have indicated that cytokines, including tumour necrosis factor, LIGHT (also known as TNFSF14), interferon-γ, interleukin-13 (IL-13) and IL-17 can modify epithelial barrier function by mechanisms that include new protein synthesis, membrane trafficking, kinase activation, cytoskeletal modulation and epithelial apoptosis. The contributions of these events to acute and chronic barrier regulation are distinct and may complement one another.

  • Increased intestinal permeability is associated with inflammatory bowel disease but can also be present in healthy individuals. Mouse models confirm that intestinal barrier dysregulation alone is insufficient to cause disease, but they also show that enhanced tight junction permeability can accelerate disease onset and increase severity.

  • In addition to activating pro-inflammatory events, intestinal barrier dysfunction initiates immunoregulatory processes. Defects in these processes may be a cause of inflammatory disease.

  • Further investigation of pathways that integrate mucosal barrier function, or dysfunction, and immune regulation will lead to a better understanding of the mechanisms underlying these complex interactions and provide a rational basis for the development of more effective and targeted therapeutic interventions.

Abstract

Mucosal surfaces are lined by epithelial cells. These cells establish a barrier between sometimes hostile external environments and the internal milieu. However, mucosae are also responsible for nutrient absorption and waste secretion, which require a selectively permeable barrier. These functions place the mucosal epithelium at the centre of interactions between the mucosal immune system and luminal contents, including dietary antigens and microbial products. Recent advances have uncovered mechanisms by which the intestinal mucosal barrier is regulated in response to physiological and immunological stimuli. Here I discuss these discoveries along with evidence that this regulation shapes mucosal immune responses in the gut and, when dysfunctional, may contribute to disease.

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Figure 1: Anatomy of the mucosal barrier.
Figure 2: Differential effects of cytokines on tight junction structure and function.
Figure 3: The epithelium and tight junction as integrators of mucosal homeostasis.

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Acknowledgements

I am indebted to current and past members of my laboratory for discussions and investigations that contributed to this article. Thanks also to A. M. Marchiando and C. R. Weber for the images used in figures 1 and 2. Work in my laboratory is currently supported by the US National Institutes of Health (DK061931, DK068271, DK67887 and HL091889), the University of Chicago Cancer Center (CA14599), the University of Chicago Digestive Disease Research Core Center (DK042086), the US Department of Defense (W81XWH-09-1-0341), the Broad Medical Research Program (IBD-0272) and the Chicago Biomedical Consortium. I apologize to colleagues whose work and publications could not be referenced owing to space constraints.

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Glossary

Mucosa-associated lymphoid tissue

(MALT). The collections of B cells, T cells, plasma cells, macrophages and other antigen-presenting cells found in the mucosal linings of organs including the gastrointestinal tract, lungs, salivary glands and conjuctiva.

Tight junction

Also known as the zonula occludens, this is a site of close apposition of adjacent epithelial cell membranes — kiss points — that create a barrier against the free diffusion of water and solutes.

Mucins

A family of heavily glycosylated proteins that are secreted as large aggregates by mucous epithelial cells.

Unstirred layer

A thin layer of fluid at epithelial cell surfaces that is separated from the mixing forces created by luminal flow and, in the intestine, peristalsis.

Coeliac disease

A chronic inflammatory condition of the upper small intestine in humans that is caused by immunological hypersensitivity to the α-gliadin component of wheat gluten. It can cause severe villous atrophy, which can lead to malabsorption and malnutrition if gluten-containing foods are not removed from the diet.

Paracellular pathway

The route of transepithelial transport that involves passive movement through the space between adjacent cells.

Adherens junction

Also known as the zonula adherens, this junction is immediately subjacent to the tight junction and requires the activity of lineage-specific Ca2+-dependent adhesion proteins, termed cadherins.

Desmosome

An adhesive junction that connects adjacent epithelial cells. These junctions are composed of multiple protein subunits and are the points where keratin filaments attach to the plasma membrane.

Claudin

From the Latin claudere, meaning 'to close', members of this family of transmembrane proteins are variably expressed by specific epithelial cell types and thereby contribute to the unique barrier properties of different tissues.

Occludin

The first transmembrane tight junction protein identified. The function of occludin remains controversial but it is likely to have roles in barrier regulation and tumour suppression. It also serves as a cofactor in hepatitis C virus entry.

Zonula occludens 1

A peripheral membrane, or plaque, protein containing multiple protein interaction domains that, along with the related protein zonula occludens 2, is required for tight junction assembly.

Transcellular pathway

The route of transepithelial transport that involves active or passive movement across cell membranes, usually as a result of the action of specific transport channels.

Transepithelial transport

The sum of transport through the transcellular and paracellular pathways.

Thick ascending limb of Henle

The portion of the nephron just proximal to the distal tubule. This is a site of active Na+, K+ and Cl reabsorption, which generates an electrochemical gradient that drives paracellular reabsorption of Mg2+ and Ca2+.

Myosin light chain kinase

The Ca2+ – calmodulin-dependent kinase that phosphorylates myosin II regulatory light chain at serine 19 and threonine 18 to activate myosin ATPase.

Caveolae

Specialized flask-shaped invaginations of the plasma membrane that contain the protein caveolin-1 and cholesterol. These proteins mediate uptake of some extracellular materials and are involved in cell signalling.

SAMP1/yit mice

An outbred mouse strain that spontaneously develops a chronic intestinal inflammation similar to human Crohn's disease.

CD4+CD45RBhi T cell adoptive transfer colitis model

A well-characterized model of chronic colitis induced by transfer of CD4+CD45RBhi (naive) T cells from healthy wild-type mice into immunodeficient syngeneic recipients.

Latency-associated peptide

A small peptide derived from the N-terminal region of the TGFβ precursor protein; it can modulate TGFβ signalling.

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Turner, J. Intestinal mucosal barrier function in health and disease. Nat Rev Immunol 9, 799–809 (2009). https://doi.org/10.1038/nri2653

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