Role of mucus layers in gut infection and inflammation

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The intestinal mucus is an efficient system for protecting the epithelium from bacteria by promoting their clearance and separating them from the epithelial cells, thereby inhibiting inflammation and infection. The function of the colon inner mucus layer is especially important as this explains how we can harbor the large number of bacteria in our gut. The major component of this mucus system is the MUC2 mucin which organizes the mucus by its enormously large net-like polymers. Pathogenic microorganisms, in turn, have developed mechanisms for circumventing this well-organized mucus protective system.

Highlights

► Inner colon mucus layer separate bacteria from epithelial cells. ► Absence of the MUC2 mucin building the inner mucus layer causes colitis. ► The outer mucus layer is the habitat for the commensal bacteria.

Introduction

The gastrointestinal tract has a large surface exposed to the intestinal content and is as such a major entry point for pathogens. The organism's defense system against this challenge can be viewed as consisting of several ‘levels’. The first is the stratified mucus layer which together with the glycocalyx of the epithelial cells provides physical protection. This first defense line is the focus of this review. The second is the single layer of epithelial cells that form a continuous cell sheet interconnected with tight junctions. Here, the goblet cells produce the mucus, and the other major cell types, the enterocytes, have key regulatory roles in mastering the interaction with the microbiota. Both these defense lines belong to the innate immune system together with the third level-resident macrophages and dendritic cells of the intestinal stroma. Finally, the adaptive immune system builds a fourth defense line both as master regulator and as an inducible system to remove microbiota that have sidestepped earlier defense lines.

Section snippets

The gastrointestinal tract

A digestive tract is required for all advanced multicellular organisms to provide the host with both sufficient energy and molecular building blocks. The organization of this into a stable system is a formidable challenge as it must degrade and absorb ingested food at the same time as it must handle the load of ingested microorganisms. As we understand it today, this task is performed using basically the same principle in all animals, but with slightly different molecular solutions. The one

Gastrointestinal mucus and mucins

The gastrointestinal tract is covered by mucus, as revealed by detailed studies in rodents and humans [4••, 5••]. The stomach and colon have a two-layered mucus with an inner mucus layer that is 50–200 μm thick and firmly attached to the epithelium (Figure 1). The outer mucus layer is easily removed and has a less defined outer border. In contrast to colon, the small intestine has only one layer of mucus, which is possible to remove by aspiration. Normal mucus is totally transparent and

Commensal bacteria and the two mucus layers of the colon

The inner layer of the colonic mucus is attached to the epithelium, shows a compact and stratified appearance and ranges in thickness from 50 μm (mouse) and up to several hundred micrometers in humans. Its most remarkable feature is that this inner mucus layer normally is devoid of bacteria. The mucus probably accomplishes this by acting as a filter where, for example, bacteria are too large to enter [5••, 9, 16]. The inner mucus layer is renewed from below by secretion of the goblet cells and

The mucus layer of the small intestine

The small intestine is covered by a single layer of mucus built around the MUC2 mucin [4••, 7, 8]. This mucus is not attached to the epithelium and is also more permeable to bacteria (Figure 1b). The mucins are normally released at the crypt openings and the mucus will cover the villi. The small intestine has a low bacterial density compared to colon, due to the fast transit and its efficient trapping and distal transport of bacteria [23]. Hooper et al. have recently shown that the

Mechanisms for microorganisms to circumvent the mucus layers

The major function of the mucus is to limit bacterial contact with the epithelium and transport bacteria distally [26]. However, this system is not perfect and especially pathogenic bacteria have developed methods to circumvent it. As we still lack some understanding of how mucin and mucus function, we only have limited knowledge of the mechanisms for how pathogenic bacteria avoid this primary protection system. A few aspects and examples will be discussed here.

Inflammation

In the absence of MUC2, as in the Muc2-null mice, the bacteria are in direct contact with the epithelial cells. The bacteria penetrate down into the otherwise sterile crypts and are also found inside the enterocytes [5••, 43••]. These mice develop, depending on the animal housing and genetic background, a more or less severe colon inflammation with infiltration of both neutrophils and lymphocytes, diarrhea, rectal prolapses and failure to thrive [5••, 46]. The Muc2-null mice also develop cancer

Concluding remarks

The importance of the intestinal mucus has recently been rediscovered, something that is timely with the characterization of the human intestinal microbiota by novel sequencing methods. The organization of the inner mucus layer of colon is very important for homeostasis as defects in or loss of this allows bacteria to reach the epithelium and trigger inflammation. An understanding of the formation of the mucus layer and how the properties are altered, as triggered by intestinal microbiota and

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

This work was supported by the Swedish Research Council (nos. 7461, 21027, and 342-2004-4434), The Swedish Cancer Foundation, The Knut and Alice Wallenberg Foundation, IngaBritt and Arne Lundberg Foundation, Sahlgren's University Hospital (LUA-ALF), EU-FP7 IBDase (no. 200931), Wilhelm and Martina Lundgren's Foundation, Torsten och Ragnar Söderbergs Stiftelser, The Sahlgrenska Academy, and The Swedish Foundation for Strategic Research-The Mucus-Bacteria-Colitis Center (MBC) of the Innate

References (46)

  • Y.S. Kim et al.

    Intestinal goblet cells and mucins in health and disease: recent insights and progress

    Curr Gastroenterol Rep

    (2010)
  • T. Lang et al.

    Gel-forming mucins appeared early in metazoan evolution

    Proc Natl Acad Sci U S A

    (2007)
  • Z.A. Syed et al.

    A potential role for Drosophila mucins in development and physiology

    PLoS ONE

    (2008)
  • C. Atuma et al.

    The adherent gastrointestinal mucus gel layer: thickness and physical state in vivo

    Am J Physiol

    (2001)
  • M.E.V. Johansson et al.

    The inner of the two Muc2 mucin dependent mucus layers in colon is devoid of bacteria

    Proc Natl Acad Sci U S A

    (2008)
  • M.E.V. Johansson et al.

    Proteomic analyses of the two mucus layers of the colon barrier reveal that their main component, the Muc2 mucin, is strongly bound to the Fcgbp protein

    J Proteome Res

    (2009)
  • G.C. Hansson et al.

    Molecular cloning of a cDNA coding for a region of an apoprotein from the insoluble mucin complex of rat small intestine

    Biochem Biophys Res Commun

    (1994)
  • J.R. Gum et al.

    Molecular cloning of human intestinal mucin (MUC2) cDNA. Identification of the amino terminus and overall sequence similarity to prepro-von Willebrand factor

    J Biol Chem

    (1994)
  • M.E.V. Johansson et al.

    The two mucus layers of colon are organized by the MUC2 mucin, whereas the outer layer is a legislator of host–microbial interactions

    Proc Natl Acad Sci U S A

    (2011)
  • I. Carlstedt et al.

    Characterization of two different glycosylated domains from the insoluble mucin complex of rat small intestine

    J Biol Chem

    (1993)
  • N. Asker et al.

    Dimerization of the human MUC2 mucin in the endoplasmic reticulum is followed by a N-glycosylation-dependent transfer of the mono- and dimers to the Golgi apparatus

    J Biol Chem

    (1998)
  • K. Godl et al.

    The N-termini of the MUC2 mucin form trimers that are held together within a trypsin-resistant core fragment

    J Biol Chem

    (2002)
  • M.A.B. Axelsson et al.

    O-glycosylated MUC2 monomer and dimer from LS 174T cells are water-soluble, whereas larger MUC2 species formed early during biosynthesis are insoluble and contain nonreducible intermolecular bonds

    J Biol Chem

    (1998)
  • A. Herrmann et al.

    Studies on the “Insoluble” glycoprotein complex from human colon

    J Biol Chem

    (1999)
  • D. Ambort et al.

    Function of the CysD domain of the gel-forming MUC2 mucin

    Biochem J

    (2011)
  • M.E.V. Johansson et al.

    Bacteria penetrate the inner mucus layer before inflammation in the Dextran sulfate colitis model

    PLoS ONE

    (2010)
  • F. Backhed et al.

    Host-bacterial mutualism in the human intestine

    Science

    (2005)
  • J.M. Holmen Larsson et al.

    A complex, but uniform O-glycosylation of the human MUC2 mucin from colonic biopsies analyzed by nanoLC/MSn

    Glycobiology

    (2009)
  • J. Qin et al.

    A human gut microbial gene catalogue established by metagenomic sequencing

    Nature

    (2010)
  • M.W.J. van Passel et al.

    The genome of Akkermansia muciniphila, a dedicated intestinal mucin degrader, and its use in exploring intestinal metagenomes

    PLoS ONE

    (2011)
  • C.W. Png et al.

    Mucolytic bacteria with increased prevalence in IBD mucosa augment in vitro utilization of mucin by other bacteria

    Am J Gastroenterol

    (2010)
  • J. Fu et al.

    Loss of intestinal core 1-derived O-glycans causes spontaneous colitis

    J Clin Invest

    (2011)
  • M.E.V. Johansson et al.

    Keeping bacteria at a distance

    Science

    (2011)

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