Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis

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Abstract

Recent studies highlight the importance of mucins, in particular Muc2, in intestinal homeostasis. Our functional study demonstrates that an alternative secreted mucin, MUC5AC/Muc5ac, is induced in colitis to protect the colonic barrier by limiting host-bacterial interaction.

Abstract

Background

The mucus gel layer (MGL) lining the colon is integral to exclusion of bacteria and maintaining intestinal homeostasis in health and disease. Some MGL defects allowing bacteria to directly contact the colonic surface are commonly observed in ulcerative colitis (UC). The major macromolecular component of the colonic MGL is the secreted gel-forming mucin MUC2, whose expression is essential for homeostasis in health. In UC, another gel-forming mucin, MUC5AC, is induced. In mice, Muc5ac is protective during intestinal helminth infection. Here we tested the expression and functional role of MUC5AC/Muc5ac in UC biopsies and murine colitis.

Methods

We measured MUC5AC/ Muc5ac expression in UC biopsies and in dextran sulfate sodium (DSS) colitis. We performed DSS colitis in mice deficient in Muc5ac ( Muc5ac ^-/-) to model the potential functional role of Muc5ac in colitis. To assess MGL integrity, we quantified bacterial-epithelial interaction and translocation to mesenteric lymph nodes. Antibiotic treatment and 16S rRNA gene sequencing were performed to directly investigate the role of bacteria in murine colitis.

Results

Colonic MUC5AC/ Muc5ac mRNA expression increased significantly in active UC and murine colitis. Muc5ac ^-/- mice experienced worsened injury and inflammation in DSS colitis compared with control mice. This result was associated with increased bacterial-epithelial contact and translocation to the mesenteric lymph nodes. However, no change in microbial abundance or community composition was noted. Antibiotic treatment normalized colitis severity in Muc5ac ^-/- mice to that of antibiotic-treated control mice.

Conclusions

MUC5AC/Muc5ac induction in the acutely inflamed colon controls injury by reducing bacterial breach of the MGL.

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Most cited references 56

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

Malin Johansson, Jessica M Holmén Larsson, Gunnar Hansson (2011)

The normal intestinal microbiota inhabits the colon mucus without triggering an inflammatory response. The reason for this and how the intestinal mucus of the colon is organized have begun to be unraveled. The mucus is organized in two layers: an inner, stratified mucus layer that is firmly adherent to the epithelial cells and approximately 50 μm thick; and an outer, nonattached layer that is usually approximately 100 μm thick as measured in mouse. These mucus layers are organized around the highly glycosylated MUC2 mucin, forming a large, net-like polymer that is secreted by the goblet cells. The inner mucus layer is dense and does not allow bacteria to penetrate, thus keeping the epithelial cell surface free from bacteria. The inner mucus layer is converted into the outer layer, which is the habitat of the commensal flora. The outer mucus layer has an expanded volume due to proteolytic activities provided by the host but probably also caused by commensal bacterial proteases and glycosidases. The numerous O-glycans on the MUC2 mucin not only serve as nutrients for the bacteria but also as attachment sites and, as such, probably contribute to the selection of the species-specific colon flora. This observation that normal human individuals carry a uniform MUC2 mucin glycan array in colon may indicate such a specific selection.

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The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.

Thaher Pelaseyed, Joakim Bergström, Jenny Gustafsson … (2014)

The gastrointestinal tract is covered by mucus that has different properties in the stomach, small intestine, and colon. The large highly glycosylated gel-forming mucins MUC2 and MUC5AC are the major components of the mucus in the intestine and stomach, respectively. In the small intestine, mucus limits the number of bacteria that can reach the epithelium and the Peyer's patches. In the large intestine, the inner mucus layer separates the commensal bacteria from the host epithelium. The outer colonic mucus layer is the natural habitat for the commensal bacteria. The intestinal goblet cells secrete not only the MUC2 mucin but also a number of typical mucus components: CLCA1, FCGBP, AGR2, ZG16, and TFF3. The goblet cells have recently been shown to have a novel gate-keeping role for the presentation of oral antigens to the immune system. Goblet cells deliver small intestinal luminal material to the lamina propria dendritic cells of the tolerogenic CD103(+) type. In addition to the gel-forming mucins, the transmembrane mucins MUC3, MUC12, and MUC17 form the enterocyte glycocalyx that can reach about a micrometer out from the brush border. The MUC17 mucin can shuttle from a surface to an intracellular vesicle localization, suggesting that enterocytes might control and report epithelial microbial challenge. There is communication not only from the epithelial cells to the immune system but also in the opposite direction. One example of this is IL10 that can affect and improve the properties of the inner colonic mucus layer. The mucus and epithelial cells of the gastrointestinal tract are the primary gate keepers and controllers of bacterial interactions with the host immune system, but our understanding of this relationship is still in its infancy. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis

Malin Johansson, Jenny Gustafsson, Jessica Holmén-Larsson … (2013)

Objective The inner mucus layer in mouse colon normally separates bacteria from the epithelium. Do humans have a similar inner mucus layer and are defects in this mucus layer a common denominator for spontaneous colitis in mice models and ulcerative colitis (UC)? Methods and results The colon mucus layer from mice deficient in Muc2 mucin, Core 1 O-glycans, Tlr5, interleukin 10 (IL-10) and Slc9a3 (Nhe3) together with that from dextran sodium sulfate-treated mice was immunostained for Muc2, and bacterial localisation in the mucus was analysed. All murine colitis models revealed bacteria in contact with the epithelium. Additional analysis of the less inflamed IL-10−/− mice revealed a thicker mucus layer than wild-type, but the properties were different, as the inner mucus layer could be penetrated both by bacteria in vivo and by fluorescent beads the size of bacteria ex vivo. Clear separation between bacteria or fluorescent beads and the epithelium mediated by the inner mucus layer was also evident in normal human sigmoid colon biopsy samples. In contrast, mucus on colon biopsy specimens from patients with UC with acute inflammation was highly penetrable. Most patients with UC in remission had an impenetrable mucus layer similar to that of controls. Conclusions Normal human sigmoid colon has an inner mucus layer that is impenetrable to bacteria. The colon mucus in animal models that spontaneously develop colitis and in patients with active UC allows bacteria to penetrate and reach the epithelium. Thus colon mucus properties can be modulated, and this suggests a novel model of UC pathophysiology.

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Author and article information

Journal

Journal ID (nlm-ta): Inflamm Bowel Dis

Journal ID (iso-abbrev): Inflamm. Bowel Dis

Journal ID (publisher-id): ibd

Title: Inflammatory Bowel Diseases

Publisher: Oxford University Press (US )

ISSN (Print): 1078-0998

ISSN (Electronic): 1536-4844

Publication date (Print): September 2020

Publication date (Electronic): 09 May 2020

Publication date PMC-release: 09 May 2020

Volume: 26

Issue: 9

Pages: 1353-1367

Affiliations

[1 ] Department of Anesthesiology, University of Colorado School of Medicine , Aurora, Colorado, USA

[2 ] Mucosal Inflammation Program, University of Colorado School of Medicine , Aurora, Colorado, USA

[3 ] School of Medicine, Conway Institute, University College Dublin , Belfield, Dublin, Ireland

[4 ] Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Digestive Health Institute, Children’s Hospital Colorado , Aurora, Colorado, USA

[5 ] School of Biomolecular and Biomedical Science, University College Dublin , Belfield, Dublin, Ireland

[6 ] Kathleen Lonsdale Institute for Human Health Research, Department of Biology, Maynooth University , County Kildare, Ireland

[7 ] Department of Pathology, University of Colorado School of Medicine , Aurora, Colorado, USA

[8 ] Department of Medicine, Division of Gastroenterology and Hepatology, University of Colorado School of Medicine , Aurora, Colorado, USA

[9 ] Department of Medicine, Division of Infectious Diseases, University of Colorado School of Medicine , Aurora, Colorado, USA

[10 ] Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine , Aurora, Colorado, USA

Author notes

Address correspondence to: Carol Aherne, PhD, School of Medicine, Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland ( carol.aherne@ 123456ucd.ie ).

Author information

Carol M Aherne http://orcid.org/0000-0001-5653-9003

Article

Publisher ID: izaa064

DOI: 10.1093/ibd/izaa064

PMC ID: 7441107

PubMed ID: 32385500

SO-VID: a1ec3bf1-bfcd-4a25-b745-286f9fa5ab78

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 04 June 2019

Date: 11 March 2020

Page count

Pages: 15

Funding

Funded by: National Institutes of Health, DOI 10.13039/100000002;

Award ID: K01-DK099485

Award ID: R03-DK114545

Award ID: R01-DK111856

Award ID: R01-HL130938

Award ID: R01-HL080396

Funded by: Crohn's and Colitis Foundation, DOI 10.13039/100011684;

Award ID: 276536

Award ID: 601121

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Muc5ac Expression Protects the Colonic Barrier in Experimental Colitis

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Most cited references 56

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

The mucus and mucins of the goblet cells and enterocytes provide the first defense line of the gastrointestinal tract and interact with the immune system.

Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis

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