Mucosal Host-Microbe Interactions

How do we live with trillions of intestinal bacteria without getting sick? The answer lies in defense mechanisms of the mucus layer

The intestinal mucus layer separates trillions of commensal and pathogenic microbiota from the host epithelial lining. The intestinal microbiota is essential for human and animal health, but an imbalance can lead to enteropathogenic infections, Inflammatory Bowel Disease (IBD) or the development of adenocarcinomas. In the healthy gut, luminal bacteria are separated from the epithelial lining by a mucus layer which is a dynamic structure that is continuously shedding and modified. The majority of intestinal microbiota are associated with the outer mucus layer, but invasive bacteria such as Salmonella and Campylobacter can breach the mucus layer and cause infection. Epithelial cells that line the intestine also express membrane-bound mucins. These transmembrane mucins are innate defense proteins with barrier function and signaling potential that regulate the mucosal barrier, inflammatory pathways and cell proliferation. Mucin expression and glycosylation differs between humans and animals and is a major determinant in host tropism of zoonotic infections.

Figure 1. Interactions of commensal, pathogenic and tumorigenic bacteria with transmembrane (TM) mucins.

Transmembrane mucins are instrumental in sensing the intestinal lumen and mounting the appropriate (inflammatory) response. Our goal is to investigate how commensal and pathogenic bacteria trigger activation of transmembrane mucins and determine their contribution to inflammatory responses and carcinogenesis. Our research is part of the One Health program and will unravel how specific bacteria-mucin interactions impact health and disease of humans and animals. Novel insights in bacteria-mucin interactions will allow for the identification of new targets for anti-inflammatory drugs for the treatment of enterobacterial infections or inflammatory bowel disease.

In my group, we work with different intestinal and lung model systems including epithelial cell lines, tissue explants and organoids. We study the molecular mechanisms of transmembrane mucin function by using state-of-the-art molecular techniques, CRISPR/Cas9 DNA technology, protein labeling approaches including sortase technology, confocal microscopy and host-microbe infections assays and have developed our own molecular toolbox to study mucins. 

One Health explant facility - If you are interested in performing mucosal infection experiments in intestine or lung explant tissues of different animals, please contact Maitrayee Chatterjee 

Figure 2. Confocal microscopy of bacteria-mucin interactions.

Figure 1. Interactions of commensal, pathogenic and tumorigenic bacteria with transmembrane (TM) mucins. The intestinal mucus layer consists a relatively sterile inner mucus layer and an outer mucus layer with which the intestinal microbiota is associated. TM mucins are expressed on the apical surface of epithelial cells lining the intestine. TM mucins have barrier and signaling functions and regulate epithelial barrier integrity. In IBD, the mucus layer is thin and porous and can be colonized by pathobionts leading to continuous inflammation. Inflammation and the presence of tumorigenic bacteria can lead to carcinogenesis. TM mucin overexpression induces proliferation and metastasis and protects against immune recognition.  

Figure 2. Confocal microscopy of bacteria-mucin interactions. Top row: Salmonella interaction with MUC1, Salmonella SiiE adhesin clusters MUC1 on the surface of HT29-MTX cells, expression of MUC1 on HeLa cells leads to hair-like structures. Bottom row: MUC13 coordinates cell migration, E. coli inv invades MUC1-positive HeLa cells, Salmonella interacts with a MUC13-positive cell protrusion before invasion. Pictures collected by Xinyue Li, Karin Strijbis and Richard Wubbolts at the Centre for Cell Imaging (CCI) of the Faculty of Veterinary Medicine.