Microbiota-Host Interactions in the Intestine

Taking the next steps in microbiota research will lead to better prediction, treatment and cures for chronic inflammatory diseases
Location of intestinal bacteria in the intestinal tract. Particularly bacteria in the inner mucus layer exert effects on the host.

The intestinal microbiota plays a key role in the development of multiple diseases including inflammatory bowel disease, colorectal cancer, diabetes and metabolic syndrome. While the microbiota consists of more than hundred different bacterial species that vary immensely between individuals, just a limited number of ‘pathogenic’ commensal species are suspected to drive the majority of these diseases. These ‘pathobionts’ — which have characteristics of both symbionts and pathogens — often live within the intestinal mucus layer in close proximity of or attached to intestinal epithelial cells.

Crucial role in development of disease
The interactions of this pathogenic subset of the microbiota with the host epithelium and immune system are still mostly unclear but believed to play a crucial role in the development of disease. The focus of our group is therefore to reveal and characterise these intestinal bacteria, to understand the molecular mechanisms behind pathological host-microbiota interactions, and to develop and test putative therapeutic approaches.

IgA-SEQ technology: a way to identifying immunostimulatory commensals
To be able to find out which of the hundreds of bacterial species in the intestine interacts with or harm the host, we developed a novel technology called IgA-SEQ. With this technology it is now possible to identifies individual bacteria that activate potent immune responses by measuring the amount of antibody (IgA) the host has made against those bacteria; the more dangerous the immune system thinks these bacteria are, the more antibodies the host will make that selectively target these bacteria in the intestine. With this technology we found that patients with Crohn’s disease have a unique selection of immunostimulatory bacteria as compared to healthy individuals, and that many of these bacteria colonise the inner mucus layer of the intestine and drive excessive intestinal inflammation in mouse models of IBD.

The principle of IgA-SEQ: FACS sorting of bacteria by using host-produced IgA as primary antibody

Functional characterisation of anaerobic intestinal bacteria
Until recently, the vast majority (more than 99%) of the intestinal bacteria was ‘unculturable’ and therefore practically impossible to study in the lab. A number of advances, including the development of specialised growth media, a better understanding of growth conditions and zero parts-per-million anaerobic chambers has made it now possible to culture ever-increasing numbers of members of the intestinal microbiota, and for the first time study in detail their lifestyle and virulence factors.

Anaerobic chamber used to culture strictly anaerobic intestinal bacteria.

Selected publications

Immunoglobulin A coating identifies colitogenic bacteria in inflammatory bowel disease
Palm N.W. & de Zoete M.R. (co-first authors), Cullen T.W., Barry N.A., Stefanowski J., Hao L., Degnan P.H., Hu J., Peter I., Zhang W., Ruggiero E., Cho J.H., Goodman A.L., Flavell R.A.
Cell. 2014. 158(5):1000-10.

de Zoete M.R. & Palm N.W. & Zhu S. (co-first authors), Flavell R.A.
Cold Spring Harbor Perspectives in Biology 2014. 6(12):a016287.

Cleavage and activation of a Toll-like receptor by microbial proteases
de Zoete M.R., Bouwman L.I., Keestra A.M., van Putten J.P.
Proc Natl Acad Sci U S A. 2011. 108(12):4968-73.

Group members
PhD Candidate
Visiting Researcher