Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - IMMUNOBIOME (Identifying microbiotal triggers of inflammatory bowel disease through the lens of the immune system)

Teaser

Crohn’s disease and ulcerative colitis typically start in the second or third decade of life, and lead to life-long recurring inflammation of the intestinal tract which cause severe symptoms and life-long suffering. The prevalence of these diseases has massively increased in...

Summary

Crohn’s disease and ulcerative colitis typically start in the second or third decade of life, and lead to life-long recurring inflammation of the intestinal tract which cause severe symptoms and life-long suffering. The prevalence of these diseases has massively increased in ‘Western countries’ over the last 4 decades with now ~5 in 1,000 individuals affected. Over the last decade, the prevalence is also fast rising globally, especially in China. The reason for this increase remains entirely unclear, and is ascribed to unbeknownst ‘environmental factors’. Such factors are thought to trigger disease in an individual, especially if such individual carries genetic risk factors of disease. A major breakthrough has been the discovery of a ‘risk map’ across the human genome that confers susceptibility, and the identification of individual risk genes.
The inflammation that ensues from such environment – gene interaction appears directed against the intestinal microbiota, which is the entirety of microbial life that is present in our intestines. The microbiota typically consists of hundreds of different bacterial species, and overall constitutes 1-10-fold more bacterial cells than host cells. While these bacteria fulfil a very important function in health, they become the target of a pathological immune response. To gain insight into the processes that lead to Crohn’s disease and ulcerative colitis, we develop methods to uncover what this pathological immune response is directed against, and how such gene-environment interaction leads to disease. We thereby hope to unravel the fundamental basis of these diseases, which would form the basis for preventing and curing this disease.

Work performed

We have developed and refined methods that allow deciphering what the pathological immune response is directed against, and how disease risk genes predispose for that. Our data show that large parts, rather than individual members, of the microbiota are targeted by such a pathological immune response. We have discovered key mechanisms that are affected by risk genes of inflammatory bowel disease and that are triggered by environmental/microbiotal factors that instigate inflammation in the intestine. Finally, we have discovered a fundamentally important, novel immuno-metabolic pathway which, when impaired, predisposes for Crohn’s disease and infections.

Final results

We have made great inroads into understanding gene – environment – microbiota interactions that underpin intestinal inflammation in Crohn’s disease and ulcerative colitis. We have also made great technological advances, which herald substantial potential to lead to further breakthroughs during the remainder of the project.

Website & more info

More info: http://www.med.cam.ac.uk/kaser/research/.