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Identifying microbiotal triggers of inflammatory bowel disease through the lens of the immune system

Project description

Uncovering microbial triggers of inflammatory bowel disease

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the digestive tract that affects millions of people worldwide. The two main types of IBD are Crohn’s disease and ulcerative colitis. Accumulating evidence indicates that abnormal immune responses to the intestinal microbiota may be the underlying cause of inflammation that leads to IBD. Funded by the European Research Council, the IMMUNOBIOME project proposes a disruptive strategy to uncover the microbial targets of the immune response in IBD. Researchers will employ novel approaches to identify the microbes that are targeted by the immune response in IBD patients, providing important insight into the mechanism of the disease.

Objective

The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis manifest at the host-microbiota interface. The recently revealed genetic underpinning of IBD points towards an aberrant immune response to the intestinal microbiota. The prediction of genetically-impaired microbial handling is exemplified by key risk genes overlapping between leprosy, an infectious disease, and Crohn’s disease. A vigorous search for microbial triggers of IBD, which could also help explain the rising incidence and prevalence of this debilitating condition throughout the world, via high-throughput sequencing studies have indeed revealed structural alterations of the microbiota (‘dysbiosis’) compared to healthy individuals, although it is methodologically impossible to resolve cause-effect relationships of these associations.
Here we propose a two-tier strategy to overcome these limitations of current methods to uncover the microbial targets of the ‘inappropriate’ immune response that characterises IBD. The first tier is based on an entirely novel, and potentially disruptive, method (termed MiIP-Seq - Microbial Immunoprecipitation and Sequencing) that we have developed. MiIP-Seq allows directed metagenomic sequencing of microbes complexed with immunoglobulins in patients with IBD, and hence the identification of those microbes within the microbiota that are targeted by the pathological IgG immune response; induction of massive mucosal IgG exceeding IgA that prevails in health is a core characteristic of IBD. The second tier builds on transfer of the microbiota from patients with active IBD harbouring dominant IBD risk genes into mice genetically hypomorphic at the orthologues of these risk genes, and to resolve the hierarchy of immunologically targeted microbes within the humanised microbiota via MiIP-Seq.
Hence, via exploiting the lens of the immune system and harnessing genetic insight, this study will unravel the ‘environmental, microbial’ triggers and perpetuators of IBD.

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Coordinator

THE CHANCELLOR MASTERS AND SCHOLARS OF THE UNIVERSITY OF CAMBRIDGE
Net EU contribution
€ 2 304 375,00
Address
Trinity lane the old schools
CB2 1TN Cambridge
United Kingdom

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Region
East of England East Anglia Cambridgeshire CC
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00

Beneficiaries (1)