Description du projet
Découvrir les déclencheurs microbiens des maladies inflammatoires de l’intestin
Les maladies inflammatoires de l’intestin (MII) sont des troubles inflammatoires chroniques du tube digestif qui touchent des millions de personnes dans le monde. Les deux principaux types de MII sont la maladie de Crohn et la colite ulcéreuse. Des preuves de plus en plus nombreuses indiquent que des réponses immunitaires anormales au microbiote intestinal peuvent être la cause sous-jacente de l’inflammation qui conduit aux MII. Financé par le Conseil européen de la recherche, le projet IMMUNOBIOME propose une stratégie de rupture pour découvrir les cibles microbiennes de la réponse immunitaire dans les MII. Les chercheurs s’appuieront sur de nouvelles approches pour identifier les microbes ciblés par la réponse immunitaire chez les patients atteints de MII, ce qui permettra de mieux comprendre le mécanisme de ces maladies.
Objectif
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.
Champ scientifique
- natural sciencesbiological sciencesmicrobiologybacteriology
- medical and health sciencesclinical medicinegastroenterologyinflammatory bowel disease
- medical and health scienceshealth sciencesinfectious diseases
- medical and health sciencesbasic medicineimmunology
- natural sciencesbiological sciencesgeneticsgenomes
Programme(s)
Régime de financement
ERC-COG - Consolidator GrantInstitution d’accueil
CB2 1TN Cambridge
Royaume-Uni