​Rationale

The gut microbiota is composed of a huge number of diverse bacterial communities (Bacteroidetes and Firmicutes are the dominant phyla) and of abundant fungi. In humans, the coexistence of resident commensals and host cells play a beneficial role in regulating both energy harvesting from nutrients and host defense. Notably, the intestinal microbiota is able to regulate virulence of enteric bacterial pathogens, including Citrobacter rodentium. However, not all commensals are able to maintain quiescent and protective immunity, arguing for the need to decipher the nature and mechanisms of these processes.

 

​The CombInnate Consortium Comprises:

  • Microbiologists and Immunologists with expertise in gut microbiota anf intestinal immunity
  • Scientists with expertise in computer science, bioinformatics, biostatistics, text-mining and data management
  • Clinicians with strong expertise in Inflammatory bowel diseases

Objectives:

The main objective of the current proposal is to decipher, through a multidisciplinary approach, the microbiota-dependent and -independent mechanisms which regulate the pathogenicity of enteric bacterial pathogen.

More specifically, building on strong preliminary data, we will use Nod2, Ripk2 and Card9-defective mice and Citrobacter rodentium infection as models of immune defect-induced dysbiosis and intestinal infection respectively to address our objective.

The challenging but innovative tasks of this project aim at understanding how the interactions between the intestinal microbiota and its host may differentially determine outcome against enteric infection by C. rodentium, as an experimental model microorganism.

 

​Project Coordinator

 

Harry SOKOL

Associate Professor of Gastroenterology at Saint-Antoine Hospital, AP-HP, Paris

Head of the AVENIR lab « Gut Microbiota and Immunity », INSERM U1057 / UMR CNRS 7203, Université Pierre et Marie Curie

 

Actions / Work Packages

The project is structured around 3 Tasks:

  • Task 1: Identify molecular and cellular mechanisms shaping onset of a disease predisposing microbiota.
  • Task 2: Identify how disease-predisposing dysbiosis regulates Citrobacter rodentium susceptibility.
  • Task 3: Identify gut microbiota-independent role of Nod2, Ripk2 and Card9 on control of C. rodentium colitis.

​Funding

This work is supported by French state funds managed by ANR programme under reference ANR-13-BSV3-0014-01

Scientific, industrial and economic impact

Interactions between the gut microbiota and its host are complex and just started to be investigated. It has been shown that the gut microbiota plays a major role for the host physiology and particularly for the development and the maturation of the immune system. Moreover, skewed interactions between dysbiotic microbiota and genetically predisposed host have been shown to be involved in an increasing number of human diseases including inflammatory bowel diseases, rheumatoid arthritis, multiple sclerosis, type1 diabetes, obesity or non-alcoholic fatty liver disease. These diseases represent a major burden for the patients involved and more broadly a worldwide health problem. More efficient therapeutic approaches are urgently needed, but a prerequisite is an extensive understanding of the pathological role of dysbiosis and of the abnormal underlying crosstalk in these diseases.

Our CombInnate program is designed to solve this issue by revisiting the crosstalk between commensals and host molecules in the context of enteric pathogen bacterial infection.