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    Citrobacter rodentium infection in mice: a pre-clinical model to study subversion of immunometabolism and inflammatory bowel disease

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    Séminaire de l'Institut Cochin

    Lundi 20 mai 2019 - 12h00 - Salle de conférence Rosalind Franklin, 2ème étage

     


    Gad Frankel

    Imperial College London, UK

     

     invité par Sandrine Bourdoulous

    Institut Cochin, 22 rue Méchain, 75014 Paris

     

    Résumé

    The mouse pathogen Citrobacter rodentium, a model organism to study infection with human pathogenic E. coli and Inflammatory bowel disease (IBD), triggers robust IL-22-mediated proliferative repair responses and nutritional immunity. The team of Gad Frankel investigates the impact of infection with C. rodentium on physiology, metabolism and innate immunity in intestinal epithelial cells (IECs) in vivo using isobaric labelling proteomics, targeted metabolomics and in vivo imaging. This revealed that one of the major signatures of infection is re-programming of immune-metabolism in infected cells, including inhibition of central metabolism and mitochondrial functions, as well as activation of creatine, cholesterol biosynthetic and cholesterol efflux pathways. Concomitant with these changes, there is a reduction of butyrate-producing commensal bacteria and a bloom of proteobacteria, which could catabolise cholesterol. Moreover, in a mouse strain where C. rodentium infection triggers severe disease they observed up-regulation of ALPK1 and an imbalance between expression of serpins (serine protease inhibitors) in IECs and luminal neutrophil elastase (NE) activity, which was reflected by the level of tissue damage. Rebalancing the serpin / NE ratio in vivo prevented tissue damage. As enhanced NE activity is observed in patients with active IBD, this study opens new avenues to pursue diagnosis of IBD flare-ups and prevention. 

     

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