Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2
2019
Caminero, Alberto | McCarville, Justin L. | Galipeau, Heather J. | Deraison, Céline | Bernier, Steve P. | Constante, Marco | Rolland, Corinne | Meisel, Marlies | Murray, Joseph A. | Yu, Xuechen B. | Alaedini, Armin | Coombes, Brian K. | Bercik, Premysl | Southward, Carolyn M. | Ruf, Wolfram | Jabri, Bana | Chirdo, Fernando G. | Casqueiro, Javier | Surette, Michael G. | Vergnolle, Nathalie | Verdu, Elena F.
Microbe-host interactions are generally homeostatic, but when dysfunctional, they canincite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivitycharacterized by a breakdown of oral tolerance to gluten proteins in genetically predisposedindividuals, although the underlying mechanisms are incompletely understood. Here weshow that duodenal biopsies from patients with active CeD have increased proteolyticactivity against gluten substrates that correlates with increased Proteobacteria abundance,includingPseudomonas. UsingPseudomonas aeruginosaproducing elastase as a model, weshow gluten-independent, PAR-2 mediated upregulation of inflammatory pathways inC57BL/6 mice without villus blunting. In mice expressing CeD risk genes,P. aeruginosaelastase synergizes with gluten to induce more severe inflammation that is associated withmoderate villus blunting. These results demonstrate that proteases expressed by opportu-nistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.
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