Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2

Alberto Caminero, Justin L. McCarville, Heather J. Galipeau, Celine Deraison, Steve P. Bernier, Marco Constante, Corinne Rolland, Marlies Meisel, Joseph A. Murray, Xuechen B. Yu, Armin Alaedini, Brian K. Coombes, Premysl Bercik, Carolyn M. Southward, Wolfram Ruf, Bana Jabri, Fernando G. Chirdo, Javier Casqueiro, Michael G. Surette, Nathalie Vergnolle and Elena F. Verdu ()
Additional contact information
Alberto Caminero: McMaster University
Justin L. McCarville: McMaster University
Heather J. Galipeau: McMaster University
Celine Deraison: UPS
Steve P. Bernier: McMaster University
Marco Constante: McMaster University
Corinne Rolland: UPS
Marlies Meisel: University of Chicago
Joseph A. Murray: Mayo Clinic College of Medicine
Xuechen B. Yu: Columbia University
Armin Alaedini: Columbia University
Brian K. Coombes: McMaster University
Premysl Bercik: McMaster University
Carolyn M. Southward: McMaster University
Wolfram Ruf: Johannes Gutenberg University Medical Center
Bana Jabri: University of Chicago
Fernando G. Chirdo: Universidad Nacional de La Plata
Javier Casqueiro: Universidad de Leon
Michael G. Surette: McMaster University
Nathalie Vergnolle: UPS
Elena F. Verdu: McMaster University

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.

Date: 2019
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DOI: 10.1038/s41467-019-09037-9

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