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.
| Original language | English (US) |
|---|---|
| Article number | 1198 |
| Journal | Nature communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2019 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2. / Caminero, Alberto; McCarville, Justin L.; Galipeau, Heather J.; Deraison, Celine; 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.
In: Nature communications, Vol. 10, No. 1, 1198, 01.12.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Duodenal bacterial proteolytic activity determines sensitivity to dietary antigen through protease-activated receptor-2
AU - Caminero, Alberto
AU - McCarville, Justin L.
AU - Galipeau, Heather J.
AU - Deraison, Celine
AU - Bernier, Steve P.
AU - Constante, Marco
AU - Rolland, Corinne
AU - Meisel, Marlies
AU - Murray, Joseph A
AU - Yu, Xuechen B.
AU - Alaedini, Armin
AU - Coombes, Brian K.
AU - Bercik, Premysl
AU - Southward, Carolyn M.
AU - Ruf, Wolfram
AU - Jabri, Bana
AU - Chirdo, Fernando G.
AU - Casqueiro, Javier
AU - Surette, Michael G.
AU - Vergnolle, Nathalie
AU - Verdu, Elena F.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062859981&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85062859981&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-09037-9
DO - 10.1038/s41467-019-09037-9
M3 - Article
C2 - 30867416
AN - SCOPUS:85062859981
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1198
ER -