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

Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivitiesand chronic diseases. Celiac disease (CeD) is a food sensitivitycharacterized by a breakdown of oral toleranceto glutenproteins 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 glutensubstrates that correlates with increased Proteobacteriaabundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastaseas 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 elastasesynergizes with glutento 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.