Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, L8S 4K1, ON, Canada.
IRSD, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, 31300, France.
Nat Commun. 2019 Mar 13;10(1):1198. doi: 10.1038/s41467-019-09037-9.
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.
微生物-宿主相互作用通常是动态平衡的，但当它们出现功能障碍时，可能会引发食物过敏和慢性疾病。乳糜泻（CeD）是一种食物过敏，其特征是遗传易感性个体对麸质蛋白的口服耐受性丧失，尽管其潜在机制尚不完全清楚。在这里，我们表明，活动性 CeD 患者的十二指肠活检显示针对麸质底物的蛋白水解活性增加，这与变形菌丰度的增加相关，包括铜绿假单胞菌。使用产生弹性蛋白酶的铜绿假单胞菌作为模型，我们表明在没有绒毛变钝的情况下，C57BL/6 小鼠中存在与 PAR-2 介导的炎症途径的非依赖于谷蛋白的、弹性蛋白酶介导的上调，而没有绒毛变钝。在表达 CeD 风险基因的小鼠中，铜绿假单胞菌弹性蛋白酶与谷蛋白协同作用，引起更严重的炎症，与中度绒毛变钝相关。这些结果表明，机会性病原体表达的蛋白酶会影响宿主免疫反应，这与食物过敏的发展有关，而与触发抗原无关。
