Project description:Colonic aspirates were collected at diagnostic colonoscopy from inflammatory bowel disease (IBD) and control, treatment-naive children. The colonic mucosal-luminal interface (MLI) proteomes were analyzed for 18 control and 42 IBD patients by liquid-chromatography mass spectrometry.
Project description:Dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease. Nonetheless, the identity of overactive proteases released by human colonic mucosa remains unknown. Herein, we employed a serine protease-targeted activity-based probe (ABP) coupled with mass spectral analysis to identify active forms of proteases secreted by the colonic mucosa of healthy volunteers and inflammatory bowel disease patients. With this approach, we identified seven active serine proteases: cathepsin G, plasma kallikrein, plasmin, tryptase, chymotrypsin-like elastase 3A, aminopeptidase B, and thrombin. Furthermore, cathepsin G and thrombin were overactive in supernatants from inflammatory bowel disease patients once compared to healthy volunteers.
Project description:Ulcerative colitis is a chronic inflammatory disorder for which a definitive cure is still missing. This is characterized by an overwhelming inflammatory milieu in the colonic tract where a composite set of immune and non-immune cells orchestrate its pathogenesis. Over the last years, a growing body of evidence has been pinpointing gut virome dysbiosis as underlying its progression. Nonetheless, its role during the early phases of chronic inflammation is far from being fully defined. Here we show the gut virome-associated Hepatitis B virus protein X, most likely acquired after an event of zoonotic spillover, to be associated with the early stages of ulcerative colitis and to induce colonic inflammation in mice. It acts as a transcriptional regulator in epithelial cells, provoking barrier leakage and altering mucosal immunity at the level of both innate and adaptive immunity. This study paves the way to the comprehension of the aetiopathogenesis of intestinal inflammation and encourages further investigations of the virome as a trigger also in other scenarios. Moreover, it provides a brand-new standpoint that looks at the virome as a target for tailored treatments, blocking the early phases of chronic inflammation and possibly leading to better disease management.
Project description:Endoplasmic reticulum stress is closely associated with the onset and progression of inflammatory bowel disease. ERdj5 is an endoplasmic reticulum-resident protein disulfide reductase that mediates the cleavage and degradation of misfolded proteins. Although ERdj5 expression is significantly higher in the colonic tissues of patients with inflammatory bowel disease than in healthy controls, its role in inflammatory bowel disease has not yet been reported. Hence, in the current study, we utilized ERdj5-knockout mice to investigate the potential roles of ERdj5 in inflammatory bowel disease. ERdj5 deficiency causes severe inflammation in mouse colitis models and weakens gut barrier function by increasing NF-κB-mediated inflammation. ERdj5 may not be indispensable for goblet cell function under steady-state conditions, while its deficiency induces goblet cell apoptosis under inflammatory stimuli.