Abstract
Given the global burden of diarrheal diseases on healthcare it is surprising how little is known about the drivers of disease severity. Colitis caused by infection and inflammatory bowel disease (IBD) is characterised by neutrophil infiltration into the intestinal mucosa and yet our understanding of neutrophil responses during colitis is incomplete. Using infectious (Citrobacter rodentium) and chemical (dextran sulphate sodium; DSS) murine colitis models, as well as human IBD samples, we find that faecal neutrophil elastase (NE) activity reflects disease severity. During C. rodentium infection intestinal epithelial cells secrete the serine protease inhibitor SerpinA3N to inhibit and mitigate tissue damage caused by extracellular NE. Mice suffering from severe infection produce insufficient SerpinA3N to control excessive NE activity. This activity contributes to colitis severity as infection of these mice with a recombinant C. rodentium strain producing and secreting SerpinA3N reduces tissue damage. Thus, uncontrolled luminal NE activity is involved in severe colitis. Taken together, our findings suggest that NE activity could be a useful faecal biomarker for assessing disease severity as well as therapeutic target for both infectious and chronic inflammatory colitis.
Highlights
IntroductionInflammatory diarrhoea can result from infections with enteric pathogens or chronic illnesses, such as inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC).[1] the cause is different, disease pathology is similar, including dysbiosis, disruption of the mucosal barrier and extensive inflammation
Inflammatory diarrhoeal diseases are major health concerns worldwide
Mice suffering from severe C. rodentium-induced disease exhibit extensive intestinal cell death To further our understanding of the mechanisms driving colitis, we have focused on the two mouse strains, C57BL/6 (C57) and C3H/HeNCrl (C3H), which display different disease severities.[4,10]
Summary
Inflammatory diarrhoea can result from infections with enteric pathogens or chronic illnesses, such as inflammatory bowel diseases (IBDs), including Crohn’s disease (CD) and ulcerative colitis (UC).[1] the cause is different, disease pathology is similar, including dysbiosis, disruption of the mucosal barrier and extensive inflammation. Mild cases of colitis can be managed, but severe cases result in lethality in the case of infection or continual relapse and therapy resistance in IBD patients. A widely used murine model of IBD is chemically induced colitis using dextran sulphate sodium (DSS). DSS is delivered via drinking water and induces tissue damage and inflammation, which most closely resembles human UC. The mechanism by which DSS triggers colitis is not well defined, the severity of disease can be modified based on the concentration and duration of exposure.[2]
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