Coagulation factor 9-deficient mice are protected against dextran sulfate sodium-induced colitis

Abstract

Patients with inflammatory bowel disease (IBD) are susceptible to thromboembolism. Interestingly, IBD occurs less frequently in patients with inherited bleeding disorders. Therefore, we analyzed whether F9-deficiency is protective against the onset of acute colitis in a genetic hemophilia B mouse model. In the 3.5% dextran sulfate sodium (DSS)-induced colitis model, F9-deficient mice were protected from body-weight loss and had a reduced disease activity score. We detected decreased colonic myeloperoxidase activity and decreased CXCL1 levels in DSS-treated F9-deficient mice compared with wild-type (WT) littermate controls, indicating decreased neutrophil infiltration. Remarkably, we identified expression of coagulation factor IX (FIX) protein in small intestinal epithelial cells (MODE-K). In epithelial cell cultures, cellular FIX protein expression was increased following stimulation with the bacterial Toll-like receptor agonists lipopolysaccharide, macrophage-activating lipopeptide-2 and Pam3CSK4. Thus, we revealed a protective role of F9-deficiency in DSS-induced colitis and identified the intestinal epithelium as a site of ectopic FIX.This article has an associated First Person interview with the first author of the paper.

Protease‐activated receptor signaling in intestinal permeability regulation

“…Extravascular expression of clotting factors was systematically analyzed by Dashty and co‐workers in eight human primary cell types (Table ) . To complete the picture, a recent investigation demonstrated the presence of ectopic FIX in mouse small intestine, where expression was upregulated by stimulation with Toll‐like receptor (TLR) agonists, such as lipopolysaccharide (LPS) from Escherichia coli . So far, the expression and proteolytic activity of extravascular clotting factors is largely unexplored and deserves further investigation.…”

The Gut Microbiota as an Influencing Factor of Arterial Thrombosis

“…13 Research, taking advantage of germ-free mouse technology, has revealed that the gut microbiota affects host metabolism, among others increasing fat storage and impairing insulin resistance, [14][15][16] but also exerting important trophic effects on the intestine, as it promotes intestinal epithelial renewal 17 and shapes the architecture of capillary networks in the small intestine through coagulation factor signalling. 18,19 Importantly, this gut resident microbial ecosystem is largely influenced by factors that emerged in recent human cultural evolution, such as C-section delivery, 20 the use of antibiotics, 21 western nutrition 22 or the exposure to nanomaterials. 23 Although, from a mutualistic point of view, these microbiota-host interactions have evolved because they are beneficial for the host, the gut microbiota is increasingly recognized as an environmental factor that supports the progression of cardiovascular disease (CVD) states and promotes arterial thrombosis.…”