Role of Altered Intestinal Permeability and Lipopolysaccharide in Thrombotic Risk and Vascular Injury in IBD Patients

Chronic inflammatory bowel diseases (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), are characterized by chronic immune-mediated inflammation primarily affecting the gastrointestinal tract. Venous and arterial thromboembolic events are significant extra-intestinal manifestations of IBD, but their pathogenic mechanisms are not fully understood. IBD patients have double the risk of venous thromboembolism (VTE) compared to the general population, with particularly high risk in pediatric patients, and an increased mortality rate. They also face a higher risk of early atherosclerosis and future cardiovascular events, such as myocardial infarction, ischemic stroke, and peripheral artery disease. The prevalence of thromboembolic events in IBD ranges from 1.3% to 7.7%, with venous events at around 5% and ischemic heart disease, cerebrovascular disease, and peripheral artery disease at 1-2%.Several mechanisms contribute to the increased thrombotic risk in IBD, including platelet abnormalities (thrombocytosis and altered platelet function), coagulation factor alterations (e.g., fibrinogen, thrombin), and fibrinolysis defects. Increased oxidative stress and endothelial damage, especially during active disease phases, also play a role. The oxidative stress, caused by reactive oxygen and nitrogen species produced in IBD, leads to molecular and cellular damage, impaired cell homeostasis, and increased mucosal barrier permeability.These changes alone do not fully explain the heightened thrombotic risk in IBD. A reduction in intestinal microbiota diversity and the altered production of metabolites like Trimethylamine-N-oxide (TMAO) may also contribute, along with intestinal permeability changes that allow bacterial products, including lipopolysaccharide (LPS), to enter the bloodstream. LPS, a component of the outer membrane of Gram-negative bacteria, can stimulate low-grade endotoxemia, promoting atherosclerosis and increasing thrombotic risk. Although direct data on this are lacking, these pathological alterations suggest that increased intestinal permeability and circulating LPS may contribute to the elevated venous and arterial thrombotic risk in IBD patients.

• Measuring the relationship between intestinal permeability and how these factors contribute to inflammation and gut microbiota changes in health and disease. [Time frame: 1 year]