Constitutive TL1A expression under colitogenic conditions modulates the severity and location of gut mucosal inflammation and induces fibrostenosis.

Intestinal fibrostenosis is a hallmark of severe Crohn's disease and can lead to multiple surgeries. Patients with certain TNFSF15 variants overexpress TL1A. The aim of this study was to determine the effect of TL1A overexpression on intestinal inflammation and the development of fibrostenosis. We assessed the in vivo consequences of constitutive TL1A expression on gut mucosal inflammation and fibrostenosis using two murine models of chronic colitis. In the dextran sodium sulfate (DSS) and adoptive T-cell transfer models, there was proximal migration of colonic inflammation, worsened patchy intestinal inflammation, and long gross intestinal strictures in Tl1a transgenic compared to wild-type littermates. In the DSS model, myeloid- and T-cell-expressing Tl1a transgenic mice had increased T-cell activation markers and interleukin-17 expression compared to wild-type mice. In the T-cell transfer model, Rag1(-/-) mice receiving Tl1a transgenic T cells had increased interferon-γ expression but reduced T-helper 17 cells and IL-17 production. Narrowed ureters with hydronephrosis were found only in the Tl1a transgenic mice in all chronic colitis models. In human translational studies, Crohn's disease patients with higher peripheral TL1A expression also exhibited intestinal fibrostenosis and worsened ileocecal inflammation with relative sparing of rectosigmoid inflammation. These data show that TL1A is an important cytokine that not only modulates the location and severity of mucosal inflammation, but also induces fibrostenosis.

Inflammatory Bowel Disease Associated Colorectal Neoplasia.

Patients with ulcerative colitis (UC) or Crohn's colitis have a greater risk for developing colorectal cancer (CRC). Many studies have described the evolving epidemiology and risk factors for CRC in patients with inflammatory bowel disease (IBD). Recent evidence indicates that the incidence has been decreasing with the advancement of medical and surgical therapies, and surveillance has emerged as the foundation of prevention. Chemoprophylaxis is another area of research; however, given the limited efficacy of these agents, they are only being used in conjunction with endoscopic surveillance. Our ability to formulate effective strategies for the prevention of this dreaded complication expands as more is discovered of the molecular events underlying IBD carcinogenesis. Management strategies are constantly updated as new evidence and endoscopic techniques emerge. In this paper, we review the literature regarding epidemiology, pathogenesis, risk factors and chemoprophylaxis as well as the latest consensus guidelines for management of dysplasia and neoplasia in IBD patients.