Florian Rieder, MD
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
The inflammatory bowel disease (IBD) course is highly heterogenous. Intestinal fibrosis causing clinically apparent stricture formation is a common feature of both entities of IBD, Crohn’s disease and Ulcerative colitis and leads to a significantly impaired quality of life in affected patients, intestinal obstruction as well as need for surgical intervention. This constitutes a major treatment challenge, suppression of inflammation and the emergence of stronger immunosuppressive medications can only minimally reduce the incidence and prevalence of fibrostenosing IBD and no specific anti-fibrotic therapy is available.
Fibrosis results from the response of gut tissue to the insult inflicted by chronic inflammation. The underlying fibrogenic mechanisms are complex and dynamic, involving multiple cell types, interrelated cellular events, and a large number of soluble factors. These features are shared across organs, such as liver, skin, kidney or heart. Owing to a breakdown of the epithelial barrier in IBD, luminal bacterial products leak into the interstitium and induce an innate immune response mediated by activation of both immune and non-immune cells. Damage-associated molecular patterns, intracellular components released by necrotic cells, can also induce mesenchymal cell activation and contribute to stricture formation. Fat wrapping around the bowel wall, the so-called ‘creeping fat’, typical of Crohn’s disease, can drive fibrogenesis through the release of free fatty acids that induce intestinal muscle cell proliferation. Clinical and experimental evidence indicates that once fibrosis is established it can progress independently of inflammation. The composition of the intestinal extracellular matrix, its mechanoproperties and matrix bound factors are dramatically altered in chronic gut inflammation and can actively promote fibrosis. Identification of the unique mechanisms of intestinal fibrogenesis should create a practical framework to target and blockade specific fibrogenic pathways.
Our group focusses on the discovery of novel mechanisms of intestinal fibrogenesis, the prediction of fibrostenosing disease courses and innovative ways to treat IBD patients with established strictures. For this purpose, we are using primary human cells, tissues and organ culture systems as well as novel animal models of intestinal fibrosis. We have established an IBD biomarker cohort and assess endoscopic techniques to treat fibrostenosing IBD.
Rieder F., Cheng L., Harnett K.M., Chak A., Cooper G.S., Isenberg G., Ray M., Katz J.A., Catanzaro A., O`Shea R., Post A., Wong R., Sivak M.V., McCormick T., Phillips M., West G.A. Willis J.E., Biancani P., Fiocchi C. GERD-associated esophagitis induces endogenous cytokine production leading to motor abnormalities. Gastroenterology (2007) 132:154-65
Rieder F., Brenmoehl J., Artinger M., Georgieva M., Obermeier F., Rogler G. Prostaglandin E2 reduced migration of intestinal myofibroblasts. Inflamm Bowel Dis (2010) 16:1505-13
Rieder F., Kessler S., West G.A., Bhilocha S., dela Motte C., Saddler T.M., Gopalan B., Stylianou E., Fiocchi C. Inflammation-induced Endothelial-to-Mesenchymal Transition: A Novel Mechanism of Intestinal Fibrosis. Am J Path (2011) 5:2660-73
Rieder F., Nonevski I., Ma J., Ouyang Z., West G., Protheroe C., DePetris G., Schirbel A., Lapinski J., Goldblum J., Bonfield T., Lopez R., Harnett K., Lee J., Hirano I., Falk G.W., Biancani P., Fiocchi C. Th2 Cytokines, TGF-b1 and eosinophil products induce fibrogenesis and alter muscle motility in eosinophilic esophagitis. Gastroenterology (2014) 5:1266-77
Rieder F., Fiocchi C., Rogler G. Mechanisms, Management and Treatment of Fibrosis in Patients with Inflammatory Bowel Diseases. Gastroenterology (2017) 2: 340-50
The STAR Consortium Awarded $5.3 Million from the Helmsley Charitable Trust to Develop Next Generation Biomarker Tools for Crohn’s Disease Patients
The STAR consortium, led by coordinating PI Dr. Rieder, seeks to identify and develop novel biomarkers to help establish effective therapeutics for Crohn’s disease patients with fibrosis.
Dr. Rieder seeks to identify new mechanisms responsible for fibrosis and stricture formation that leads to the development of novel preventive and therapeutic treatments for Crohn’s disease.