This project proposes a comprehensive five-year mentored research development program with transition to independence. The research plan investigates the severe clinical problem of intestinal fibrosis and stricture formation in inflammatory bowel diseases (IBD). It explores the entirely novel concept of a direct effect of bacterial components on intestinal mesenchymal cells, the chief pro-fibrotic cell type, in vitro and in vivo. We found that human intestinal myofibroblasts respond to activation of bacterial sensing pattern recognition receptors, but only flagellin increases secretion of the extracellular matrix (ECM) components fibronectin and collagen 1. This response is post-transcriptionally regulated and dependent on caspase 1, implicating the inflammasome in intestinal fibrosis. Therefore, we propose to explore the following hypothesis: the gut microbiota induces intestinal fibrosis through a flagellin mediated pathway. This hypothesis will be tested through three interrelated, but indepedent specific aims: (1) to define the mechanisms of flagellin- induced post-transcriptional regulation of ECM secretion in vitro (2) to determine the role of flagellin mediated inflammasome activation in the pro-fibrogenic responses in primary human mesenchymal cells in vitro and (3) to explore the effect of abrogating flagellin signaling in experimental fibrosis in vivo during induction and resolution of intestinal fibrosis. Post-transcriptional regulation and inflammasome activation via caspase 1 are two entirely original mechanisms of intestinal fibrosis. We will use a cutting edge transgenic mouse model that allows control of the timing of deletion of bacterial sensing in vivo specifically in mesenchymal cells. This enables exploration of microbial sensing in the prevention and resolution of intestinal fibrosis. The research will be carried out in the laboratory of Dr. Fiocchi MD, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by a panel of international experts in human and experimental fibrogenesis, translational regulation and the microbiota. The advisory panel has worked out a structured career development program, including formal coursework in microbiology, translational regulation and statistics. An ideal intellectual and technical environment is in place locally in the LRI. My career goal is to build and lead an independent research program that will advance scientific knowledge and patient care in the field of intestinal fibrosis. My prior experience with primary human cell systems and animal models gives me the ideal basis to be a successful K08 awardee. The proposed study will provide novel evidence for the direct effect of the microbiota in intestinal mesenchymal cell induced fibrogenesis and stricture formation. These findings could lead to a completely novel approach of targeting the microbiota as a therapeutic strategy to abrogate fibrosis.

Public Health Relevance

Intestinal stricture formation in inflammatory bowel diseases is a major health burden in the USA. This projects aims to discover the role of the intestinal microbiota in progression and resolution of intestinal stricture formation and the mechanisms involved. The results from this project could lead to a completely novel approach of targeting the microbiota as a therapeutic strategy to abrogate fibrosis.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Saslowsky, David E
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
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Momozawa, Yukihide; Dmitrieva, Julia; Théâtre, Emilie et al. (2018) IBD risk loci are enriched in multigenic regulatory modules encompassing putative causative genes. Nat Commun 9:2427
Rieder, Florian (2018) Managing Intestinal Fibrosis in Patients With Inflammatory Bowel Disease. Gastroenterol Hepatol (N Y) 14:120-122
Rieder, F; Bettenworth, D; Ma, C et al. (2018) An expert consensus to standardise definitions, diagnosis and treatment targets for anti-fibrotic stricture therapies in Crohn's disease. Aliment Pharmacol Ther 48:347-357
Chen, Yu-Jun; Mao, Ren; Md, Xue-Hua Li et al. (2018) Real-Time Shear Wave Ultrasound Elastography Differentiates Fibrotic from Inflammatory Strictures in Patients with Crohn's Disease. Inflamm Bowel Dis 24:2183-2190
Gordon, I O; Agrawal, N; Willis, E et al. (2018) Fibrosis in ulcerative colitis is directly linked to severity and chronicity of mucosal inflammation. Aliment Pharmacol Ther 47:922-939
Kamm, Florian; Strauch, Ulrike; Degenhardt, Frauke et al. (2018) Serum anti-glycan-antibodies in relatives of patients with inflammatory bowel disease. PLoS One 13:e0194222
Li, Xue-Hua; Mao, Ren; Huang, Si-Yun et al. (2018) Characterization of Degree of Intestinal Fibrosis in Patients with Crohn Disease by Using Magnetization Transfer MR Imaging. Radiology 287:494-503
Ben-Horin, Shomron; Andrews, Jane M; Katsanos, Konstantinos H et al. (2017) Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis: A global survey of physicians' practice. World J Gastroenterol 23:2995-3002
Latella, Giovanni; Rieder, Florian (2017) Intestinal fibrosis: ready to be reversed. Curr Opin Gastroenterol 33:239-245
Rieder, Florian; Fiocchi, Claudio; Rogler, Gerhard (2017) Mechanisms, Management, and Treatment of Fibrosis in Patients With Inflammatory Bowel Diseases. Gastroenterology 152:340-350.e6

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