Barrier function alterations in post-infectious irritable bowel syndrome

Project: Research project

Project Details


? DESCRIPTION (provided by applicant): Irritable bowel syndrome (IBS) is a chronic gastrointestinal (GI) disorder that affects approximately 15% of the U.S. population, generates 3.6 million physician visits, and accounts for an estimated $20 billion in health care costs annually. The pathophysiological mechanisms responsible for IBS remain poorly understood. Post- infectious IBS (PI-IBS) is a subset of IBS characterized by development of symptoms following an episode of acute gastroenteritis. It has been estimated that 3 to 36% of people who suffer from gastroenteritis develop PI- IBS. Infectious gastroenteritis is common in the U.S. (48 million cases annually); however, there is limited mechanistic insight into development of PI-IBS. I am interested in studying PI-IBS following infection with Campylobacter jejuni, a leading cause bacterial enteritis in the U.S. and a reportable illness to the public health departments. I will study the pathophysiological mechanisms of PI-IBS with a focus on intestinal barrier function and microbiota changes. Through collaboration with the Minnesota Department of Health (MDH) that I established for this proposal, acute C. jejuni enteritis cases will be identified and recruied. My strong preliminary data suggest that PI-IBS is common (22%) following C. jejuni enteritis in people from Minnesota, and in vivo and ex vivo colonic mucosal barrier function is impaired in PI-IBS. My preliminary data also suggests that C. jejuni strains that lead to PI-IBS cause greater disruption of in vitro barrier function than the control strains (that did not lead to PI-IBS). Additionally, I found that fecal microbial community diversity is decreased in C. jejuni PI-IBS patients. Based on these preliminary data, my overall hypothesis is that C. jejuni leads to PI-IBS by causing a strain and host-dependent alteration in barrier function and microbiota changes. I will test this hypothesis in 3 specific aims. I will identify culture-positive C. jejuni enteritis ases through the MDH and the Mayo Medical Laboratory. In specific aim 1, I will assess the structure and function of the colonic epithelial barrier in acute C. jejuni enteritis patients and follow thee patients at 6 months to ascertain PI-IBS development. I will then assess barrier function in PI-IBS patients and controls (infection but no subsequent development of PI-IBS). In specific aim 2, I will study effects of PI-IBS and control C. jejuni strains on barrier function, especially delineating the role of myosin light chain phosphorylation in barrier function and determine genomic differences among strains using whole genome sequencing. In specific aim 3, I will study the role of fecal and mucosal microbiota changes in development of PI-IBS. I will determine if there are microbiota signatures during acute C. jejuni enteritis that help predict development of PI-IBS. This proposal will uniquely allow the study of mechanisms for PI-IBS development following confirmed C. jejuni infection in samples derived from the U.S. communities using integrative in vivo and ex vivo techniques with the aim of identifying high-risk enteritis cases for development of PI-IBS and developing strategies for future interventions to prevent or treat PI-IBS. My long-term goal with a K23 mentored patient-oriented research career development award is to become an independent investigator involved in translational studies determining mechanisms of IBS. The experimental results and mechanistic information gained from the proposed study will form the foundation for and generate preliminary data for R03 and R01 applications. Over the next five years, I will be involved in a number of career development and training activities. These will be focused around the measurement of mucosal barrier function, molecular biology, C. jejuni genomics, host microbiota sequencing and bioinformatics. Additionally, I will take relevant didactic coursework, attend and present at seminars and national meetings to gather feedback and expand collaborations for future translational work in the area. This period will involve structured mentoring from Dr. Michael Camilleri and Dr. Gianrico Farrugia, both internationally-renowned, NIH-funded investigators in areas of research in neurogastroenterology and motility disorders with an exceptional track record of mentoring. The research environment at Mayo Clinic, including the Center for Clinical and Translational Science, the Center for Cell Signaling in Gastroenterology and the Center for Individualized Medicine together with my collaboration with MDH, provides me a productive, collegial, and collaborative atmosphere to pursue the proposed research and training activities. At the conclusion of this career development award, I will be positioned to be an independent physician-scientist leading a multidisciplinary translational research team.
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