The Role of Fiber in the Etiopathogenesis of Fecal Incontinence

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PROJECT SUMMARY/ABSTRACT The candidate is an accomplished neurogastroenterologist with formal training in epidemiological methods and a commitment to a career in clinical and translational research in the study of functional GI disease. The candidate’s long-term career goal is to become an independently-funded physician investigator, maintaining a clinical research program in functional GI diseases. The candidate’s short-term career goals are to: 1) develop large analytic datasets based upon established cohorts; 2) design and interpret metagenomic data, including application of microbiota-environment interaction methodology; 3) acquire skills in the analysis and interpretation of gut metabolomics data; 4) evolve clinical trial skills into multimodal models with potential for mechanistic and causative analyses; 5) establish and maintain a longitudinal cohort with detailed dietary, lifestyle, and physiologic measurements of subjects with FI; 6) produce the data and publications necessary to transition into a successful R01 application. This application outlines the institutional commitment, research plan, career development activities, and key mentors involved to ensure the candidate accomplishes these goals. In prior work, the candidate has demonstrated that dietary fiber is associated with a lower risk of incident fecal incontinence (FI) among elderly women, suggesting a preventative role for fiber in the development of FI. Nonetheless, data on the influence of fiber in other populations and potential biological mechanisms underlying associations with FI are lacking. In this proposal, the candidate seeks to fill this knowledge gap through a comprehensive examination of the complex interaction between fiber and alterations in the intestinal microbial environment in the etiology and severity of FI. The specific goals of this study are to 1) estimate the relative benefit of increased dietary fiber in the development and progression of FI using large well-characterized cohorts; 2) determine specific metagenomic profiles associated with prevalent FI and determine the mediating effect of dietary fiber on risk of FI; 3) examine the effects of fiber supplementation on symptom severity, anorectal physiology, and the gut microbiome in women with IBS-D and FI. As an integral part of this proposal, the candidate’s career development will be complemented by participation in advanced coursework to develop expertise in nutritional epidemiology, clinical trial design and conduct, and bioinformatics including the approach to metagenomic and metabolomic data. A formal mentorship committee, consisting of multidisciplinary experts in nutritional epidemiology, the microbiome, and GI motility will provide supervision, guidance, and assistance for the candidate to achieve his goals. The research environment, which includes the Clinical and Translational Epidemiology Unit, the Channing Laboratory, and the Harvard School of Public Health will provide a rich, collaborative, and intellectually stimulating atmosphere to ensure the candidate’s success. Through this award, the candidate will emerge as an independent clinical investigator by contributing to our understanding of the role of fiber in the etiopathogenesis of FI through a series of studies that bridge epidemiologic correlation and disease causation.