A Systems Biology Approach Using Fecal Microbiota and Metabolomics to Identify Novel Subtypes in Irritable Bowel Syndrome.

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PROJECT SUMMARY/ABSTRACT Candidate: Dr. Allen Lee, MD is a gastroenterologist with advanced training in gastrointestinal motility whose research focuses on identifying abnormalities in host-microbial interactions to improve care in irritable bowel syndrome (IBS). Dr. Lee’s long-term career goals are to identify novel subgroups of IBS patients which inform biological responses to therapies and guide management. The proposed K23 mentored career development award includes a 3-year plan for training, didactics, and research activities that will provide Dr. Lee with the necessary skills and experience to become a successful independent investigator. Career Development: Dr. Lee will develop skills in the following four areas: 1) culture-independent approaches to study host-microbial interactions in IBS; 2) advanced biostatistical methods to study longitudinal datasets, including mixed models or generalized additive models; 3) laboratory-based translational techniques; 4) predictive analytics, such as machine learning algorithms. These training goals will directly contribute to Dr. Lee’s long-term career goals and prepare him to submit a successful R01 application. Research Context: Common treatments in diarrhea-predominant IBS (IBS-D) are effective in ≤50% patients. Additionally, there are currently no methods to identify patients more likely to respond to different treatments. The current paradigm for managing IBS patients revolves around identifying and treating the predominant symptom complexes. However, this is a hugely inefficient model and leads to frustration for both patients and health care providers. This proposal seeks to determine whether a systems biology approach, which incorporates microbiome and metabolomics data along with detailed clinical phenotype information, may identify novel subgroups that inform treatment decisions in IBS-D. Research Plan: This career development award leverages an on-going clinical trial comparing the effects of a nonabsorbable antibiotic rifaximin with a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) in IBS-D patients to identify differences in microbial community structure and function in responders vs. non-responders to therapy. Specific Aim 1 will identify fecal microbial features by 16S rRNA sequence analysis characteristic of treatment response to rifaximin or a low FODMAP diet. Specific Aim 2 will determine how treatments with rifaximin or low FODMAP diet affect the fecal metabolome, including short chain fatty acids and bile acids, in IBS-D patients. Specific Aim 3 will develop predictive models to identify subsets of IBS-D patients responsive to treatment. We will also identify risk factors for non-response to either rifaximin or low FODMAP diet. Results from this proposal will inform two future R01 proposals to validate these findings as well as to understand the mechanisms by which host-microbial interactions may mediate response to different therapies in IBS.