Harnessing Microbial-Metabolite Signals to Guide Endoscopic and Transmural Healing for Pediatric Crohn's Disease

PROJECT SUMMARY/ABSTRACT Anti-TNF therapy is the only FDA-approved medication for children with Crohn’s disease (CD). However, therapeutic failure due to anti-drug antibodies or non-immunogenic accelerated drug clearance constitutes a critical concern, and broad variation in drug clearance makes it difficult to predict which patients will be at risk. While etiological factors remain unclear, evidence suggests that there may be variation between the microbiome and microbial-derived metabolites for patients with/without anti-drug antibodies and patients with/without a therapeutic response. Thus, research that examines microbes/metabolites in conjunction with pharmacokinetics will enhance our understanding about how these markers can guide us to achieve healing. This K23 Mentored Patient-Oriented Career Development Award will further elucidate the relationship between high unexplained variability and microbial metabolites, thereby providing an avenue for microbiome modification and critically prolonging therapeutic durability. Dr. Colman’s specific aims are 1) to further define the relationship between microbial and metabolomic signatures and anti-TNF pharmacokinetics in CD and to harness these signatures as pharmacodynamic markers in machine-learning models to predict endoscopic healing, 2a) to test these endoscopic healing machine learning models in an external cohort and 2b) to evaluate these pharmacodynamic markers for anti-TNF agents and predict deeper transmural healing as assessed by intestinal ultrasound in a new cohort. This Award will harness data from both a prior multicenter study and new cohort that will be leveraged for future R01 proposals. The objective of this Career Development Award is to provide Ruben Colman, MD, PhD with advanced training to establish an independent patient-oriented research career focused on elevating therapeutic efficacy through the innovative application of precision medicine for children with inflammatory bowel disease (IBD). He is an Instructor of Pediatrics and board-certified pediatric gastroenterologist at Stanford University. Dr. Colman will complete comprehensive training in 1) computational microbiome and metabolomics analysis, 2) integration of ‘-omics data into systems pharmacology decision applications, 3) machine-learning approaches, 4) Team Science and 5) leadership and translational research execution. Dr. Colman has assembled a world-class Scientific Advisory Committee at Stanford, including his primary mentor Dr. Michael J. Rosen, Prof, Director Stanford Medicine Center for IBD & Celiac Disease and physician-scientist in translational IBD research, co-mentor Dr. Justin Sonnenburg, Prof Microbiology, co-director of the Center for Human Microbiome Studies and co-mentor Dr. Ivana Marić, Assistant Prof, expert in machine learning methods. Expertise of other advisors include computational bioengineering/data science of pharmacology applications, pharmacometrics and IBD biomarker discovery via multicenter trials. In summary, this Award will provide Dr. Colman with the required expertise to establish an independent research career focused on transforming precision medicine innovations into clinically applicable solutions to further elevate care for children with IBD.