Dietary Impacts to Microbial Composition and Function in Eosinophilic Esophagitis

Utah State Higher Education System--University Of Utah, Salt Lake City UT

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT This K23 Patient-Oriented Mentored Award Proposal presents a structured 5-year research and career development plan to prepare the candidate, Amiko Uchida, MD, to be an independent physician-scientist and leader in the field of eosinophilic esophagitis (EoE). EoE is a chronic inflammatory esophageal disease affecting nearly 1 in 1000 US individuals and is increasing in incidence. Despite the high frequency of EoE, its pathophysiology is incompletely understood, resulting in limited treatment options and reliance on expensive endoscopies for diagnosis and monitoring. One treatment is a food elimination diet. About half of EoE patients respond to empiric removal of wheat and dairy (2FED) from the diet. While this has led to the idea that certain foods trigger an inappropriate immune response against dietary antigen(s), there is a paucity of data to support food-specific immune responses (e.g. antibodies) as the sole driver of EoE. Interestingly, eliminating more foods does not always result in more remission, suggesting that EoE may be more complex and depend on environmental factors like the microbiota. The microbiota is a crucial factor for many intestinal diseases and is well-known to be affected by diet. The effects of 2FED on the intestinal microbiota composition and metabolites, like short chain fatty acids (SCFAs), are unknown in EoE. Given our limited understanding of EoE pathophysiology, there is a critical unmet need to understand how diet induced microbial changes impact EoE to allow for novel therapies. Dr. Uchida is uniquely positioned to close this knowledge gap as she is an Adult Gastroenterologist and co-Director of the Eosinophilic GI Disease Clinic at the University of Utah conducting translational research on EoE. Dr. Uchida will build on her previous scientific and clinical training by determining how 2FED impacts the microbiome and can be leveraged in EoE. Specifically, she will 1) Characterize the fecal microbial metagenome, metatranscriptome, and metabolome associated with 2FED- induced EoE remission, 2) Define serum IL-33 and metabolite changes associated with 2FED-induced EoE remission, and 3) Delineate the contribution of SCFAs to eosinophil-intrinsic anti-inflammatory responses. Dr. Uchida will investigate these aims under the guidance of her primary mentor June Round, PhD, who is a world- renowned microbiome immunologist as well as her co-mentor Kathryn Peterson, MD MSCI, an acclaimed EoE expert and clinician investigator. Both have long histories of training successful scientists and have established a productive, integrated team with the candidate. Dr. Uchida will achieve her goals through the guidance of her mentors, a scientific advisory committee, formal coursework, seminars, and hands-on training in advanced laboratory techniques. The scientific environment of the University of Utah is particularly strong and offers numerous scientific and career development resources. Successful completion of this project will inform the development of new microbial-based therapeutics and non-invasive disease markers in EoE, and open avenues of independent research for the candidate.