Revealing the mechanisms of increased intestinal epithelial cell barrier permeability in peanut allergy

PROJECT SUMMARY/ABSTRACT This proposal represents a five-year research career development program focused on understanding intestinal epithelial cell (IEC) barrier dysfunction in peanut allergy and on providing a strong foundation for the applicant, Dr. Erin Steinbach, to build an independent basic and translational research career. The candidate is currently

a tenure track Assistant Professor of Medicine at the University of North Carolina (UNC) School of Medicine in the Division of Rheumatology, Allergy, and Immunology. She is a member of the Thurston Arthritis Research Center and Center for Gastrointestinal Biology and Disease. The proposal builds on the candidate’s previous

mucosal immunology research and clinical allergy training by integrating five new realms of expertise represented by her mentor team of Drs. Shehzad Sheikh and Wesley Burks and her advisors’ expertise in IEC biology, gene regulation, metabolomics and integration of large datasets, and prospective human studies. This

work will add to the existing knowledge of a diverse group of diseases associated with increased IEC permeability and will foster the development of novel therapies targeting the intestines for severe allergic reactions. Through formal coursework, seminars, and guidance from her team, the candidate will develop the skills needed to run a

successful research program. She will develop a unique skillset for competing successfully for R01-level grants that will support her transition to an independent physician scientist career. Peanut is the most common cause of death from food-related anaphylaxis. Severity of a food allergic reaction is

partly determined by IEC barrier dysfunction, suggesting that peanut is adept at affecting the IEC barrier. No one has worked out how or why people with peanut allergy have increased IEC barrier permeability. Our preliminary data show that barrier permeability after the development of peanut allergy persists even in isolated, cultured

IECs. We will use a novel Collaborative Cross mouse model (CC027 strain) and primary human 2D “enteroids” (primary human-derived IEC monolayers) to broaden the understanding of increased IEC permeability in peanut allergy. CC027 mice develop peanut allergy through the oral route without adjuvant, which is normally needed

in animal models to establish peanut allergy. The CC027 peanut-allergic mouse develops increased intestinal permeability. Peanut-allergic CC027 mouse-derived IECs have altered proliferation and cholesterol metabolism, gut dysbiosis, and produce very high levels of Angiopoietin-like 4 (ANGPTL4). Serum ANGPTL4 levels are higher

in peanut-allergic, compared to non-allergic, pediatric patients. Alterations in the gut microbiota are present in food allergy and affect the IEC barrier, but its effects in IEC barrier function in peanut allergy remain elusive. We hypothesize that in established peanut allergy, more local IEC ANGPTL4 production and an altered microbial

metabolome disrupts intestinal epithelial stem cell metabolism and ultimately IEC barrier integrity.