PROJECT SUMMARY This CoFAR application brings together seasoned clinical and laboratory investigators in food allergy (FA) with expertise in clinical studies and trials and translational immunologic, microbiome and metabolomic pathways. The investigators have long track records in implementing single sites and multi-site clinical trials and observational studies in allergic diseases, including FA, to the standards of NIH funded clinical research networks, in conducting NIH fundamental research on disease mechanisms in FA and in training generations of investigators in FA research. In part A we demonstrate that we have the personnel and facilities to conduct CoFAR network-wide and Clinical Research Center-specific research, and a great capacity to recruit subjects from all age groups and different racial and ethnic backgrounds. We have a highly experienced team, a very solid and rich clinical research and laboratory infrastructure, data management facility with quality control plans, and capability to upload data into the NIAID designated repositories. In part B our network-wide trial proposes to evaluate the safety and efficacy of microbiota transplantation therapy (MTT) in teens with peanut allergy. Our basic and translational studies have provided critical evidence on the role of microbiome manipulation in FA. Our cutting-edge phase I trial in adults showed very promising results. We hypothesize that MTT with and without low dose peanut oral immunotherapy will be safe in peanut-allergic teens, will increase their threshold dose of reactivity to peanut and will lead to immunological and microbiome changes. In Part C, we propose to investigate FA novel immunological biomarkers identified in our laboratories. Specifically, RORgt+ Treg cells play a critical in mediating oral tolerance while Th2 cell-like reprogrammed regulatory T (Treg) cells play an essential role in disease pathogenesis. The thymic stromal lymphopoietin receptor (TSLPR) expression is predictive of Th2 cell-like reprogramming and disease promotion. Resistin-like beta (RELMβ) is elevated in FA in inverse relationship with RORgt+ Treg cells and plays a critical role in disease pathogenesis by promoting anaphylaxis. We hypothesize that changes in Treg cell subpopulations and markers and RELMb play a critical in the outcome of natural tolerance or successful peanut desensitization. This project evaluates novel microbiome therapies and mechanisms fundamental to FA and pave the way for future intervention and biomarker driven approaches to inform future precision therapy. We address a critical need in investigating novel therapeutic approaches and immunological pathways associated with peanut allergy. We will contribute extensively to the CoFAR as a CoFAR-Clinical Research Center, with our infrastructure and expertise.