Biomarkers of Atopy Beginning Early (BABE)

PROJECT SUMMARY/ABSTRACT – OVERALL Atopic dermatitis (AD) often precedes sensitization to food allergens and the development of clinical food allergy (FA) due to compromised skin barrier function allowing allergen sensitization through skin. A large body of data from Europe and North America suggest that living on farms is associated with a decreased risk of asthma and

atopic diseases. Asthma has been a focus of farming lifestyle studies; however, little is known about the protective mechanisms of farming lifestyle on development of AD and FA which often precede respiratory allergies and asthma. The farm lifestyle protection against allergic diseases comprises likely three prerequisites:

1) innate immune training and a modified immune response upon re-exposure, 2) generation of suppressive regulatory T cells, and 3) preserved barrier function. Here, we propose to assess these preconditions in an extended longitudinal birth cohort study among the Old Order Mennonites (OOM), a population practicing

traditional, single-family farming with a lower rate of asthma and allergic diseases, including atopic dermatitis and food allergies in early childhood. Biomarkers of Atopy Beginning Early (BABE) will test the overall hypothesis that perturbed skin barrier function, immune millieu and microbiome drive the development of atopic

dermatitis, Th2 inflammation, allergic sensitization and FA, whereas a healthy gut microbiome modulates the protective metabolite pool such as short chain fatty acids and tryptophan metabolites and protective Treg immune development. Project 1 utilizes deep metagenomic sequencing to assess infant gut microbiome

composition and corresponding metabolome to show that OOM infant gut microbiome is distinct from urban infants. Project 2 assesses markers of allergic sensitization and protective immune development utilizing multiparameter spectral flow, unbiased clustering analysis and transcriptomic studies to demonstrate that urban

infants have a higher number of hyperinflammatory monocytes and Th2-skewed T cell subsets detected in early infancy, whereas OOM have gut-homing memory Tregs. Project 3 will characterize skin barrier function, microbiome and immune cell transcriptome. Our longitudinal birth cohort ZOOM1, funded by a U01 grant, is

now 2-5-years old and is a shared foundation for the three projects (78 OOM and 79 urban). We will add another 120 infants as a ZOOM2 cohort (80 urban and 40 OOM). We will also replicate key T cell biomarkers in larger infant cohorts (Start Eating Early Diet ”SEED” and Microbiome and Allergic Asthma Precision Prevention

“MAAP2”). The infrastructure to recruit, collect and share samples and data is provided by the Cohort Admin & Biorepository and Data Management & Bioinformatics Cores. The Admin Core will provide overall financial and administrative infrastructure. These studies aim to identify biomarkers, mechanisms, and protective strategies

against atopic and food allergy.