PROJECT SUMMARY / ABSTRACT Asthma and allergic diseases continue to be major public health problems resulting in significant disability and resource utilization globally. Most asthma is diagnosed before the age of six. Thus, prenatal and early life exposures play an important role in the development of asthma and allergies. On the basis of finding an inverse association between family size and atopy, it was postulated that reduced microbial exposure in early life explains the epidemic of allergic diseases (the “hygiene hypothesis”). The original hygiene hypothesis has undergone changes and refinement, and is now taken to mean not just simply a reduced microbial exposure, but perhaps changes in the breadth and types of microorganisms coupled with changing environments. The gut flora is, quantitatively, the most important postnatal source of microbial stimulation of the immune system. Significant differences between the gut flora of children in industrialized and developing nations suggest that the high prevalence of asthma in affluent nations may be due to changes in the intestinal flora of young infants. This concept of “dysbiotic drift,” whereby environmental forces related to Westernized lifestyles leads to a shift of the developing microbiota away from the norm, may explain why many chronic inflammatory conditions, such as asthma, are associated with Westernized lifestyles. Dysbiosis is a potential mechanism by which the environment interacts with the early developing immune system to program risk for chronic disease. While there are a growing number of studies that are investigating the role of the intestinal microbiome in asthma, these have examined stool samples obtained at one point in time. Since the intestinal microbiome undergoes rapid changes before it becomes established between the ages of 1 and 3 years of life, longitudinal studies are needed. Additionally, no studies have accounted for the host genetic background, which may determine both the development of dysbiosis and who develops asthma when faced with dysbiosis. The overarching hypothesis of this proposal is that vitamin D deficiency in the pre-, peri-, and immediate post-natal periods, in addition to host genetic influences, lead to intestinal dysbiosis in early life. Dysbiosis, in the proper host genetic context, then increases the risk for development of asthma. While we have collected information on a host of other relevant exposures, this proposal will focus on vitamin D as the primary exposure of interest. We have put together 2 vitamin D clinical trial populations – Vitamin D Antenatal Asthma Reduction Trial (VDAART) and Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010) – with prospective collection of exposures during pregnancy and early life, that we will leverage to test our hypotheses. This proposal is in response to FOA RFA-OD-16-004, Environmental Influences on Child Health Outcomes (ECHO) Pediatric Cohorts (UG3/UH3). In these cohorts, we will first determine the patterns of change in the early intestinal microbiome (both composition and metabolic function) up to age 6 years that are related with vitamin D deficiency in the prenatal and perinatal periods. We will also investigate genetic markers of the host that affect these patterns in the intestinal microbiome. We will then investigate the relationship of these patterns of change in the microbiome with the presence of asthma by age 6 years. Findings from this project will point to potential mechanisms by which early environmental exposures interact with the developing intestinal microbiome and the host to confer risk for asthma.

PROJECT NARRATIVE Asthma and allergies are the most common chronic disorders in children. There is a lack of understanding of the risk factors and mechanisms that lead to asthma and allergies. We will investigate the role of two novel risk factors – vitamin D and the intestinal microbiome – on the risk of asthma and allergies in the child, and findings from this important and efficient study could form the basis for development of new and important approaches to reduction of these conditions.