Epidemiologic identification and mechanistic investigation of early life environmental risk factors for eosinophilic esophagitis

点击翻译按钮获取中文摘要

Epidemiologic identification and mechanistic investigation of early life environmental risk factors for eosinophilic esophagitis ABSTRACT Eosinophilic esophagitis (EoE) is a recently recognized immune-mediated disease defined by abnormal infiltration of eosinophils into the esophageal mucosa, leading to failure to thrive, abdominal pain, vomiting, and heartburn in children, and progressing to esophageal stenosis and food impaction in adults. Though initially thought to be rare, the incidence and prevalence are rising dramatically, and over the past decade EoE has rapidly become a major cause of upper gastrointestinal morbidity. Despite increases in the understanding of the condition, it is currently not possible to determine why individual patients develop EoE. This is frustrating for patients and practitioners alike. EoE is considered to be an immune/allergen-mediated disease, and epidemiologic studies support a primarily environmental etiology. However, environmental risk factors have not been extensively studied in EoE, and prior studies, including by our own group, are limited by a crude assessment of exposures, recall bias, inability to assess fetal biomarkers, and lack of mechanistic understanding. Our goal is to address this knowledge gap by using an innovative method to precisely measure early life exposures in deciduous (primary, or “baby”) teeth that may be implicated in EoE development. Of particular interest are early life antibiotic exposure and duration and intensity of breastfeeding (which can be derived from barium levels in teeth). Increased antibiotic exposure and decreased breastfeeding have been linked to risk of atopic diseases. Measuring selected environmental exposures in teeth has never been applied to EoE, but we have documented the feasibility of this approach. This assessment, together with the use of novel cellular and molecular techniques for elucidating the mechanisms underlying the effects of these early life exposures, has the potential to greatly enhance our understanding of the pathogenesis of EoE. Our hypothesis is that the risk of EoE related to early life exposures is primarily due to an impaired esophageal epithelial barrier, and that genetic susceptibility will interact with the exposures to modify risk. The specific aims are to 1) determine the association between early life antibiotic exposure and EoE; 2) determine whether breastfeeding is associated with EoE, and evaluate whether the susceptibility genotype for CAPN14 modifies the association between breastfeeding and EoE; and 3) determine the functional significance and mechanisms of early life exposures on esophageal epithelial architecture and barrier function. To achieve these aims, we will conduct a case-control study to characterize temporal exposures, and in parallel will perform mechanistic analyses. This innovative, hypothesis-driven, and rigorously designed study will lead to robust and unbiased results. It will be conducted by a multidisciplinary team with recognized expertise in EoE, epidemiology, clinical/translational/lab research, and exposure science. The results will have a major impact on the understanding of EoE etiology and by potentially identifying opportunities for disease prevention which could lead to the development of new treatment options.