Towards Integrative Omics To Predict Celiac Disease Onset in At-risk Infants

点击翻译按钮获取中文摘要

Industrialized nations have seen a tremendous rise in the incidence of autoimmune disease. Celiac disease (CD), a chronic autoimmune enteropathy triggered by the ingestion of gluten in genetically predisposed individuals, is no exception. CD is unique among autoimmune disorders in that the genetic predisposition, human leukocyte antigen (HLA), triggering factor (gluten), and auto antibodies produced are known. However, the early steps following the intestinal mucosal exposure to gluten leading to the loss of tolerance and development of the autoimmune process are still largely unknown. Additionally, the loss of tolerance to gluten does not always occur at the time of gluten introduction as was once thought, but may occur at any point due to unknown environmental triggers. Thus, genetic predisposition and exposure to gluten are necessary but not sufficient to develop CD. This discovery, along with the profound increase in diagnosis over the last four decades consistent with other autoimmune disorders, must be explained by environmental factors. Recent work published by my mentor has shown that a unique interplay between the microbiota and host may lead to alterations in the microbiome resulting in the production of specific metabolites prior to the onset of autoimmune disease. The intestinal microbiome develops during infancy, is essential to the development of the immune system, and assembles into an adult-like pattern in the first three years after birth, suggesting that the environmental influences in infancy may have important lasting effects. Therefore, I propose to investigate the role of the gut microbiome as a factor that may play a key role in early steps involved in the onset of the disease. I hypothesize that infants genetically at risk for CD will have a particular intestinal microbiota composition that, in combination with influences from other environmental factors, can contribute to the loss of gluten tolerance and to the onset of autoimmunity. My objective is to identify and validate specific microbiome profiles that can predict loss of tolerance in subjects genetically at risk of autoimmunity. The proposed project has three major aims. In Aim 1 I will determine underlying differences in the developing microbiome according to infants’ genetic risk. In Aim 2 I will examine how environmental factors such as birthing delivery mode, infection, and antibiotic use alter the developing microbiome. In Aim 3 I will investigate how dietary regimen alters the developing microbiome and examine changes that occur in the microbiome and serum before and after the development of autoantibodies that are indicative of CD. Through these aims I can provide the foundation to understand how early factors impact the developing microbiome. This pilot work will provide the basis for a K23 application which will expand the sample size and analysis to genomics, metabolomics, and epigenetics. This work will lay the foundation to reach my ultimate goal of becoming a translational investigator blending expertise in basic science, with clinical expertise in CD, to develop predictive models and eventually programs for personalized medicine for patients at risk for autoimmune disease.