The goal of this project is to examine stool and sera of 900 children previously collected from the prospective cohort TEDDY study, to determine if changes in microbiome or virus infections or both are linked to development of autoimmunity that leads to celiac disease. Previous studies and emerging evidence have implicated several viruses and microbiome signatures with celiac disease but have not proven strong linkage and have resulted inconclusive findings for the celiac disease field. The current application is an ancillary research project of the large international 15 year prospective TEDDY Study that is designed to find environmental triggers of Type 1 Diabetes and has had 297 children develop celiac disease but not T1D autoimmunity. The project will utilize the large scale and international scope of TEDDY and its rich genetic and dietary data on these children, to study this new celiac case-control cohort. We will use proven next generation sequencing, qRT-PCR and serologic approaches recently carried out for microbiome and virome analysis for T1D outcomes with TEDDY.
Aim 1 will discover and analyze the complete stool virome in these children over time, before conversion to tTGA autoimmunity and celiac disease, to identify viruses associated with celiac autoimmunity and disease.
Aim 2 will examine the microbiome structure over time to determine bacterial taxa or functions associated with celiac disease development and will derive complete genomic sequences of key variant bacteria found associated with disease outcomes. Both of these aims will identify agents that contribute independently to the risk of celiac outcomes, controlling for confounders or other components of the disease with regression approaches.
Aim 3 will probe further to determine if there is synergy or interactions of viruses or bacteria with other known risk factors such as the child's gluten intake and genetic risk (HLA and known associated SNPs). This will identify the set(s) of components that may contribute synergistically to cause CD outcomes. The proposed work is significant since it will apply the power of the larger and international TEDDY cohort and its rich database of genetic analyses of children to study progressively collected stools and sera to determine viruses and/or microbiome signatures that are linked to tTGA autoimmunity and celiac disease. The proposed work is innovative because it will provide the first comprehensive analysis of virome and microbiome components sufficient to cause celiac disease outcomes that may work synergistically. These findings will lead to a better understanding of what triggers celiac disease that will be more relevant for developing hypotheses of causal mechanisms and will open conceptual avenues for key diagnostic or preventative interventions.
This proposal will determine the role of viruses (virome) and bacteria (microbiome) in triggering the development of autoantibody responses to the celiac disease autoantigen tTGA, gluten, and the development of celiac disease in children under the age of four, and several smaller studies by others have implicated some bacteria and viruses, but produced somewhat conflicting results. This study provides a unique opportunity to examine both the virome and microbiome in sequential stool samples taken over time from 900 children, from a much larger international cohort of children, that also has excellent access to serum and genetics data from the same children. This study will clarify our knowledge of exactly which virus(es) or bacteria can trigger the development of celiac disease, when that may occur in early childhood, and provide insights into the mechanisms involved, links to key genetic variants in the children and can lead to preventative strategies in the future.
