Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study

Gut. 2020 Aug;69(8):1416-1422. doi: 10.1136/gutjnl-2019-319809. Epub 2019 Nov 19.


Objective: Higher gluten intake, frequent gastrointestinal infections and adenovirus, enterovirus, rotavirus and reovirus have been proposed as environmental triggers for coeliac disease. However, it is not known whether an interaction exists between the ingested gluten amount and viral exposures in the development of coeliac disease. This study investigated whether distinct viral exposures alone or together with gluten increase the risk of coeliac disease autoimmunity (CDA) in genetically predisposed children.

Design: The Environmental Determinants of Diabetes in the Young study prospectively followed children carrying the HLA risk haplotypes DQ2 and/or DQ8 and constructed a nested case-control design. From this design, 83 CDA case-control pairs were identified. Median age of CDA was 31 months. Stool samples collected monthly up to the age of 2 years were analysed for virome composition by Illumina next-generation sequencing followed by comprehensive computational virus profiling.

Results: The cumulative number of stool enteroviral exposures between 1 and 2 years of age was associated with an increased risk for CDA. In addition, there was a significant interaction between cumulative stool enteroviral exposures and gluten consumption. The risk conferred by stool enteroviruses was increased in cases reporting higher gluten intake.

Conclusions: Frequent exposure to enterovirus between 1 and 2 years of age was associated with increased risk of CDA. The increased risk conferred by the interaction between enteroviruses and higher gluten intake indicate a cumulative effect of these factors in the development of CDA.

Keywords: coeliac disease; gluten; small bowel.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / isolation & purification
  • Autoantibodies / blood
  • Autoimmune Diseases / blood
  • Autoimmune Diseases / etiology*
  • Autoimmune Diseases / genetics
  • Autoimmunity
  • Case-Control Studies
  • Celiac Disease / blood
  • Celiac Disease / etiology*
  • Celiac Disease / genetics
  • Child, Preschool
  • Diet
  • Enterovirus / isolation & purification*
  • Feces / virology*
  • Female
  • GTP-Binding Proteins / immunology
  • Genetic Predisposition to Disease
  • Glutens / administration & dosage*
  • HLA-DQ Antigens / genetics
  • Humans
  • Infant
  • Male
  • Metagenomics
  • Protein Glutamine gamma Glutamyltransferase 2
  • Risk Factors
  • Transglutaminases / immunology


  • Autoantibodies
  • HLA-DQ Antigens
  • HLA-DQ2 antigen
  • HLA-DQ8 antigen
  • Glutens
  • Protein Glutamine gamma Glutamyltransferase 2
  • Transglutaminases
  • GTP-Binding Proteins