Understanding Predictors of Crohn's Disease: Determinants of Altered Barrier Function in Pre-Disease Phase of Crohn's Disease

Anna Neustaeter, Haim Leibovitzh, Williams Turpin, Kenneth Croitoru*, Maria Abreu, Paul Beck, Charles Bernstein, Kenneth Croitoru*, Levinus Dieleman, Brian Feagan, Anne Griffiths, David Guttman, Kevan Jacobson, Gilaad Kaplan, Denis O. Krause, Karen Madsen, John Marshall, Paul Moayyedi, Mark Ropeleski, Ernest SeidmanMark Silverberg, Scott Snapper, Andy Stadnyk, Hillary Steinhart, Michael Surette, Dan Turner, Thomas Walters, Bruce Vallance, Guy Aumais, Alain Bitton, Maria Cino, Jeff Critch, Lee Denson, Colette Deslandres, Wael El-Matary, Hans Herfarth, Peter Higgins, Hien Huynh, Jeff Hyams, David Mack, Jerry McGrath, Anthony Otley, Remo Panancionne, Maria Abreu, Guy Aumais, Robert Baldassano, Charles Bernstein, Maria Cino, Lee Denson, Colette Deslandres, Wael El-Matary, Anne M. Griffiths, Charlotte Hedin, Hans Herfarth, Peter Higgins, Seamus Hussey, Hien Hyams, Kevan Jacobson, David Keljo, David Kevans, Charlie Lees, David Mack, John Marshall, Jerry McGrath, Sanjay Murthy, Anthony Otley, Remo Panaccione, Nimisha Parekh, Sophie Plamondon, Graham Radford-Smith, Mark Ropeleski, Joel Rosh, David Rubin, Michael Schultz, Ernest Seidman, Corey Siegel, Scott Snapper, Hillary Steinhart, Dan Turner

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

Abstract

The pathogenesis of Crohn's disease (CD) remains unknown. The current working theory is that genetic susceptibility influences host-microbe interactions, resulting in chronic inflammation. Case-control studies fail to explain the triggers or pathogenesis of the disease, notably due to confounding factors in patients with established disease. Investigating the pre-disease phase of CD improves the capacity to assess these confounding factors and enables us to identify biomarkers associated with increased risk of CD. The Crohn's Colitis Canada-Genes, Environment, Microbial (CCC-GEM) project is a prospective cohort of healthy first-degree relatives of patients with CD, allowing us to interrogate the pre-disease phase of CD. The CCC-GEM Project has led to the identification of several demographic, serological, and microbiome composition markers associated with an increased risk of disease in pre-clinical participants. Notably, altered intestinal barrier function, as measured by the fractional urinary excretion of lactulose mannitol ratio, is associated with a significantly increased risk of CD. We review the intrinsic and external factors that are associated with altered intestinal barrier integrity, including genetic risk, subclinical inflammation, serum proteomics, intestinal microbiome composition, and environmental components, such as diet and lifestyle. Providing insights into the factors and mechanisms of altered barrier function contributes to our understanding of the pathogenic mechanisms of CD. These advances may aid in developing strategies for preventing disease in high-risk individuals. Further research and personalized strategies are needed to optimize these mitigation strategies for individuals at-risk for CD.

Original languageEnglish
Pages (from-to)68-77
Number of pages10
JournalJournal of the Canadian Association of Gastroenterology
Volume7
Issue number1
DOIs
StatePublished - 1 Feb 2024

Bibliographical note

Publisher Copyright:
© 2024 Crown copyright.

Keywords

  • Crohn's Colitis Canada-Genes
  • Crohn's disease onset
  • Environment
  • Fecal calprotectin
  • Inflammatory bowel disease
  • Lactulose to mannitol ratio
  • Leaky gut
  • Metabolomic
  • Microbial (CCC-GEM) Project
  • Microbiota

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