Understanding Predictors of Crohn’s Disease: Determinants of Altered Barrier Function in Pre-Disease Phase of Crohn’s Disease
Authors: Neustaeter Anna , Leibovitzh Haim , Turpin Williams , Croitoru Kenneth ,   CCC GEM consortium, Abreu Maria , Beck Paul , Bernstein Charles , Croitoru Kenneth , Dieleman Levinus , Feagan Brian , Griffiths Anne , Guttman David , Jacobson Kevan , Kaplan Gilaad , Krause Denis O , Madsen Karen , Marshall John , Moayyedi Paul , Ropeleski Mark , Seidman Ernest , Silverberg Mark , Snapper Scott , Stadnyk Andy , Steinhart Hillary , Surette Michael , Turner Dan , Walters Thomas , Vallance Bruce , Aumais Guy , Bitton Alain , Cino Maria , Critch Jeff , Denson Lee , Deslandres Colette , El-Matary Wael , Herfarth Hans , Higgins Peter , Huynh Hien , Hyams Jeff , Mack David , McGrath Jerry , Otley Anthony , Panancionne Remo , Abreu Maria , Aumais Guy , Baldassano Robert , Bernstein Charles , Cino Maria , Denson Lee , Deslandres Colette , El-Matary Wael , Griffiths Anne M , Hedin Charlotte , Herfarth Hans , Higgins Peter , Hussey Seamus , Hyams Hien , Jacobson Kevan , Keljo David , Kevans David , Lees Charlie , Mack David , Marshall John , McGrath Jerry , Murthy Sanjay , Otley Anthony , Panaccione Remo , Parekh Nimisha , Plamondon Sophie , Radford-Smith Graham , Ropeleski Mark , Rosh Joel , Rubin David , Schultz Michael , Seidman Ernest , Siegel Corey , Snapper Scott , Steinhart Hillary , Turner Dan 
Published: January 2024

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.