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

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. Lay Summary Crohn’s disease, or CD, is a chronic condition that causes inflammation in the gut. We still do not know the cause of CD. Possibly, a mixture of genes and the environment can activate the immune system in an unusual way, leading to CD. Studying what causes CD is complex, but the Crohn’s Colitis Canada-Genes, Environment, Microbial (CCC-GEM) project is helping. We follow up people who might get CD over time to learn what happens before they get sick. We have found that if the gut’s protective lining is weak, a person is more likely to get CD. Other things that increase the chances of getting CD include inflammation, gut bacteria changes, and certain proteins in the blood. Surprisingly, owning a dog and being in a bigger f