Abstract
Background & Aims: Increased intestinal permeability has been associated with Crohn's disease (CD), but it is not clear whether it is a cause or result of the disease. We performed a prospective study to determine whether increased intestinal permeability is associated with future development of CD. Methods: We assessed the intestinal permeability, measured by the urinary fractional excretion of lactulose-to-mannitol ratio (LMR) at recruitment in 1420 asymptomatic first-degree relatives (6–35 years old) of patients with CD (collected from 2008 through 2015). Participants were then followed up for a diagnosis of CD from 2008 to 2017, with a median follow-up time of 7.8 years. We analyzed data from 50 participants who developed CD after a median of 2.7 years during the study period, along with 1370 individuals who remained asymptomatic until October 2017. We used the Cox proportional hazards model to evaluate time-related risk of CD based on the baseline LMR. Results: An abnormal LMR (>0.03) was associated with a diagnosis of CD during the follow-up period (hazard ratio, 3.03; 95% CI, 1.64–5.63; P = 3.97 × 10–4). This association remained significant even when the test was performed more than 3 years before the diagnosis of CD (hazard ratio, 1.62; 95% CI, 1.051–2.50; P =.029). Conclusions: Increased intestinal permeability is associated with later development of CD; these findings support a model in which altered intestinal barrier function contributes to pathogenesis. Abnormal gut barrier function might serve as a biomarker for risk of CD onset.
| Original language | American English |
|---|---|
| Pages (from-to) | 2092-2100.e5 |
| Journal | Gastroenterology |
| Volume | 159 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 2020 |
Bibliographical note
Funding Information:Funding This study was supported by grants from Crohn’s and Colitis Canada grant no. CCC-GEMIII , Canadian Institutes of Health Research (CIHR) grant no. CMF108031 , and the Helmsley Charitable Trust . Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology/Ferring Pharmaceuticals Inc. Williams Turpin, Sun-Ho Lee, and Juan Antonio Raygoza Garay are recipients of a fellowship from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Ernest Seidman is supported in part by a Canada Research Chair in Immune-Mediated Gastrointestinal Disorders and the Bruce Kaufman Chair in Inflammatory Bowel Disease at McGill. Kenneth Croitoru is partially supported by a Canada Research Chair in Inflammatory Bowel Diseases.
Funding Information:
Funding This study was supported by grants from Crohn's and Colitis Canada grant no. CCC-GEMIII, Canadian Institutes of Health Research (CIHR) grant no. CMF108031, and the Helmsley Charitable Trust. Williams Turpin is a former recipient of a Postdoctoral Fellowship Research Award from the CIHR Fellowship/ Canadian Association of Gastroenterology/Ferring Pharmaceuticals Inc. Williams Turpin, Sun-Ho Lee, and Juan Antonio Raygoza Garay are recipients of a fellowship from the Department of Medicine, Mount Sinai Hospital, Toronto, Canada. Ernest Seidman is supported in part by a Canada Research Chair in Immune-Mediated Gastrointestinal Disorders and the Bruce Kaufman Chair in Inflammatory Bowel Disease at McGill. Kenneth Croitoru is partially supported by a Canada Research Chair in Inflammatory Bowel Diseases.We thank the members of the CCC GEM Global Project Office. Charles Bernstein is supported in part by the Bingham Chair in Gastroenterology. Authors in the CCC GEM Project Research Consortium: The CCC GEM Project Research Consortium is composed of: Maria Abreu, Paul Beck, Charles Bernstein, Kenneth Croitoru, Leo Dieleman, Brian Feagan, Anne Griffiths, David Guttman, Kevan Jacobson, Gilaad Kaplan, Denis O. Krause∗, Karen Madsen, John Marshall, Paul Moayyedi, Mark Ropeleski, Ernest Seidman∗, Mark 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, and Remo Panancionne. The CCC GEM Project recruitment site directors include 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, and Dan Turner (∗deceased). Data availability: Requests for raw and analyzed data should follow the instructions given at http://www.gemproject.ca/data-access/. All submissions will be reviewed by the GEM Project Operating Committee to ensure that the requested samples/data will not interfere in any way with the intended GEM Project analysis of the nested cohort as per the original GEM Project Study Design and is not a duplication of analysis already ongoing. Those proposals meeting this evaluation will be distributed to all members of the GEM Project Steering Committee for review and open discussion. This review will focus on the global scientific merit of the proposal. This review will assess the basic scientific merit and the availability of requested samples and data, ensuring there is no compromise of the original intent of the GEM project. It would be of value to contact a member of the Steering Committee who could help sponsor your application. Those projects achieving a majority vote of approval at the GEM Project Steering Committee will be informed that the GEM Project will provide a letter of support stating that the requested samples or data will be made available to the applicants once the applicant receives funding from a granting agency that applies an independent peer review process to the proposal. The criteria to be used for review of all submissions will include the “scientific relevance” of the proposal and the judged availability of biological material requested. The budget to be requested from a funding agency must allow for any expenses in processing samples or in setting up the appropriate queries of the database. The intent is to allow sufficient time for applicants to consider submission for funding opportunities. Williams Turpin, PhD (Conceptualization: Supporting; Data curation: Equal; Formal analysis: Lead; Investigation: Supporting; Supervision: Supporting; Visualization: Lead; Writing – original draft: Lead; Writing – review & editing: Lead). Sun-Ho Lee, MD (Data curation: Lead; Formal analysis: Lead; Investigation: Lead; Methodology: Lead; Writing – original draft: Lead; Writing – review & editing: Lead). Juan Antonio Raygoza Garay, PhD (Formal analysis: Supporting; Methodology: Supporting; Writing – original draft: Supporting). Karen L. Madsen, PhD (Data curation: Lead; Formal analysis: Lead; Methodology: Supporting; Resources: Supporting; Supervision: Equal; Writing – original draft: Supporting; Writing – review & editing: Supporting); Jonathan B. Meddings, MD (Conceptualization: Lead; Data curation: Supporting; Formal analysis: Supporting; Investigation: Supporting; Supervision: Equal; Writing – original draft: Equal; Writing – review & editing: Equal). Larbi Bedrani, PhD (Formal analysis: Supporting; Methodology: Supporting). Namita Power, MSc (Formal analysis: Supporting). Osvaldo Espin-Garcia, PhD (Methodology: Supporting). Wei Xu, PhD (Supervision: Supporting). Michelle I. Smith, PhD (Formal analysis: Supporting; Methodology: Supporting; Project administration: Equal; Writing – original draft: Supporting; Writing – review & editing: Supporting). Anne M. Griffiths, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Paul Moayyedi, MB (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Dan Turner, MD, PhD (Resources: Supporting). Ernest G. Seidman, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Hillary A. Steinhart, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). John K. Marshall, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Kevan Jacobson, MB (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). David Mack, MD (Conceptualization: Supporting; Resources: Supporting). Hien Huynh, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Charles N. Bernstein, MD (Conceptualization: Supporting; Resources: Supporting; Writing – original draft: Supporting). Andrew D. Paterson, MD (Data curation: Supporting; Formal analysis: Supporting; Methodology: Supporting; Resources: Supporting; Supervision: Supporting; Writing – original draft: Supporting). Kenneth Croitoru, MD (Conceptualization: Lead; Funding acquisition: Lead; Investigation: Lead; Resources: Supporting; Supervision: Lead; Visualization: Supporting; Writing – original draft: Lead; Writing – review & editing: Lead).
Publisher Copyright:
© 2020 AGA Institute
Keywords
- Crohn's Risk
- FDR Study
- Gut Barrier
- IBD