Williams Turpin1, Sun-Ho Lee1, Juan Antonio Raygoza Garay1, Karen L Madsen2, Jonathan B Meddings3, Larbi Bedrani4, Namita Power5, Osvaldo Espin-Garcia6, Wei Xu6, Michelle I Smith5, Anne M Griffiths7, Paul Moayyedi8, Dan Turner9, Ernest G Seidman10, A Hillary Steinhart1, John K Marshall8, Kevan Jacobson11, David Mack12, Hien Huynh13, Charles N Bernstein14, Andrew D Paterson15, Kenneth Croitoru16. 1. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 2. University of Alberta, Edmonton, Alberta, Canada. 3. Department of Medicine, Cumming School of Medicine, Calgary, Alberta, Canada. 4. Department of Medicine, University of Toronto, Toronto, Ontario, Canada. 5. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada. 6. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. 7. Division of Gastroenterology, The Hospital for Sick Children, Toronto, Ontario, Canada. 8. Department of Medicine, McMaster University, Farncombe Family Digestive Health Research Institute, Hamilton, Ontario, Canada. 9. The Juliet Keidan Institute of Pediatric Gastroenterology and Nutrition, Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Jerusalem, Israel. 10. Inflammatory Bowel Disease Centre, Division of Gastroenterology, McGill University Health Centre, Montréal, Quebec, Canada. 11. Canadian Gastro-Intestinal Epidemiology Consortium, Canada; British Columbia Children's Hospital, Vancouver, British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada. 12. Division of Gastroenterology, Hepatology & Nutrition, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ontario, Canada. 13. Department of Pediatrics, University of Alberta, Edmonton, Alberta, Canada. 14. University of Manitoba Inflammatory Bowel Disease Clinical and Research Centre and, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Manitoba, Winnipeg, Canada. 15. Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Genetics and Genome Biology, The Hospital for Sick Children Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada. 16. Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address: Ken.Croitoru@sinaihealth.ca.
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.
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.
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