Increased intestinal permeability have been associated with Crohn's disease (CD), but it is not clear whether these are 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.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 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.An abnormal LMR (> 0.03) was associated with 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).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.