Baseline stool TIMP-2 predicts strictures and penetrating disease progression in Crohn's patients

Longstanding subclinical Crohn's Disease (CD) can progress to complications such as intestinal strictures and penetrating (intestinal fistulae, abscesses, or perforations) disease. Despite the advances in non-invasive diagnostics for IBD, there is a dearth of biomarkers for predicting disease progression and complications in CD. Here, we investigate four baseline stool biomarkers, BDNF, MMP-8, TIMP-2, and Calprotectin (S100A8/A9), for their ability to predict disease progression in pediatric CD.

Baseline stool samples from forty-seven patients recruited into the Pediatric RISK Stratification study were analyzed using an aptamer-based screening assay followed by validation by Enzyme-linked Immunosorbent Assays.

All four stool proteins were associated with disease activity at baseline. Baseline stool BDNF, MMP-8, and TIMP-2, but not Calprotectin distinguished progressors from non-progressors. Stool TIMP-2 predicted progression to stricturing and penetrating disease in CD, with higher levels predicting worse progression whereas an inverse relationship was seen with stool MMP-8, supporting the role of TIMP-2/MMP balance in driving fibrotic disease in CD. Indeed, stool TIMP-2 exhibited outstanding odds ratios of ~42 in predicting disease progression, outperforming all current protein or genetic markers of IBD. Stool BDNF was the next strongest performer associated with disease progression in CD.

Stool TIMP-2 emerges as a novel predictor of disease progression in CD.