The IBDs, Crohn’s disease and ulcerative colitis, are chronic inflammatory conditions of the gastrointestinal tract resulting from an aberrant immune response to enteric microbiota in genetically susceptible individuals. Disease presentation and progression within and across IBDs, especially Crohn’s disease, are highly heterogeneous in location, severity of inflammation and other phenotypes. Current clinical classifications fail to accurately predict disease course and response to therapies. Genome-wide association studies have identified >240 loci that confer risk of IBD, but the clinical utility of these findings remains unclear, and mechanisms by which the genetic variants contribute to disease are largely unknown. In the past 5 years, the profiling of genome-wide gene expression, epigenomic features and gut microbiota composition in intestinal tissue and faecal samples has uncovered distinct molecular signatures that define IBD subtypes, including within Crohn’s disease and ulcerative colitis. In this Review, we summarize studies in both adult and paediatric patients that have identified different IBD subtypes, which in some cases have been associated with distinct clinical phenotypes. We posit that genome-scale molecular phenotyping in large cohorts holds great promise not only to further our understanding of the diverse molecular causes of IBD but also for improving clinical trial design to develop more personalized disease management and treatment.
The inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, are highly heterogeneous in presentation, disease course and response to therapy.
Genome-wide association studies have identified >240 loci associated with IBD, but this knowledge has not yet contributed to improved patient care.
Sequencing-based assays enable the identification and quantification of molecular phenotypes, including gene and microRNA expression levels, locations of active regulatory elements and gut microbial composition, that are altered in disease.
Genome-wide characterization of tissues and cells from patients with Crohn’s disease has identified specific molecular subtypes that are associated with different clinical phenotypes.
Molecular profiling in specific intestinal cell populations is necessary to pinpoint mechanisms that contribute to disease phenotypes, including those caused by genetic variation.
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The work of the authors is supported by 1R01DK104828-01A1 from National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (to T.S.F. and S.Z.S.), P01-DK094779-01A1 from NIDDK (to S.Z.S.), P30-DK034987 from NIDDK (to S.Z.S.), 1-16-ACE-47 American Diabetes Association Pathway Award (to P.S.), University of North Carolina (UNC) Nutrition Obesity Research Center Pilot & Feasibility Grant P30DK056350 (to P.S.), the Crohn’s and Colitis Foundation PRO-KIIDS NETWORK (to S.Z.S. and P.S.), the Sinai-Helmsley Alliance for Research Excellence (SHARE) from the Helmsley Trust (to T.S.F. and S.Z.S.) and the UNC University Cancer Research Fund (UCRF; to T.S.F. and P.S.).
The authors declare no competing interests.
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Furey, T.S., Sethupathy, P. & Sheikh, S.Z. Redefining the IBDs using genome-scale molecular phenotyping. Nat Rev Gastroenterol Hepatol 16, 296–311 (2019). https://doi.org/10.1038/s41575-019-0118-x
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