Redefining the IBDs using genome-scale molecular phenotyping

Abstract

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.

Fig. 1 ∣. Contributing factors to IBD phenotypes.

Differentiation establishes the identities of all types of intestinal cells. This cellular programme is shaped by the underlying host genetic architecture and internal and external environmental contributors, including the gut microbiota. Incorrectly programmed cells, reflected in their aberrant epigenetic landscape and transcriptional profiles, fail to maintain proper intestinal homeostasis and lead to disease. Specific disease presentation evolves over time in response to cellular dysfunction and changing environmental conditions, including therapeutic agents

Fig. 2 ∣. overview of connections between molecular and disease phenotypes.

Genome-wide levels of host gene and microRNA expression, the state of the chromatin landscape that governs transcriptional regulation and the composition of enteric microbial communities reveal cellular processes and microbiota members that are associated with IBD subtypes. In turn, these IBD subtypes are linked to diverse clinical phenotypes. CD, Crohn’s disease; ECM, extracellular matrix; IPAA, ileal pouch–anal anastomosis; MHC, major histocompatibility complex; ROS, reactive oxygen species; T_reg cell, regulatory T cell; UC, ulcerative colitis.

Fig. 3 ∣. Clinical characteristics of Crohn’s disease.

Crohn’s disease is highly heterogeneous in several aspects. Disease can present as unrelenting mucosal inflammation, stricturing resulting in obstruction and penetrating disease that results in internal or external fistulas or intestinal perforation. Clinical phenotypes can also include perianal manifestations of Crohn’s disease (fistulas, fissures and abscesses) with and without intestinal involvement. Intestinal location of disease can include only the colon, only the ileum or both, as well as the upper gastrointestinal tract (mouth, oesophagus, stomach, duodenum or jejunum) and the rectum and anus in some instances.