FROM GUT
Researchers have identified two distinct molecular subclasses of Crohn’s disease, based on gene expression and phenotype, which could help with better tailoring of treatment.
Crohn’s disease is a chronic inflammatory disorder with a diverse clinical presentation and pattern of progression, yet the molecular and genetic factors underlying the disease are not well understood.
This complicates treatment – which currently relies on doctors’ subjective clinical classification – and makes it difficult to develop an evidence-based personalized approach.
Writing in the Oct. 14 online edition of Gut, Matthew Weiser, a graduate student in the genetics department at the University of North Carolina at Chapel Hill and his coauthors report the results of a genetic and molecular analysis of noninflamed colon tissue from a cohort of 21 adult patients with Crohn’s disease and from healthy controls.
This analysis revealed two distinct molecular phenotypes in colon tissue, which they labeled as “colon-like” and “ileum-like.” They found significant differences in cellular metabolism and immune pathways (Gut. 2016 Oct 14. doi: 10.1136/gutjnl-2016-312518 ).
In the colon-like subtype, the tissue samples – which were all taken from the colon – showed gene expression patterns that were typical of cells from the colon. However, in the ileum-like subtype, the gene expression patterns in these colon cells more closely resembled the gene expression of ileum cells.
They also saw significant differences in other molecular traits, such as chromatin accessibility, and pathways involved in lipid and xenobiotic metabolism.
“Furthermore, chromatin accessibility data suggest these subclasses exist due to stable molecular transformations of the genomic architecture in colon tissue cells, and not transient differences due to external cellular signaling,” researchers reported.
To rule out the possibility that these differences might be from treatment history, researchers conducted a similar analysis using samples from 201 treatment-naive pediatric patients with Crohn’s disease and found the same molecular and genetic patterns.
“Together, these data strongly suggest that the colon-like and ileum-like molecular signatures define two forms of [Crohn’s disease] present, regardless of tissue sampling location, patient age, or treatment status.”
The researchers also examined the impact the two subtypes might have on the clinical disease and therefore the therapeutic approach taken. In the cohort of treatment-naive pediatric patients, they found that patients with the more colon-like Crohn’s disease were more likely to have both colon and ileum involvement, have deep ulcers, and show more macroscopic inflammation than those with more ileum-like Crohn’s disease.
They also found that adults in the colon-like disease subclass were the only ones who were likely to have rectal disease or require a colectomy, although they noted that the sample size was small.
More patients with the ileum-like disease showed no inflammation and were also more likely to have involvement of the colon only.
“Although our sample size is small, these data suggest that molecular subtypes of [Crohn’s disease] can stratify patients into clinically distinct and relevant subgroups and may prospectively identify those more likely to require intensive medical therapy,” the authors wrote.
“As a first step, molecular stratifications of archived patient tissue and serum from major clinical trials could be performed in the context of response to biological and microbial therapies for [Crohn’s disease].”
The authors pointed out that they did not study samples from both intestinal regions in each patient but suggested that their findings should motivate future studies in larger cohorts using matched tissue samples from both the colon and ileum.
“These data emphasize the need to continue and expand these studies over time to incorporate the evolving clinical phenotype in both adult and pediatric patients, and the need to study both tissues in the same patient.”
The study was supported by the National Institute of Environmental Health Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, American Gastroenterological Association, Broad Medical Research Program, Crohn’s and Colitis Foundation of America, International Human Microbiome Consortium, UNC Team Translational Science Award, and Helmsley Charitable Trust SHARE 2, Project 3. No conflicts of interest were declared.
