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Two distinct cell types can initiate Crohn's disease

A new discovery could lead to personalized treatment for the debilitating gastrointestinal disorder called Crohn's. There appear to be two distinct disease types. One expressed in normal colon tissue, the other in the small intestine. Detecting which type a patient has will assist her in her treatment and desire to get pregnant or carry a pregnancy.

Crohn's disease is a common inflammatory disorder of the intestinal tract, but it has devastating effects on patients' — children and adults — quality of life. Conceiving during a disease flare is not advised. It is very hard to treat because it varies so much from one person to the next. Now, however, scientists from the University of North Caroline (UNC) School of Medicine have discovered what might explain that variability. Crohn's appears to have at least two distinct subtypes, each with its own gene expression and mix of clinical features.

Published in the journal Gut, the discovery could lead to more effective strategies for treating Crohn's, which affects close to one million people in the United States alone. Although people with Crohn's typically receive powerful immune-suppressing drugs, roughly 70 percent eventually require surgery to remove portions of blocked intestinal tract or other tract problems caused by severe inflammation. Even after surgery, the disease is not cured and often recurs.

"The one-treatment-fits-all approach doesn't seem to be working for Crohn's patients. It's plausible that this is because only a subset of patients has the type of disease that responds to standard therapy, whereas, for the rest of the patients, we're really not hitting the right targets."

Shehzad Z. Sheikh MD, PhD, Assistant Professor, University of North Caroline, departments of Medicine and Genetics, and co-senior author of the study.

For the new study, Sheikh teamed up with Terry Furey PhD, associate professor in UNC's departments of genetics and biology. They mapped levels of gene expression in non-inflamed, healthy-looking colon tissue samples from 21 Crohn's patients — and two clear groups dominated.

"Although we saw a difference between the Crohn's samples and samples from people without Crohn's, we saw an even greater difference at the molecular level between these two subsets of the Crohn's samples," Furey added.

The team described how in one subtype, the pattern mostly resembled normal colon tissue. In the other, the pattern looked more like the ileum (the small intestine which empties into the cecum then colon). The ileum is often the first affected in Crohn's.

"It was surprising. Many of the genes that were different between the two Crohn's subtypes are markers that distinguish the colon from the ileum, despite these being colon biopsies."

Jeremy Simon PhD, Assistant Professor, Department of genetics, UNC, and co-first author of the study with former graduate student Matthew Weiser PhD.

The team looked not only at specific gene protein products in the sampled tissue, but also at the "epigenetic" state of its' DNA - that pattern of molecular switches on chromosomes permitting or repressing nearby genes. Here was a distinction between the two Crohn subtypes, differences in gene expression from differences in the basic programming of affected cells.

Adults submitting colon samples had all undergone surgery, opening the possibility that their treatment and disease histories played a role in their gene expression patterns. So the team then looked at a gene expression dataset from 201 children with newly diagnosed, never-treated Crohn's. Although tissue samples were from the ileum, researchers observed the same colon-like and ileum-like disease patterns.

Sheikh: "This suggests that these molecular programs or baseline genomic signatures of Crohn's subtypes exist independently of patients' ages or treatment histories."

Importantly, these two signatures are linked to different patterns of clinical illness. "Colon-like" cases, for example, are more likely to have gut inflammation visible during colonoscopy, rectal disease (notoriously difficult to manage), and severe enough colon inflammation to require surgical removal of the colon (colectomy).

Sheikh, Furey, and their colleagues now want to translate these results into a diagnostic test on tissue from routine colonoscopies, or perhaps even on blood samples. Such tests could help doctors classify Crohn's patients and choose the best therapies.

"We hope one day to be able to test Crohn's patients for the subtype of the disease they have, and thus determine which treatment should work best. The idea is to find the best therapeutic course for each patient as quickly and efficiently as possible."

Shehzad Z. Sheikh MD, PhD

Objective The clinical presentation and course of Crohn's disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.

Design We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult patients with CD and control patients. To support the generality of our findings, we analysed previously published expression data from a large cohort of treatment-naïve paediatric CD and control ileum.

Results We found that adult patients with CD clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Furthermore, gene expression from the ilea of a treatment-naïve cohort of paediatric patients with CD could be similarly subdivided into colon-like and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behaviour, including rectal disease and need for colectomy.

Conclusions Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.

Gut doi:10.1136/gutjnl-2016-312518

Authors: Matthew Weiser, Jeremy M Simon, Bharati Kochar, Adelaide Tovar, Jennifer W Israel, Adam Robinson, Gregory R Gipson, Matthew S Schaner, Hans H Herfarth, R Balfour Sartor, Dermot P B McGovern, Reza Rahbar, Timothy S Sadiq, Mark J Koruda, Terrence S Furey, Shehzad Z Sheikh

The other co-authors of the study were UNC GI fellow Bharati Kochar, MD; UNC graduate student Adelaide Tovar; UNC postdoctoral fellow Jennifer W. Israel, PhD; former UNC graduate students Adam Robinson, PhD, and Gregory R. Gipson, PhD; UNC research technician Matthew S. Schaner; Hans H. Herfarth, MD, PhD, professor of medicine at the UNC School of Medicine; R. Balfour Sartor, MD, the Midgette Distinguished Professor of Medicine and Microbiology & Immunology and co-director of the UNC Multidisciplinary Center for IBD Research and Treatment; Reza Rahbar, MD, assistant professor of surgery at UNC; Timothy S. Sadiq, MD, assistant professor of surgery at UNC; Mark J. Koruda, MD, professor of surgery; and Dermot P.B. McGovern, MD, PhD, professor of medicine, Director of Translational Medicine, and the Joshua L. and Lisa Z. Greer Endowed Chair in IBD Genetics at the David Geffen School of Medicine at UCLA and Cedars-Sinai Medical Center.

The work was supported by the American Gastroenterological Association, the Broad Medical Research Program, Crohn's and Colitis Foundation of America, and the National Institutes of Health.Return to top of page

Oct 17, 2016   Fetal Timeline   Maternal Timeline   News   News Archive   

Physical characteristics of Crohn's disease take many forms. Children also suffer.
Image Credit:
Girl's with guts.org


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