Crohn’s disease: Discovery of two subtypes could lead to better treatments

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Crohn’s disease is notoriously difficult to treat due to the course and severity of the disease varying from one case to another. Research by University of North Carolina School of Medicine has discovered two subtypes of the disease – with different gene expressions and clinical features – which may reveal why such variations in disease progression surface between patients.

Crohn’s disease – a long-term condition that causes inflammation to the lining of the digestive system – affects almost 1 million people in the United States. While there is no cure for Crohn’s, treatment with anti-inflammatory drugs and immune system suppressors can help improve symptoms.

Around 70 percent of people with Crohn’s will eventually require surgery to remove damaged portions of the digestive tract and reconnect to healthy sections, and as many as 39 percent will require repeated surgery. Surgery may also close fistulas and drain abscesses.

The study findings – published in the journal Gut – build upon existing knowledge of the biology of Crohn’s disease, and they could potentially lead to more effective strategies and personalized treatments to target the debilitating gastrointestinal condition.

“The one-treatment-fits-all approach doesn’t seem to be working for Crohn’s patients,” says co-senior study author Dr. Shehzad Z. Sheikh, Ph.D., assistant professor in University of North Carolina’s (UNC) departments of medicine and genetics.

“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,” he adds.

Genes that varied between subtypes distinguish colon from ileum

With co-senior author Terry Furey, Ph.D., associate professor in UNC’s departments of genetics and biology, Sheikh and team analyzed colon tissue samples that looked healthy and non-inflamed in 21 Crohn’s patients who had undergone surgery. They then mapped levels of gene expression patterns amongst the samples, finding that there were two distinct groups.

“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 – the healthy tissue from Crohn’s patients and the inflamed samples from Crohn’s patients,” says Furey.

Co-first author Jeremy Simon, Ph.D., a research assistant professor in UNC’s department of genetics, notes that how the two disease subtypes differed was surprising.

Despite the samples being colon biopsies, Simon says, many of the genes that were varied between the two Crohn’s subtypes were markers that distinguish the colon from the ileum – the portion of the small intestine that empties into the colon and is usually the first area to be affected by Crohn’s disease.

The pattern of gene expression in one of the disease subtypes resembled healthy colon tissue. However, the gene expression in the second subtype resembled patterns seen in the ileum.

In addition to analyzing gene expression in the sampled tissue, Sheikh and colleagues observed indicators of the epigenetic state of the DNA tissue that can permit or repress nearby gene activity. The team saw a distinction between the two Crohn’s subtypes in the results that suggest the differences in gene expression emerge from variations in the core programming of the affected cells.

Crohn’s subtypes linked to two different clinical illness patterns

The researchers ensured that the fact that the samples were from adults who had undergone surgery did not skew the results, due to treatment and disease histories, by comparing their data to another dataset.

The team examined data from 201 children who had recently been diagnosed with Crohn’s and had not yet been treated. While the tissue samples in the data were from the ileum, the same colon-like and ileum-like disease classes were observed.

“This suggests that these molecular programs or baseline genomic signatures of Crohn’s subtypes exist independently of patients’ ages or treatment histories,” says Sheikh. He also points out that the two signatures are linked to different patterns of clinical illness.

For example, patients with the colon-like subtype were more likely to be characterized by gut inflammation found during colonoscopy, rectal disease, and colon inflammation severe enough to require colon removal.

In future work, Sheikh, Furey, and collaborators aim to develop a diagnostic test for use on tissue or blood samples taken from routine colonoscopies. By identifying which Crohn’s subtype a patient has, healthcare providers can determine the best therapy for treatment.

“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.”

Dr. Shehzad Z. Sheikh, Ph.D.

The researchers are planning a follow-up study to confirm their findings using a larger set of patient samples. They are also going to undertake a long-term study to follow patients from disease diagnosis for many years to see if the assigned Crohn’s subtype predicts the course of the disease.

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