Crohn’s disease, a common inflammatory disorder of the intestinal tract, can have devastating consequences for a patient’s quality of life. Although people with the disease are typically treated with powerful immune-suppressing drugs, roughly 70% eventually require surgery to remove portions of the intestinal tract that have developed blockages or other problems caused by severe inflammation. Even after surgery, the disease often recurs and is therefore not curative. Therefore, a deeper understanding of the biology of Crohn’s disease should enable doctors to target it more effectively. Now, a study from researchers at the UNC School of Medicine explains why Crohn’s is so variable; the disease appears to have at least two distinct subtypes, each with its own pattern of gene expression and mix of clinical features. The team state that their findings could lead to more effective strategies for treating Crohn’s.
Previous studies show that the one-treatment-fits-all approach doesn’t appear to be working for Crohn’s patients. The general consensus suggests 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, this is not case. The current study seeks to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterise the cellular processes associated with disease phenotypes.
The current study maps the levels of gene expression in non-inflamed, healthy-looking colon tissue samples taken from 21 Crohn’s patients. The lab state that when they began looking at the gene expression patterns in these patients, two clear groupings dominated. They go on to add that although a difference was noted between the Crohn’s samples and samples from people without Crohn’s, there was an even greater difference at the molecular level between these two subsets of the Crohn’s samples.
Results show that 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. Data finding show that in one disease subtype, the pattern of gene expression mostly resembled that of normal colon tissue, and in the other, gene expression shifted towards the pattern normally seen in the ileum, the part of the small intestine that empties into the colon, and is often the first area affected in Crohn’s.
The group also mapped indicators of the epigenetic state of the tissue DNA, the pattern of molecular switches on chromosomes that effectively permit or repress nearby gene activity. Results also show a distinction between the two Crohn’s subtypes, suggesting that their differences in gene expression stemmed from differences in the basic programming of the affected cells.
The team then investigated a gene expression dataset from 201 children with newly diagnosed, never-treated Crohn’s, and although the tissue samples this time were from the ileum, the researchers again observed the same two colon-like and ileum-like disease classes. The group state that this suggests these molecular programs or baseline genomic signatures of Crohn’s subtypes exist independently of patients’ ages or treatment histories.
The lab stress that these two signatures were linked to different patterns of clinical illness. They explain that the ‘colon-like’ cases, for example, were more likely to have gut inflammation visible during colonoscopy, rectal disease, and severe enough colon inflammation to require surgical removal of the colon.
The team surmise that the molecular signatures identified in their study define two clinically relevant forms of Crohn’s disease irrespective of tissue sampling location, patient age or treatment status. For the future, the researchers state that they plan a broadened study to confirm their findings in a much larger set of patient samples. They also hope to undertake a long-term study, in which they would test patients for their Crohn’s subtype when they are initially diagnosed with the disease, and then follow them for several years to see whether the assigned subtype predicts the disease course.
Source: UNC School of Medicine
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