Zebrafish provide insights into how Crohn's disease and colitis develop

Feb 21 2015 - 12:23pm
Duke University researchers uncover epigenetic changes that lead to IBD, thanks to zebrafish

Researchers know that people with inflammatory bowel disease have higher levels of tumor necrosis factor or TNF that is an inflammatory cytokine. Therapy for Crohn's disease and ulcerative colitis is geared toward inhibiting the pro-inflammatory protein to control symptoms. New information from Duke researchers gives insights into epigenetic changes that cause up-regulation of TNF and inflammation associated with the bowel disorders, thanks to zebrafish.

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For their study published in the Proceedings of the National Academy of Sciences,.the researchers used zebrafish that are transparent as embryos to visualize changes in the gut that occur in response to induced genetic mutations.

Scientists believe it may be a combination of factors that contribute to inflammatory bowel diseases including genetics, environmental exposure to autoimmune triggers and intestinal bacteria. The exact cause of Crohn's disease and colitis is still unknown.

Methylation defect plays a role in IBD

Michel Bagnat, Ph.D. who is an assistant professor of cell biology at Duke University School of Medicine explains: "We already knew that genetic susceptibility could play a part, but we've found that it is not just the immune genes themselves, but also the regulation of those genes (through epigenetics), that can cause problems."

For their study, Bagnat and his assistant Lindsay Marjoram, a postdoctoral fellow, used chemicals to create genetic mutations in zebrafish. Next they screened for gene mutations that thinned the protective lining of the gut. The next step was to hone in on genes that cause inflammation.

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To find out what happens the researchers engineered a zebrafish with the inflammatory genes that would "signal" by turning green when the TNF gene was turned on. A rise in anti-tumor necrosis factor is a hallmark of inflammatory bowel disease.

Gene discovery uncovers cause of IBD

The result led to a discovery that uncovered the cause of increased TNF activity. A gene known as uhrf1 was found to control TNF activity. When the gene is turned "off", through a process known as DNA methylation, it causes TNF to be produced and released.

The last step was to find out whether bacteria played a role in stimulating the activity of TNF. The researchers found TNF activity that leads to IBD persisted even without the influence of bacteria, though to a lesser degree. The study authors found uhrf1 restored the protective barrier of the intestines and is necessary to stop TNF from causing inflammation.

Bagnant said: "Our findings provide a new take on how inflammatory bowel diseases can emerge and develop." The next step is to study humans for methylation defects associated with Crohn's and colitis and other forms of IBD. The finding could lead to new therapies and ways to diagnose inflammatory bowel conditions.

Image credit: Flickr Creative Commons

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Comments

I have crohn's and have beenon treatment for 12 years .