Crohn’s Disease Research Links Epigenetic Changes to Chronic Flares

Scientists have known for some time that microbiota likely drives the gut inflammation associated with inflammatory bowel disease (IBD). But why do some children with Crohn’s disease, the most serious form of IBD, experience frequent flares, even when they receive good medical care? A recent study at Cincinnati Children’s shows that epigenetics may play an important role.

Epigenetics is the study of external modifications to DNA and associated proteins that result in genes being switched on or off in cells. The researchers discovered that intestinal microbiota may induce important epigenetic changes within a network of about 300 inflammatory genes. A trigger, such as stress or a viral infection, can cause these genes to be expressed at a high level, resulting in a flare.

Toward a more stable remission

The researchers published their findings in JCI Insight in a study led by principal investigator Theresa Alenghat, VMD, PhD, from the Cincinnati Children’s Division of Immunobiology. The study’s basic science and translational data could lead to the development of diagnostic, staging and treatment strategies for patients with IBD, which impacts an estimated 1.6 million people in the United States.

“We feel that one reason a lot of patients with Crohn’s keep having flares is because they have epigenetic changes that don’t revert back to normal with current therapy,” says one of the study’s co-authors, Lee (Ted) Denson, MD, director of the Schubert-Martin IBD Center at Cincinnati Children’s. “If we can learn how to reverse the epigenetic changes, we can get closer to helping patients achieve a more stable remission or even a cure.”

The study involved analyzing intestinal epithelial cells from newly diagnosed, treatment-naïve patients. The researchers used state-of-the-art methylation technology to identify which genes had epigenetic changes that increased or decreased the level of inflammatory gene expression. They tied in complementary studies in germ-free mice, which observed how the addition of bacteria regulated epigenetic changes. The data showed an overlap between genes that were regulated at an epigenetic level in mice and genes that were regulated in the same direction (up or down) in patients.

DUOX2 as a key regulator

Denson says that the network of genes affected by microbiota is complex and includes dual oxidase 2 (DUOX2), which previous research has identified as a key driver for inflammation. DUOX2 can cause inflammation on its own, but Denson and his colleagues also believe it is a key regulator of many other genes in the network.

A related clinical trial at Cincinnati Children’s is testing the potential benefits of prebiotics in restoring a healthy microbiome. Specifically, the study is testing two different doses of the prebiotic 2'-fucosyllactose (2FL), an oligosaccharide present in breast milk. It is the first National Institutes of Health-sponsored, randomized controlled trial to study 2FL. When mice in a previous study were given 2FL, one of the effects was a reduction in the expression of DUOX2.

Patient enrollment in the 2FL study is open to patients with IBD age 11 to 25 who are doing well on Remicade^® (infliximab) or Humira^® (adalimumab).

For more information, contact Denson at Lee.Denson@cchmc.org.