Researchers Uncover Key Role for MicroRNA in Inflammatory Bowel Disease

An international team of researchers has discovered that a microRNA produced by certain white blood cells can prevent excessive inflammation in the intestine. The study, “Myeloid-derived miR-223 regulates intestinal inflammation via repression of the NLRP3 inflammasome,” which will be published May 9 in The Journal of Experimental Medicine, shows that synthetic versions of this microRNA can reduce intestinal inflammation in mice and suggests a new therapeutic approach to treating patients with Crohn’s disease or ulcerative colitis.

Inflammatory bowel disease (IBD), including Crohn’s disease and ulcerative colitis, affects almost 2 million people in the US. Although IBD is caused by a complex mix of genetic and environmental factors, it is thought to be initiated by an excessive immune response against bacteria in the gut. This immune response involves the recruitment of various white blood cells, such as neutrophils and monocytes, into the intestine and the activation of a protein complex in these cells known as the inflammasome. The inflammasome, in turn, activates the proinflammatory signaling molecules IL-1β and IL-18, which stimulate the further influx of white blood cells.

MicroRNAs are small RNA molecules that can bind and repress protein-coding messenger RNAs. An international team of researchers led by Eóin McNamee at the University of Colorado-Anschutz Medical Campus found that IBD patients showed increased levels of a microRNA called miR-223 during active bouts of inflammation. This microRNA was also elevated in laboratory mice with colitis.

miR-223 is produced by neutrophils and monocytes and has previously been shown to repress the messenger RNA encoding NLRP3, a key component of the inflammasome. McNamee and colleagues found that mice lacking miR-223 expressed higher levels of NLRP3, causing increased IL-1β production and enhanced susceptibility to intestinal inflammation.

In contrast, mice treated with lipid nanoparticles containing synthetic RNA molecules that mimic miR-223 showed lower levels of NLRP3 and IL-1β and were accordingly protected from experimentally induced colitis.

“Our study highlights the miR-223–NLRP3–IL-1β regulatory circuit as a critical component of intestinal inflammation,” McNamee says. “miR-223 serves to constrain the level of NLRP3 inflammasome activation and provides an early brake that limits excessive inflammation. Genetic or pharmacologic stabilization of miR-223 may hold promise as a future novel therapy for active flares in IBD.”

Study Finds Arthritis Drug Significantly Effective in Treating Crohn’s Disease

Researchers at University of California San Diego School of Medicine have shown that ustekinumab, a human antibody used to treat arthritis, significantly induces response and remission in patients with moderate to severe Crohn’s disease. Results of the clinical trial will appear in the November 16 issue of the New England Journal of Medicine.

“A high percentage of the patients in the study who had not responded to conventional therapies were in clinical remission after only a single dose of intravenous ustekinumab,” said William J. Sandborn, MD, professor of medicine at UC San Diego School of Medicine and director of the Inflammatory Bowel Disease Center at UC San Diego Health. “Finding effective new treatment options for this patient population is critical because Crohn’s disease can dramatically impact a person’s quality of life. Patients suffering from this disease may go to the bathroom up to 20 times a day and experience abdominal pain, ulcers and a reduced appetite.”

Crohn’s disease is a chronic inflammatory disease of the gastrointestinal tract that affects approximately 700,000 people in the United States. It can affect any part of the GI tract but it is more commonly found at the end of the small intestine (the ileum) where it joins the beginning of the large intestine (or colon). Crohn’s disease is usually treated with glucocorticoids, immunosuppressants, tumor necrosis factor (TNF) antagonists or integrin inhibitors.

“The drawbacks of these therapies include an increased risk of infection and cancer, and limited efficacy,” said Sandborn. “Ustekinumab has not been associated with an increased risk of serious adverse events.”

The rates of remission response in the randomized study at week six among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving a placebo. The study also found subcutaneous (injected) ustekinumab every 8 to 12 weeks maintained remission in patients.

“This study indicates that ustekinumab may have a long duration of action, a likelihood that may become better understood in future trials,” said Sandborn. “Our current findings offer hope for those suffering from this debilitating gastrointestinal tract disease.”

The Inflammatory Bowel Disease (IBD) Center at UC San Diego Health is dedicated to diagnosing and treating people with IBD from around the world. The center’s leadership in IBD medical research means patient access to clinical trials for the newest therapies and advanced surgical techniques for the treatment of this challenging condition. Care is provided by a multidisciplinary team of specialists in gastroenterology, endoscopy, oncology, surgery, transplantation and radiology.