On Target: Treating Gut Inflammation

Could this breakthrough lead to safer, more effective therapies that reduce immune suppression?

Inflammatory bowel disease (IBD) is characterized by an overreactive immune system causing inflammation in the digestive tract, including the intestines, the body’s largest immune organ. Most drugs used to treat IBD are immunosuppressive, increasing susceptibility to infections. What if researchers could create a more precisely targeted treatment without these widespread side effects? Children’s Hospital Colorado and University of Colorado School of Medicine researchers believe they have. They’re calling it a “refined bullet” — a way to treat IBD without global effects.

In IBD, the immune system is dysregulated causing immune T cells to attack healthy tissues instead of targeting invaders. “The goal is to find ways to turn the overreactive immune system off, but not turn it off too much,” explains Edwin de Zoeten, MD, PhD, Director of Children’s Colorado’s Pediatric IBD Center.

How it began with CD4+ T cells

Tissue hypoxia, in which there are low oxygen levels in the intestinal tissues at the site of inflammation, is a defining trait of IBD. The low oxygen acts like a trigger, worsening inflammation. For Dr. de Zoeten, who is interested in cellular stress, hypoxia was the perfect place to begin searching for a better treatment. He and the team of researchers wanted to examine how low oxygen environments impact T cells. Specifically, they were interested in CD4+ T cells — immune cells found in inflamed intestinal tissue — and how these conditions influence immune system behavior.

In individuals with IBD, T cells become overactive and mistakenly attack the body, causing inflammation. Previous research by Sean Colgan, PhD, at the University of Colorado School of Medicine, indicated hypoxia-inducible transcription factors (HIFs), proteins that regulate the body’s response to low oxygen environments, can help recover from inflammation. HIFs help cells adapt to low oxygen by activating genes that promote survival and regulate immune responses. Still, prior studies didn’t give clarity on how the hypoxic environment affected the T cells in IBD.

In Dr. de Zoeten’s study, the team exposed CD4+ T cells to both a normal and hypoxic environment. They then analyzed these cells for the presence of microRNAs (miRNAs), small noncoding RNA molecules that regulate immune cells. That’s where they made a crucial discovery. They identified a miRNA called miR29a, which was produced in high quantities under hypoxic conditions.

The importance of miR29a

MiRNAs help control which genes are expressed and regulate different processes, including immune responses. In this case, they suppress overactive immune responses and promote anti-inflammatory pathways.

Dr. de Zoeten and the team proved the production of miR29a begins with a chain reaction. First, inflammation stimulates hypoxia, which leads to an increase in HIF-2a production. HIF-2a, like other HIFs, plays a role in regulating immune responses. Specifically, HIF-2a promotes the production of miR29a. This domino effect helps regulate the immune response and inflammation, unveiling a pathway not fully known before this study.

After identifying how miR29a production is increased, researchers then looked at the miRNA’s impact on inflammation. Using lipid nanoparticles to deliver a miRNA mimetic, a chemically altered miRNA, researchers discovered another key relationship. The preclinical models that received the mimetic experienced less inflammation. The inverse is also true. The models with a miR29a deficiency presented with enhanced intestinal inflammation. Researchers believe by increasing the production of miR29a, they can suppress the overactive T cells, reducing inflammation and improving overall symptoms in patients with IBD.

The impact of this potential treatment

“This concept is really targeting one regulatory pathway. It’s upstream from many of the targets that we have currently,” Dr. de Zoeten says. “It targets the function of the cell rather than the product of the cell.”

Not only do current medications suppress the entire immune system, but the medications also only work for about half of those with IBD. According to the Centers for Disease Control and Prevention, IBD affects up to 3 million people in the United States, with symptoms ranging from chronic diarrhea to abdominal pain and fatigue. In children, this can lead to growth delays, weight loss and other complications.

For Dr. de Zoeten, this research is personal. Originally trained as a cancer immunologist, Dr. de Zoeten found a passion for IBD after the loss of his mother, who passed away from complications of the disease. In the decades since, researchers like him have made incredible advancements in the treatment of IBD.

“We don’t even use most of the medications [that were] available to my mother. I would say the advances over the last 25 years have been tremendous. They’ve changed patients’ lives for the better,” Dr. de Zoeten says.

The fight continues. Dr. de Zoeten and the multidisciplinary team are still looking for ways to refine treatment further, avoiding off-target effects and whole-body immune suppressions. In future studies, they plan to investigate other cell types that may be affected by HIF-2a, the long-term efficacy of miR29a, mimetic therapy and methods to improve delivery.

“It’s how do we target the right cell at the right time. It’s working with people on campus and across the world to assess the best nanoparticle, the best way to target inflammation. It’s a collaborative effort, and it’s not just one person,” Dr. de Zoeten says.

With groundbreaking discoveries like miR29a, the prospect of targeted therapies offers new hope, ensuring better outcomes for millions living with IBD.