Researchers have identified early molecular warning signs of inflammatory bowel disease that can appear before symptoms and remain active even when patients appear well.
The study, led by WEHI in collaboration with the Royal Melbourne Hospital, discovered a hidden defect in intestinal cells that may make them vulnerable to damage. The problem was still detectable in some patients whose disease appeared to be well controlled.
Published in ScienceThe findings may help explain why people with inflammatory bowel disease can experience sudden attacks even after reaching remission.
Key findings
WEHI researchers identified a “latent” molecular defect in the intestinal cells of people with inflammatory bowel disease.
The defect involves abnormal cell death and could be detected even in patients whose disease was well controlled.
The work, carried out through extensive collaboration with the Royal Melbourne Hospital, could eventually lead to earlier prediction of outbreaks, more precise monitoring and more tailored treatment for each patient.
A hidden problem in intestinal cells
Inflammatory bowel disease (IBD), which includes conditions such as Crohn’s disease and ulcerative colitis, is a chronic condition that affects around 180,000 Australians.
People with IBD may experience serious symptoms including rectal bleeding, abdominal pain, diarrhea, fatigue, and weight loss.
Modern therapies can help many patients achieve remission, but diagnosing and treating IBD remains a challenge.
The disease often alternates between periods when symptoms are controlled and sudden outbreaks that can become severe enough to require hospital care.
Study co-author Dr. Andre Samson said the researchers found that intestinal cells could remain vulnerable even when patients felt well and their illness seemed stable.
“Once you’re diagnosed, IBD doesn’t go away. Even if you become symptom-free with current treatments, we know there’s a chance you’ll have a flare or relapse,” Dr. Samson said.
“What we found in patient samples was that intestinal cells are primed to die. Even in patients who are essentially asymptomatic, there is still this persistent problem.”
Cell Death May Help Drive IBD
The results challenge the assumption that cell death in IBD is simply damage caused by inflammation. Instead, researchers say abnormal cell death may be involved in helping drive the disease itself.
The defect was already present during the early stages of disease activity, even in patients with clinically mild IBD. Detecting it required detailed molecular analysis.
Study co-author Professor James Murphy said the discovery revealed a “latent” molecular problem and encouraged researchers to focus more closely on what happens early in the disease process.
“Most people have focused on the main clinical problem, when someone comes to hospital with severe intestinal inflammation,” said Professor Murphy, WEHI deputy director and laboratory head.
“We’ve gone to the other end of the spectrum and looked at intestinal tissue that has no clear signs of active disease. What we’re finding is that this molecular defect occurs very early in the progression of the disease—one of the first dominoes to fall.”
Human tissue reveals clues about future outbreaks
The research was based entirely on human tissue and patient-derived organoids.
Working with doctors at the Royal Melbourne Hospital, the team collected around 900 biopsies from 80 people with and without IBD. The researchers used those samples to grow organoids, lab-grown tissues derived from patients, allowing them to investigate the disease directly in human cells.
Study co-author Professor Edwin Hawkins, director of the Colonial Foundation Diagnostic Center where the samples were analysed, said the size and nature of the patient group were important strengths of the research.
“While cell death has been implicated in IBD for a long time, it is unclear how it arises in humans, probably because most studies are based on mouse models that often do not accurately mimic the human condition,” said Professor Hawkins, head of the WEHI laboratory.
“Our study is based on human tissue and patient biopsies.”
The researchers then followed the patients for more than two years. They found that people who showed stronger intestinal cell death signaling were also more likely to experience a relapse.
Towards earlier detection of IBD
IBD can behave very differently from person to person, making it difficult to know who will respond to a particular treatment or who is most likely to relapse.
Study co-author Dr. Jiyi Pang said the newly identified molecular signals could eventually help scientists develop more precise tools to monitor patients and select treatments based on an individual’s disease biology.
“The causes of IBD are largely unknown and quite variable,” Dr. Pang said.
“Using mini intestinal organoids grown in a dish and working alongside a diverse team of researchers and clinicians, we uncovered the inflammatory signals responsible for this cell death response.”
“We now have the hallmarks of what underlies the disease at the molecular level. The question is which of these are therapeutically viable and whether they could help us better tailor treatments to patients, based on how their disease behaves at the molecular level.”
You could follow a more personalized treatment
Study co-author Dr. Aysha Al-Ani cautioned that the findings are unlikely to yield a new diagnostic test or therapy immediately. However, they provide a basis for future research into better prognostic tools and potential treatments.
“It opens new avenues for different prognostic tools, using more sophisticated and refined methods than those currently used clinically,” said Dr. Al-Ani.
“The ethos behind IBD therapy is to reduce the frequency and severity of flares, stop disease progression and improve patients’ lives. More sensitive molecular detection can help us keep patients in deep remission for longer and introduce new treatments.”
The research team included scientists and doctors from the University of Melbourne, Royal Melbourne Hospital, Royal Children’s Hospital, Monash Institute of Pharmaceutical Sciences, Hudson Institute of Medical Research and Monash University.
This work is supported by the Kenneth Rainin Foundation, the National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council, the Stafford Fox Medical Research Foundation, the Colonial Foundation, Crohn’s and Colitis Australia and the State Government of Victoria.