Molecular Warning Sign May Explain Recurring IBD Flares

Researchers have identified early molecular warning signs of inflammatory bowel disease (IBD) that can appear before symptoms emerge and persist even when patients appear to be in remission.

A study led by the Walter and Eliza Hall Institute of Medical Research (WEHI) in partnership with the Royal Melbourne Hospital has revealed a hidden defect in intestinal cells that leaves them vulnerable to damage. The defect was still detectable in some patients whose disease appeared to be well controlled.

Published in Science, the findings may help explain why IBD can flare suddenly after long periods without symptoms.

Key findings

WEHI researchers found a persistent, “smouldering” molecular defect in the gut cells of people with IBD. The abnormality involves irregular cell death and can remain detectable even when clinical symptoms are minimal or absent.

The research, conducted with clinicians at the Royal Melbourne Hospital, could eventually support earlier predictions of relapse, more precise disease monitoring and treatments tailored to individual patients.

A hidden problem in intestinal cells

IBD encompasses chronic conditions including Crohn’s disease and ulcerative colitis and affects approximately 180,000 Australians. Symptoms can include abdominal pain, diarrhoea, rectal bleeding, fatigue and weight loss.

Although modern treatments enable many patients to reach remission, diagnosing and managing IBD remains difficult. The disease can alternate between controlled periods and severe flare-ups that require urgent or hospital-based care.

Study co-author Dr. Andre Samson said intestinal cells may remain vulnerable even when patients feel well and their disease appears stable.

“IBD does not disappear after diagnosis,” Dr. Samson said. “Even when current treatments eliminate symptoms, patients remain at risk of a flare or relapse. Our samples showed that intestinal cells are primed to die, and that this underlying problem can persist despite an absence of symptoms.”

Cell death may contribute to IBD

The results challenge the view that cell death in IBD is merely a consequence of inflammation. Instead, the researchers suggest that abnormal cell death may help drive the disease itself.

The defect was present at the earliest stages of disease activity, including in patients with clinically mild IBD. Detecting it required detailed molecular analysis.

Study co-author Professor James Murphy said the discovery highlighted a molecular problem that continues to smoulder at the beginning of disease progression.

“Much of the field has focused on severe gut inflammation when patients present in hospital,” said Professor Murphy, a WEHI deputy director and laboratory head. “We examined gut tissue without clear signs of active disease and found that this molecular defect occurs very early—one of the first changes that may set later events in motion.”

Human tissue points to future flare-ups

The research used human tissue and patient-derived organoids, which are lab-grown tissues that reproduce key features of the intestine.

Working with Royal Melbourne Hospital clinicians, the team collected about 900 biopsies from 80 people with IBD and 80 without the disease. Researchers used the samples to grow organoids and investigate how the condition develops in human cells.

Study co-author Professor Edwin Hawkins, head of the Colonial Foundation Diagnostics Center where the samples were analysed, said the size and composition of the patient group strengthened the findings.

“Cell death has been linked to IBD for many years, but its origins in humans have remained unclear, partly because mouse models do not always reproduce the human disease,” said Professor Hawkins, a WEHI laboratory head. “Our study is grounded in human tissue and patient biopsies.”

The researchers followed patients for more than two years. Those with stronger intestinal cell-death signalling were more likely to experience a relapse.

Toward earlier IBD detection

IBD varies substantially between patients, making it difficult to predict treatment responses and determine who is most likely to relapse.

Study co-author Dr. Jiyi Pang said the newly identified molecular signals could eventually support more precise tools for monitoring patients and selecting treatments according to the biology of their disease.

“The causes of IBD are still largely unknown and differ considerably between individuals,” Dr. Pang said. “By studying mini-intestinal organoids grown in the laboratory and working with an interdisciplinary team of researchers and clinicians, we identified the inflammatory signals that trigger this abnormal cell-death response.”

“We have now identified molecular hallmarks underlying the disease. The next challenge is determining which of these mechanisms can be targeted therapeutically and using them to match treatments more effectively to individual patients.”

More personalized treatment may follow

Study co-author Dr. Aysha Al-Ani cautioned that the findings are unlikely to produce a new diagnostic test or therapy in the immediate future. They nevertheless provide a foundation for developing better tools to forecast relapses and identify potential treatment targets.

“This opens new possibilities for prognostic testing using methods that are more sophisticated than those currently available in clinical practice,” Dr. Al-Ani said.

“The goal of IBD therapy is to reduce the frequency and severity of flare-ups, slow disease progression and improve patients’ lives. More sensitive molecular detection could help maintain deep remission for longer and guide the development of new treatments.”

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