A hidden molecular defect in inflammatory bowel disease may help explain why flare-ups can return even when patients appear well.
Even when inflammatory bowel disease appears under control, intestinal cells may remain primed to die. In a WEHI-led study, researchers found this hidden molecular defect in patients with few or no symptoms, and higher levels of cell death signaling were linked to a greater likelihood of relapse during more than two years of follow-up.
The findings, produced in partnership with the Royal Melbourne Hospital and published in Science, challenge the idea that intestinal cell death is simply a consequence of inflammation. Instead, the defect appeared during the earliest stages of disease activity, including in patients with clinically mild disease, suggesting it may be involved in the disease process itself.
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, affects around 180,000 Australians. Symptoms can include rectal bleeding, abdominal pain, diarrhea, fatigue, and weight loss. Although modern treatments can help many patients reach remission, IBD remains difficult to diagnose and treat, and periods of controlled symptoms can be interrupted by sudden flare-ups that sometimes require hospital care.
Damage persists even during remission
Study co-author Dr. Andre Samson said the researchers found that intestinal cells remained vulnerable even when patients appeared well, and their disease seemed controlled.
“Once you’ve got the diagnosis, IBD doesn’t go away. Even if you become symptom-free on the current treatments, we know there’s a likelihood you’re going to have a flare or relapse,” said Dr. Samson.
“What we found in patient samples was that intestinal cells are primed to die. Even in patients with essentially no symptoms, there’s still this persistent problem sitting there.”
Detecting the problem required detailed molecular analysis because it was present before obvious signs of active disease. Study co-author Professor James Murphy described it as a ‘smoldering’ defect that shifted the researchers’ attention toward what happens early in IBD rather than only during severe inflammation.
“Most people have been focusing on the major clinical problem, when someone comes to hospital with severe gut inflammation,” Prof Murphy, a WEHI deputy director and lab head, said.
“We’ve gone to the other end of the spectrum and looked at gut tissue that doesn’t have clear signs of active disease. What we’re finding is this molecular defect happening very early in disease progression – one of the first dominoes to fall.”
Human tissue reveals an early defect
Unlike studies that rely primarily on animal models, this work was based entirely on human tissue and patient-derived organoids. The research team, which included clinicians from the Royal Melbourne Hospital, collected around 900 biopsies from 80 people with and without IBD.
Those samples were used to create organoids, lab-grown tissues derived from patients that allowed the researchers to examine the disease directly in human cells.
Study co-author Professor Edwin Hawkins, head of the Colonial Foundation Diagnostics Centre where the samples were analyzed, said the large patient cohort and focus on human tissue were major strengths.
“While cell death has been implicated in IBD for a long time, how it arises in humans has remained unclear, probably because most studies rely on mouse models which often do not accurately mimic the human condition,” Prof Hawkins, a WEHI lab head, said.
“Our study is based on human tissue and patient biopsies.”
Cell death signals track relapse risk
The researchers followed the patients for more than two years and found that those with higher levels of intestinal cell death signaling were also more likely to relapse.
That association is especially relevant because IBD can behave very differently from one patient to another, making it difficult to anticipate who will relapse or respond to a particular treatment.
Study co-author Dr. Jiyi Pang said the findings could eventually support more precise disease monitoring and help researchers better match treatments to individual patients.
“The causes of IBD are largely unknown and quite variable,” Dr. Pang said.
“Using mini-intestinal organoids grown in a dish and by 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 disease at the molecular level. The question is which of those are therapeutically actionable and whether they might help us to better match treatments to patients, based on how their disease behaves at a molecular level.”
Better monitoring could improve remission
The findings do not immediately provide a new diagnostic test or treatment. Study co-author Dr. Aysha Al-Ani said they instead establish a foundation for future work, including potential therapies and more refined ways of assessing a patient’s outlook.
“It opens new avenues for different prognostic tools, using more sophisticated and refined methods than are currently used clinically,” Dr. Al-Ani said.
“The ethos behind IBD therapy is to reduce the frequency and severity of flares, halting disease progression and improving patients’ lives. More sensitive molecular detection may help us keep patients in deep remission for longer and introduce new treatments.”
Reference: “A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease” by Jiyi Pang, Aysha H. Al-Ani, Komal M. Patel, Yunzhuo Zhou, Samuel N. Young, Jinjin Chen, Isabella Kong, Marilou Barrios, James A. Rickard, Siqi Chen, Xiuquan Ma, Farzaneh Shojaee, Seong-Beom Kim, Siavash Foroughi, Wayne Cawthorne, Annette V. Jacobsen, Asha Jois, Ashley L. Weir, Lachlan W. Whitehead, Pradeep Rajasekhar, Christopher R. Horne, Ruqian Lyu, Lucy J. Mather, Raymond K. H. Yip, Ellen Tsui, Imadh Azeez, Tao Tan, Weiwei Liang, Suresh Sivanesan, Andrew Metz, Ash Patwardhan, Natalie Shea, Guru Iyngkaran, Daniel Schneider, Alexander T. Elford, William Beattie, Finlay Macrae, Gianmaria Liccardi, Henning Walczak, Yuxia Zhang, Oliver M. Sieber, Tim Spelman, Lisa Giulino-Roth, Michael Christie, Yunshun Chen, Kelly L. Rogers, Rory Bowden, Sandra E. Nicholson, Kate E. Lawlor, Edwin D. Hawkins, Britt Christensen, Andre L. Samson, James E. Vince and James M. Murphy, 27 August 2026, Science.
DOI: 10.1126/science.aeh7112
This work is supported by the Kenneth Rainin Foundation, National Health and Medical Research Council of Australia (NHMRC), the Australian Research Council, Stafford Fox Medical Research Foundation, the Colonial Foundation, Crohn’s and Colitis Australia and the Victorian State Government.
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