Researchers identify early molecular warning signs of inflammatory bowel disease

While modern treatments can help many people reach remission, IBD remains difficult to diagnose and treat.

Patients often cycle between periods where symptoms are controlled and sudden flare-ups, which can require hospital care.

Study co-author Dr Andre Samson said the team found that even when patients seemed well and their disease appeared under control, their intestinal cells were primed for damage.

“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.”

The findings challenge the idea that cell death in IBD is simply a consequence of inflammation, suggesting it may instead be part of the process driving disease. The defect appeared in the earliest stages of disease activity, including in patients with clinically mild disease and required detailed molecular analysis to detect.

Study co-author Professor James Murphy said the work revealed a ‘smouldering’ defect at the molecular level, shifting their attention to the earliest stages of IBD.

“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.”

Patient samples help predict future flares

The 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 individuals with and without IBD. These were then used to create organoids, lab-grown tissues from patient samples, to enable detailed study of IBD in human cells.

Study co-author Professor Edwin Hawkins, head of the Colonial Foundation Diagnostics Centre where samples were analysed, said this large patient cohort was a major strength.

“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.”

The team followed these patients for more than two years and found that people with higher levels of intestinal cell death signalling were also more likely to relapse.

Towards earlier detection, tailored treatment

IBD varies widely between patients, making it difficult to predict who will respond to various treatments or relapse.

Study co-author Dr Jiyi Pang said the findings could help researchers develop more precise ways to monitor disease and, in the future, better match treatments to 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.”

Study co-author Dr Aysha Al-Ani said while the findings may not immediately translate into a new diagnostic test or treatment, they provide a strong foundation for future work, including therapeutics.

“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.”

The research team included scientists and clinicians from the University of Melbourne, the Royal Melbourne Hospital, Royal Children’s Hospital, Monash Institute of Pharmaceutical Sciences, the Hudson Institute of Medical Research and Monash University.

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.

The study, “A necroptotic-to-apoptotic signaling axis underlies inflammatory bowel disease”, is published in Science (DOI: 10.1126/science.aeh7112).