The push to prevent Crohn's disease

For more than 40 years, Jean-Frederic Colombel, MD, has cared for patients with inflammatory bowel disease and watched the same pattern repeat itself: months of vague symptoms, delayed referrals, and cycles of steroids. By the time Crohn’s disease is firmly diagnosed, irreversible damage has often already occurred.

“What really matters is early,” Dr. Colombel, who directs the Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at the Icahn School of Medicine at Mount Sinai, New York, told GI & Hepatology News. “If you are able to catch the disease early, it’s a completely different story.”

That conviction now underpins one of the most ambitious prevention efforts in gastroenterology: the INTERCEPT study, a sweeping European initiative designed to predict and potentially prevent CD before the first clinical symptom appears.

A prevention mindset

Across medicine, prediction is becoming the new frontier. In 2022, endocrinologists celebrated the FDA approved teplizumab, a therapy that can delay stage 3 type 1 diabetes, the culmination of decades of work identifying high-risk individuals before disease onset. Neurologists and rheumatologists are pursuing similar strategies in multiple sclerosis and rheumatoid arthritis. IBD, Dr. Colombel believes, is ready for its own leap forward.

In the US, as many as half of patients with CD wait up to two years between first symptoms and diagnosis. During that time, inflammation can silently progress. “If you let the disease progress, it’s too late,” Dr. Colombel said. “The key word is early.”

Launched in 2025, INTERCEPT aims to shift the timeline — moving intervention upstream, into the silent biological phase before symptoms begin.

Mining the preclinical window

The study is supported by the Innovative Health Initiative Joint Undertaking (IHI JU) with Takeda Pharmaceutical Company as the industry lead, creating a public-private partnership valued at more than $30 million. It is co-led by Geert D’Haens, MD, PhD, of Stichting Amsterdam University Medical Center and involves multiple partners from several European countries as well as the United States and South Korea. Its first objective is to validate a blood-based risk score capable of identifying people who are likely to develop CD within the next few years.

The blood-based risk score will be directly informed by a blood score being developed in the US and Canada by the PROMISE Consortium (Prediction and Prevention through Omics, Microbiome, Immune System, and Environment), funded by The Leona M. and Harry B. Helmsley Charitable Trust. This research group is exploring the predictive and preventative aspects of omics- and microbiome-related, immunological and environmental factors contributing to the development of CD.

Working in this consortium since 2024, Dr. Colombel, along with Icahn School of Medicine colleague Inga Peter, PhD; Dr. Ken Croitoru, MD, of Mount Sinai Hospital in Toronto; and Hamed Khalili, MD, MPH, of Massachusetts General Hospital, have used rare and powerful preclinical cohorts to support their research. One comes from the US Department of Defense serum repository, which stores blood samples from military recruits. Researchers identified 200 individuals who later developed CD, along with 100 matched controls. For each future case, four samples are available: one at diagnosis, and others taken two, four and up to 10 years earlier. The repository offers a unique biological timeline, revealing how immune signals evolve long before symptoms surface.

A second cohort, known as The GEM Project, has followed 5,000 first-degree relatives of CD patients in Canada and other countries for more than a decade. About 150 participants have developed the disease during follow-up, providing another invaluable set of pre-diagnostic samples.

The third resource is the Nurses’ Health Study, a long-running U.S. study that has collected blood samples from thousands of nurses while tracking a wide range of health outcomes, including IBD.

Together, the cohorts span men and women, younger and older adults, relatives of patients and individuals without known family history. “It’s interesting because we can validate our biomarkers across different populations,” Dr. Colombel said.

A 'multi-omics' search

Rather than focusing on a single marker, the research team adopted a broad, multi-omics approach. They analyzed antibodies already associated with CD, scanned more than a thousand circulating proteins, evaluated metabolites and even examined markers of environmental exposure. The process is deliberately expansive and unbiased. But Dr. Colombel expects the final risk score to be practical and streamlined. “What we hope,” he said, “is that by measuring just six or seven biomarkers, you have a very good prediction of the development of Crohn’s disease within the next two years.”

Importantly, that prediction would apply to individuals who feel well and are asymptomatic for CD.

According to Dr. Colombel, there is a gray zone between truly preclinical disease and silent inflammation. Elevated fecal calprotectin, a stool marker of intestinal inflammation, may signal that microscopic disease has begun and could also help to predict future development of CD. But from a clinical perspective, the distinction matters less than timing. “The most important is to catch the disease before the symptoms,” he said.

From 10,000 to 100

Validation is only the first step. INTERCEPT also includes a massive prospective recruitment effort across seven European countries. The goal: enroll 10,000 first-degree relatives of CD patients and offer them a blood-based risk assessment.

Family history alone increases risk, but not enough to justify preventive therapy. The blood score is designed to refine that risk. Participants with a high-risk profile will undergo stool testing for calprotectin. Those with both a high blood score and elevated stool calprotectin will be eligible for a randomized placebo-controlled prevention trial with vedolizumab.

Because CD remains relatively uncommon — even among relatives — researchers must begin with thousands to identify individuals at sufficiently high risk to test preventive treatment. Recruitment has begun in several countries, though Dr. Colombel describes the cross-border regulatory process as difficult. Still, momentum is building.

The ethics of knowing

Predicting disease in healthy people raises ethical questions. How will individuals respond to being told they are at high risk? To find out, the team conducted surveys in both Europe and the US. According to Dr. Colombel, nearly all respondents supported the concept of prediction and prevention. Most were comfortable with blood or stool testing; some even indicated willingness to undergo colonoscopy if necessary.

When it came to preventive treatment, enthusiasm depended on safety and certainty. “For prevention to work, you have to have a very predictive score and a very effective therapy,” he said.

At the Icahn School of Medicine at Mount Sinai, a team of gastroenterologists and pediatricians led by Ryan Ungaro, MD, MS, and Elizabeth A. Spencer, MD, MS, have launched an IBD prevention clinic to counsel families and discuss research participation. The clinic reflects a larger philosophical shift, from reacting to established disease to anticipating and intercepting it.

“INTERCEPT reflects ongoing international efforts to move IBD care from a more reactive to a proactive approach in which the disease is identified in its earliest stages when treatments are most effective,” said Dr. Ungaro, who is a member of the study’s steering committee. “Ultimately, the work being done by INTERCEPT will usher in a new era of preventative medicine in IBD in which gastroenterologists will be counseling and treating people at risk of IBD in order to delay and ultimately prevent the development of these chronic diseases.”

A beginning, not an end

PROMISE and INTERCEPT have been years in the making, and Dr. Colombel is realistic about the timeline. Prevention science moves slowly, requiring careful validation, ethical oversight, and long-term follow-up.

“It will take a long time, but it could transform the care of IBD,” he said.

Dr. Colombel and Dr. Ungaro reported having no conflicts of interest.