A simple blood test can predict Crohn’s disease years before symptoms appear

Sinai Health researchers have shown a blood test that can predict Crohn’s disease years before symptoms appear, opening the doors to early diagnosis and potentially prevention.

The test measures a person’s immune response to flagellin, a protein found on gut bacteria. This response is elevated in individuals long before they develop Crohn’s Disease, a team led by Dr. Ken Croitoru, a clinician scientist at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health, has found. The team also included gastrointestinal medical resident, Dr. Richard Wu, and clinician scientist, and staff gastroenterologist Dr. Sun-Ho Lee.

Drs. Croitoru and Lee are also a part of Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease (IBD), a globally recognized center focused on inflammatory bowel disease research.

Their findings, published in Clinical Gastroenterology and Hepatology, highlight the interplay between the gut’s bacteria and immune system responses as a critical step in developing Crohn’s Disease.

Crohn’s disease is a chronic inflammatory condition of the gastrointestinal tract that causes persistent digestive symptoms, pain and fatigue, significantly affecting quality of life. Its incidence among children has doubled since 1995, and rates continue to rise. Crohn’s and Colitis Canada, a non-profit dedicated to curing IBD, estimates about 470,000 Canadians will be living with IBD by 2035.

The presence of flagellin antibodies long before any symptoms appear suggests that this immune reaction may contribute to triggering the onset of the disease, rather than being a consequence of it, Dr. Croitoru said. He believes that a better understanding of this early process could open the door to new approaches for predicting, preventing and treating the disease.

“With all of the advanced biologic therapy we have today, patients’ responses are partial at best. We haven’t cured anybody yet, and we need to do better” said Dr. Croitoru, who hold Canada Research Chair in Inflammatory Bowel Diseases.

This research is part of the Genetic, Environmental and Microbial (GEM) Project, a global cohort of more than 5,000 healthy first-degree relatives of people with Crohn’s disease, led by Dr. Croitoru. Since 2008, the project has collected genetic, biological and environmental data to better understand how the disease develops. To date, 130 participants have developed Crohn’s, giving researchers a rare opportunity to study the earliest pre-disease stages.

Previously, the team discovered that long before Crohn’s disease develops, an inflammatory immune response targeting gut bacteria can appear. In healthy individuals, bacteria coexist peacefully in the gut and play an essential role in maintaining digestive health. In Crohn’s disease, however, the immune system appears to mount an abnormal response against normally beneficial microbes.

Collaborators at the University of Alabama led by Dr. Charles Elson had previously developed a test to detect antibodies against flagellin and showed that individuals with Crohn’s have elevated antibody levels targeting flagellin from Lachnospiraceae bacteria.

Drs. Croitoru and Lee now wanted to determine whether this immune response could also be detected in healthy individuals who are at risk of developing the disease.

“We wanted to know: do people who are at risk, who are healthy now, have these antibodies against flagellin?” said Dr. Croitoru. “We looked, we measured, and yes indeed, at least some of them did.”

This study followed 381 first-degree relatives of Crohn’s patients, 77 of whom went on to develop the disease. Among them, 28 individuals – more than a third – had elevated antibody responses. The responses were strongest in siblings, highlighting the role of shared environmental exposure, as previously shown by Dr. Croitoru.

The researchers also confirmed that this pre-disease response to the Lachnospiraceae flagellin was associated with intestinal inflammation and gut barrier dysfunction, both of which are characteristics of Crohn’s disease. The typical timeline from blood sample collection to the pre-disease individuals being diagnosed with Crohn’s was nearly two and a half years.

“Confirming our previous study immune response against bacterial flagellins show strong associations with future risk of Crohn’s in healthy first-degree relatives” said Dr. Lee.  “We found that this immune response is driven by a conserved domain of the flagellin protein. This raises the potential for designing a flagellin-directed vaccine in selected high-risk individuals for prevention of disease. Further validation and mechanistic studies are underway.”

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