A research team has identified an elevated immune response to flagellin, a protein found on gut bacteria, in individuals years before they develop Crohn's disease. This finding suggests a potential early marker for the chronic inflammatory condition and could inform new strategies for prediction, prevention, and treatment.
Introduction to the Discovery
A research team, led by Dr. Ken Croitoru from the Lunenfeld-Tanenbaum Research Institute at Sinai Health, has identified an elevated immune response to flagellin. This protein is present on gut bacteria, and its heightened response was observed in individuals years before they were diagnosed with Crohn's Disease. The team also included Dr. Richard Wu and Dr. Sun-Ho Lee, associated with Mount Sinai Hospital’s Centre for Inflammatory Bowel Disease. The findings were published in Clinical Gastroenterology and Hepatology.
Understanding Crohn's Disease
Crohn's Disease is a chronic inflammatory condition of the gastrointestinal tract, characterized by persistent digestive symptoms, pain, and fatigue. Its incidence has increased among children, and estimates suggest approximately 470,000 Canadians may live with Inflammatory Bowel Disease (IBD) by 2035.
Researchers hypothesize that the presence of flagellin antibodies long before the onset of symptoms indicates this immune reaction may contribute to triggering the disease, rather than being a consequence of it. Understanding this early process could lead to new approaches for predicting, preventing, and treating the condition.
Research Methodology: The GEM Project
This research is part of the Genetic, Environmental and Microbial (GEM) Project, a global cohort of over 5,000 healthy first-degree relatives of Crohn's disease patients, also led by Dr. Croitoru. The project collects genetic, biological, and environmental data to understand the factors involved in disease development. To date, 130 participants from the cohort have developed Crohn’s, providing data on pre-disease stages.
Previous work by the team indicated that an inflammatory immune response targeting gut bacteria can appear before Crohn’s develops, where the immune system reacts abnormally to beneficial microbes. Collaborators at the University of Alabama, led by Dr. Charles Elson, had previously developed a test for antibodies against flagellin, demonstrating elevated levels in Crohn's patients specifically targeting flagellin from Lachnospiraceae bacteria.
Drs. Croitoru and Lee aimed to determine if this immune response could be detected in healthy individuals at risk. The study followed 381 first-degree relatives of Crohn’s patients, 77 of whom later developed the disease.
Study Findings
Among the 77 individuals who developed Crohn's, 28 individuals (more than one-third) showed elevated antibody responses to flagellin. These responses were observed to be particularly strong in siblings, suggesting a role for shared environmental exposure.
Researchers confirmed that this pre-disease response to Lachnospiraceae flagellin was associated with intestinal inflammation and gut barrier dysfunction, characteristics of Crohn's disease. The average time from blood sample collection, where the elevated immune response was detected, to a Crohn's diagnosis in these pre-disease individuals was nearly two and a half years.
Implications for Prediction and Prevention
The confirmation of an immune response against bacterial flagellins showing strong associations with future Crohn’s risk in healthy first-degree relatives is considered significant. This response is driven by a conserved domain of the flagellin protein. This discovery raises the potential for designing a flagellin-directed vaccine for disease prevention in high-risk individuals. Further validation and mechanistic studies are currently underway.
This research received funding from Crohn's and Colitis Canada, the Canadian Institutes of Health Research (CIHR), and The Leona M. and Harry B. Helmsley Charitable Trust.