Sun-Ho Lee, MD, PhD, is a gastroenterologist at Sinai Health Zane Cohen Centre for Digestive Diseases.

Sun-Ho Lee, MD, PhD

Early Prediction and the Path Toward Prevention in Crohn’s Disease, With Sun-Ho Lee, MD, PhD

As evidence grows that Crohn’s disease begins years before symptoms appear, research is moving beyond early detection to what intervention might be possible. Identifying immune signals that precede disease onset raises critical questions about mechanism, causality, and whether these pathways can be modified to reduce risk, shifting the field toward prediction and prevention.

In a recent study, Sun-Ho Lee, MD, PhD, a gastroenterologist at Sinai Health Zane Cohen Centre for Digestive Diseases, and colleagues identified a blood test that can predict Crohn’s disease years before symptoms appear by measuring a person’s immune response to flagellin. They followed 381 first-degree relatives of Crohn’s patients as part of the Genetic, Environmental, and Microbial (GEM) Project, 77 of whom went on to develop the disease. Additional assay-based analyses revealed 19 of 49 IgG antimicrobial antibody responses were significantly associated with the risk of Crohn’s.

Check out part 1 of Lee’s interview with HCPLive Gastroenterology on preclinical Crohn’s and his research 

“With these 2 assays, especially the second one, we were able to show with an alternative assay, that it is one of the strong, key, crucial signals coming from the immune response against the hinge region of the flagellin,” Lee told 

At the same time, he was careful to underscore the many unanswered questions that remain. It is still unclear why some individuals develop antibodies to these flagellins before disease onset, or whether this reflects a failure of immune tolerance, increased microbial translocation across a compromised gut barrier, or another upstream trigger altogether. He noted that disentangling these mechanisms will require additional work.

Despite these unknowns, Lee described vaccination as an interesting possibility that emerges from narrowing the immune signal to a specific epitope. He pointed to prior animal studies demonstrating that vaccination against Salmonella flagellin can protect against colitis, as well as work showing that CD4+ T-cell responses to flagellins can be modulated in experimental models.

Based on this body of evidence, Lee and colleagues hypothesize that targeting pathogenic flagellin responses through vaccination could, in theory, blunt their role in Crohn’s disease development. He stressed, however, that this idea remains speculative and would require validation.

“There is really a growing interest in this early prediction and prevention in the field of IBD,” Lee said, describing other research groups and ongoing projects seeking to advance the field’s understanding of early disease.

Editors’ Note: Lee reports no relevant disclosures.

Wu RY, Xue M, Zhao Q, et al. Serum IgG Response to a Conserved Domain of Commensal Flagellins Predicts Future Risk of Crohn's Disease in First-degree Relatives. 

Lunenfeld-Tanenbaum Research Institute. A simple blood test can predict Crohn’s disease years before symptoms appear. EurekAlert! 

https://www.eurekalert.org/news-releases/1111855

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Lee explains how understanding immune responses years before Crohn’s symptoms may open the door to earlier intervention and prevention strategies.

Pre-Symptomatic Detection of Crohn’s Disease Through Flagellin Antibodies, With Sun-Ho Lee, MD, PhD

Crohn’s disease is typically diagnosed only after patients develop overt gastrointestinal symptoms, yet mounting evidence suggests that the pathogenic process begins years earlier.

During this silent, preclinical phase, immune dysregulation and host-microbe interactions may already be driving disease evolution. Understanding these earliest events has become a key priority in inflammatory bowel disease research, with the goal of identifying biomarkers that can predict risk, inform surveillance, and ultimately enable strategies to delay or prevent disease onset.

A new study from the Lunenfeld-Tanenbaum Research Institute and Mount Sinai Hospital’s Center for Inflammatory Bowel Disease has identified a blood test that can predict Crohn’s disease years before symptoms appear by measuring a person’s immune response to flagellin.

“Up until this study, it was unclear, especially in healthy first relatives, what type of flagellin antigens were the drivers or triggered the immune response, and if these antibody responses were associated with other biomarkers that are related to onset of Crohn's,” study investigator Sun Ho Lee, MD, PhD, a gastroenterologist at Sinai Health Zane Cohen Centre for Digestive Diseases, told 

Seeking to address that gap and build upon previous research regarding immune response against gut microbes prior to Crohn’s diagnosis, he and a team of investigators followed 381 first-degree relatives of Crohn’s patients as part of the Genetic, Environmental, and Microbial (GEM) Project, a global cohort of > 5000 healthy first-degree relatives of people with Crohn’s disease. Among the population in the present study, 77 went on to develop the disease.

Using 2 complementary assays, the researchers evaluated antibody responses to 49 recombinant flagellin antigens. Results showed 19 of 49 IgG antimicrobial antibody responses were significantly associated with the risk of Crohn’s. These antibodies were reactive to the Lachnospiraceae family, particularly Roseburia-derived flagellins.

Additionally, 5 antibodies positively correlated with fecal calprotectin, whereas 3 positively correlated with lactulose-to-mannitol ratio. Of note, these IgG-seroreactive flagellins shared significant amino acid sequence homology, characterized by a conserved "hinge peptide" within D0-D1 domains of the amino-terminus. The cytometric bead array confirmed that elevated IgG seroreactivity to the hinge peptide is associated with future risk of Crohn’s, independent of both lactulose-to-mannitol ratio and fecal calprotectin.

Taken together, Lee emphasized that these findings help refine the understanding of preclinical Crohn’s disease and narrow the focus to specific microbial antigens and epitopes. He suggested that such highly specific immune signatures could form the basis for future biomarkers aimed at identifying individuals at risk of Crohn’s before clinical symptoms emerge.

Lee explains what is known about the preclinical phase of Crohn’s disease before symptoms appear and describes his study on the role immune dysregulation plays.

Sun-Ho Lee, MD, PhD

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