Immune Clues to Crohn’s Disease Appear Years Before Symptoms

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Crohn’s disease often develops silently for years before symptoms appear, making early detection especially challenging. However, according to new research published in Clinical Gastroenterology and Hepatology, certain immune antibodies can be detected years before Crohn’s disease is diagnosed in people with a family history of the condition.

“With all of the advanced biologic therapy we have today, patients’ responses are partial at best,” said Ken Croitoru, M.D.C.M., a clinician scientist at the Lunenfeld-Tanenbaum Research Institute, part of Sinai Health. “We haven’t cured anybody yet, and we need to do better.”

The discovery of flagellin antibodies years before Crohn’s disease symptoms appear suggests that immune changes may begin long before diagnosis, and could play a role in setting the disease in motion. Croitoru and his team say this challenges the idea that these immune responses are simply a consequence of inflammation and instead points to an early biological process that might be targeted for prevention or earlier treatment.

Investigators looked at healthy first-degree relatives (parents, siblings or children) of people with Crohn’s disease to see whether subtle immune changes could predict who might later develop the condition. Blood samples were collected years before diagnosis and analyzed for antibodies — immune proteins that signal how the body is reacting to certain bacteria in the gut.

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

In total, 381 relatives were included in the analysis, of whom 77 eventually developed the disease. Among this group, more than one-third (28 people) had elevated antibody responses, which were strongest in siblings. Croitoru’s previous work also highlighted the role of shared environmental exposure.

The team found that some people who later developed Crohn’s disease already had higher levels of specific antibodies in their blood, even while they were still healthy. These antibodies were directed against flagellins, proteins found on certain gut bacteria, particularly bacteria from the Lachnospiraceae family, including Roseburia species, which are normally part of a healthy gut microbiome. Importantly, the antibody responses weren’t random: Many targeted the same shared region, or “epitope,” of these bacterial proteins.

These immune signals were also linked to early signs of gut changes, such as increased intestinal permeability (“leaky gut”) and inflammation markers found in stool tests. Even after accounting for these markers, antibody responses to a specific conserved flagellin peptide remained strongly associated with future Crohn’s disease risk. This suggests the immune system may begin reacting abnormally to gut bacteria well before Crohn’s disease becomes clinically apparent.

Despite advances in biologic therapies, current treatments often fall short of fully controlling the disease, highlighting the need for new strategies. The findings come from the international Genetic, Environmental and Microbial (GEM) Project, which has followed thousands of healthy relatives of people with Crohn’s disease since 2008, giving researchers a rare window into how abnormal immune responses to otherwise helpful gut bacteria may emerge well before disease onset.

While this research does not yet change clinical care, it opens the door to earlier identification, monitoring and possibly prevention strategies, long before symptoms start.

“Confirming our previous study, immune response against bacterial flagellins show strong associations with future risk of Crohn’s in healthy first-degree relatives,” said study investigator Sun-Ho Lee, M.D., a clinician scientist and staff gastroenterologist at Mount Sinai Hospital. “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.”