The onset of inflammatory bowel disease (IBD) may occur long before patients become symptomatic, according to a recent study. Incipient immune signatures of future IBD, silently underway, may be detectable through broad serologic testing as far back as 10 years before diagnosis, offering new insights into the disease’s prodromal phase and a potential path toward earlier identification of high-risk patients.

“For practicing clinicians, the main message is that IBD should increasingly be viewed not as a disease that begins suddenly at diagnosis but as the endpoint of biological changes that may have been evolving for many years,” coauthors Arno Bourgonje, MD, PhD, Jean-Frederic Colombel, MD, and Saurabh Mehandru, MD, all associated with the Precision Immunology Institute and the Department of Medicine, Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York City, told Medscape Medical News in a joint e-mail.

“The antibody patterns we identified could contribute to identifying people at increased risk and perhaps even distinguishing those more likely to develop particular disease phenotypes,” they said.

The study was published online in Gut.

Clinically Silent Phase?

IBD is usually diagnosed only after symptoms and intestinal inflammation have developed, the authors said. However, research pioneered by Colombel’s group and the Canadian GEM cohort has “demonstrated that the biological processes leading up to IBD begin much earlier, during a clinically silent or minimally symptomatic prodromal phrase.”

Mehandru and colleagues found that a novel autoantibody, anti-avb6, can be detected before ulcerative colitis (UC) onset. Colombel’s group identified another autoantibody, anti-GMCF to precede clinical diagnosis of Crohn’s Disease (CD). “Here, we wanted to take a much broader, unbiased look at the immune system and study how antibody responses would evolve within the same individuals over many years.”

They noted that the PREDICTS study, which repeatedly collected serum samples from US military personnel prior to their development of IBD, “provided a unique opportunity to study this early phase of the disease.” Their central motivation, they said, “was to understand when immune dysregulation begins, what types of microbial or self-antigens are involved, and whether these early signals might eventually support earlier detection and risk stratification.”

To investigate the question, the researchers studied 2000 longitudinal serum samples from 500 individuals who participated in the US. Defense Medical Surveillance System, including 200 who later developed CD, 200 who later developed UC, and 100 matched healthy control individuals who remained free of IBD. Study groups were matched for age at diagnosis (mean, ~33 years) and were also matched for sex and race to “minimize known confounders affecting antibody repertoires.”

Using a technology called phage-display immunoprecipitation sequencing (PhIP-Seq), the researchers profiled antibody responses against approximately 357,000 microbial-, viral-, food-associated, and human peptides in the samples, which were collected and analyzed up to 10 years before IBD diagnosis and then shortly after diagnosis.

Window of Opportunity

Antibody repertoire variability was found to be increased up to approximately 4 years prior to IBD diagnosis. In patients who later developed CD, differential analyses found elevated herpesvirus-directed responses (particularly Epstein-Barr virus [EBV]) as well as anti-flagellin antibodies up to 10 years prediagnosis.

“Some of these responses were especially prominent in individuals who subsequently developed ileal or complicated CD,” the authors commented.

By contrast, the responses to encapsulated bacteria (eg, Streptococcus pneumoniae, Haemophilus, and Neisseria) progressively declined toward diagnosis.

In pre-UC, the researchers found “combined antimicrobial, antiviral and autoantibody signatures, including antibodies against the MAP kinase-activating death domain protein.”

Their large-scale serologic profiling of archived prediagnostic samples that identified disease-specific immune trajectories years before IBD onset provides “novel insights into disease pathogenesis in its prodromal phase,” they wrote in their paper.

They emphasized to Medscape Medical News that their study was “designed to identify immune trajectories,” so it couldn’t “unravel the underlying mechanisms.” Still, they offered some potential mechanistic suggestions.

The antibody patterns “may reflect a combination of altered exposure to microbes, changes in the intestinal barrier and microbiome, viral reactivation, and progressive dysregulation of immune tolerance,” they said. Thus, the increasing responses against bacterial flagellins preceding CD “may indicate that the immune system is becoming abnormally exposed or reactive to normally tolerated intestinal bacteria.” This could occur because of early impairment of the intestinal barrier or altered regulation of immune responses to the microbiome. The EBV findings “could reflect changes in viral control or reactivation.”

Molecular mimicry is another potential mechanism, they suggested. This refers to situations in which an immune response against a microbial or viral antigen cross-reacts with structurally similar human proteins. A loss of B-cell tolerance could further amplify such responses.

They cautioned that their data “do not demonstrate that EBV or any specific bacterium causes IBD” and that the “declining responses against encapsulated bacteria should likewise not be interpreted simply as reduced exposure.” These findings may indicate a “broader impairment or redistribution of humoral immune responses when inflammation and immune dysregulation gradually develop towards IBD.

The mechanistic hypotheses therefore “need to be tested experimentally and in other prospective cohorts.”

Furthermore, although IBD may one day be preventable with early flagging of these pathogenic mechanisms, “we’re not there yet,” they cautioned. “Our study supports the concept that there may be a substantial window of opportunity before clinical diagnosis, during which the biological processes leading up to IBD could theoretically be identified and perhaps modified.”

The first step “will be to validate these antibody signatures in independent and more diverse populations and combine them with other information, such as genetics, symptoms, microbiome composition, intestinal permeability, and inflammatory biomarkers.” Other steps would also be needed before these findings translate into actional preventive approaches in clinical settings.

A Better Roadmap

Commenting for Medscape Medical News, Supriya Rao, MD, managing partner, Integrated Gastroenterology Consultants, and clinical assistant professor, Tufts University School of Medicine, Boston, said the study “helps us confirm that IBD doesn’t begin when symptoms first appear.”

The research “helps us understand the early stages of IBD,” she continued. “By looking at those immune responses over time — vs one or two antibodies — we can uncover patterns we likely wouldn’t have seen otherwise. This gives us a better roadmap for studying the disease and treatment and even how Crohn’s and UC develop.”

Rao thinks that studies like this “move us closer to answers, course of treatment, and hopefully — one day—prevention.” A caveat is that “more studies would be needed to confirm these findings.” 

The study nevertheless has some take-home messages. Researchers should bear in mind that the “years before diagnosis deserve just as much attention as the disease itself.” Clinicians should be aware that “biologic change occur long before a patient walks into our room.”

This work was supported by NIH/NIDDK and an anonymous donor. Bourgonje reported being supported by the Dutch Science Foundation, the EU Horizon Health Consortium, and the Innovation Health Initiative Joint Undertaking. Colombel JFC co-coordinates the Innovation Health Initiative Joint Undertaking (IHI JU) grant INTERCEPT. Mehandru declared having no relevant financial relationships. The other authors’ disclosures are listed on the original paper. Rao declared having no relevant financial relationships. 

Batya Swift Yasgur, MA, LSW is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books.