It was a discovery that startled Mount Sinai researcher Jean-Frederic Colombel, MD. He and his colleagues were looking at the level of antibodies against microbes and more than 1,000 proteins in sera stored in the U.S. Department of Defense Serum Repository from hundreds of patients with Crohn’s disease and ulcerative colitis, as well as healthy individuals. They identified 51 protein biomarkers, including C-reactive protein and complement C5, which combined with serum antibodies were predictive of a Crohn’s disease diagnosis within five years with high accuracy.
“For the first time, we have evidence that there is an activation of the gut immune system illustrated by high levels of antibodies against microbes years before patients experience their first symptom of Crohn’s disease,” says Dr. Colombel, Professor of Medicine (Gastroenterology) at the Icahn School of Medicine at Mount Sinai and Co-Director of Mount Sinai’s Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center. “Although these results suggest we can use these biomarkers to predict the disease with relatively high accuracy, the predictive value is still not strong enough and thus further research is required to achieve better sensitivity and specificity.”
That study, PREDICTS (Proteomic Evaluation and Discovery in an IBD Cohort of Tri-service Subjects), with Dr. Colombel as senior author, is one of four by Mount Sinai researchers that have identified biomarkers and environmental factors that may be implicated in the development and progression of inflammatory bowel disease (IBD). Published on March 9, 2020, in Gastroenterology, each study provides a unique lens on the impact of these factors among different IBD patient populations. Together, they offer potential pathways for early prognosis and therapeutic interventions that could enable prevention of the disease.
Deep Remission at 1 Year Prevents Progression of Early Crohn’s Disease
In this study, Mount Sinai researchers assessed the impact of achieving deep remission—both clinical and endoscopic—among patients with Crohn’s disease using follow-up data collected from 122 participants in CALM (The Effect of Tight Control Management on CD). Half of the participants had been assigned to a tight control group and the other half were assigned to a clinical management group. Researchers observed that naïve patients with moderate to severe Crohn’s disease who achieved deep remission at one year had an 81 percent decrease in risk for adverse outcomes over a median of three years.
“Even more striking, we found that patients who achieved deep remission had greater protection against complications, says lead author Ryan Ungaro, MD, MS, Assistant Professor of Medicine (Gastroenterology) at the Icahn School of Medicine. “These data demonstrate that by achieving early remission among Crohn’s disease patients we can significantly decrease the risk of long-term complications and modify the disease course.”
Association Between Early-life Exposures and Inflammatory Bowel Diseases, Based on Analyses of Deciduous Teeth
Enabled by a Portuguese cultural tradition of preserving baby teeth, Mount Sinai researchers and colleagues in Portugal conducted the first-ever study exploring the association between early exposure to metals and risk of developing IBD. Similar to tree rings, baby teeth retain information related to environmental exposures that occur from development in the womb to the time they are shed. Using a technique developed by Manish Arora, PhD, Professor of Environmental Medicine and Public Health, and Dentistry, at the Icahn School of Medicine, teeth from 12 patients with IBD and 16 healthy controls were dissected and then mapped using lasers to detect the presence of four metals—chromium, copper, lead, and zinc. Researchers observed an accumulation of lead and chromium in the teeth of patients who developed Crohn’s disease but not among the controls. The study’s lead author was Nilendra Nair, formerly a Mount Sinai research coordinator.
“We know that when you expose mice with colitis to lead, it tends to worsen the disease,” Dr. Colombel says. “This is the first time we have been able to show an association between lead exposure and IBD in humans, but this is a preliminary study, so it needs confirmation. We are in the process of collecting more teeth so we can explore this association further.”
Inflammatory Bowel Disease Clusters Within Affected Sibships in Ashkenazi Jewish Multiplex Families
IBD is about four times as prevalent among Ashkenazi Jews as in the general population. Seeking to determine the impact of environment on disease distribution, Mount Sinai researchers are following 100 multiplex families (i.e., multiple members who have the same disease) who have three or more first-degree family members with IBD. Thirty-eight of these families have multiple affected siblings, and researchers observed that the disease was more likely to be sequentially distributed within sibling groups, or in other words, clustered among siblings.
“For example, if you have a family with five children and two of them have IBD, that means that if one of the two is the third child, then the other is most likely to be the second- or fourth-born,” notes lead author Elizabeth A. Spencer, MD, Assistant Professor of Pediatrics (Pediatric Gastroenterology) at the Icahn School of Medicine and Mount Sinai Kravis Children’s Hospital. “This speaks to the shared environment between these two siblings who are closer in age, and our study is continuing to examine what exposures these siblings share to shed light on this phenomenon and possibly achieve disease prevention if we can alter exposure triggers.”
Although further study is required on all four fronts, Dr. Colombel is optimistic that these findings will help usher in a new era in assessment and treatment of IBD, one that moves away from focusing on what happens after onset to intervening in the preclinical phase. “If we can further expand on the evidence we have that there is something going on years before the first symptoms manifest, we can find a predictive tool that is sensitive and specific enough to enable prevention, and that would effectively be the cure of IBD,” he says.
Ryan Ungaro, MD
Assistant Professor of Medicine (Gastroenterology)
Jean-Frederic Colombel, MD
Professor of Medicine (Gastroenterology)