Studying first- and second-generation immigrants living in Canada may be the key to identifying the underlying mechanisms of inflammatory bowel diseases (IBD), a cluster of digestive diseases (also known as Crohn’s disease and ulcerative colitis) that are prevalent in Canada, where the rate of incidence is among the highest in the world.
Scientific understanding of the genetic factors involved in IBD has skyrocketed in the past 15 years, with more than 190 disease-relevant genes identified, up from just one in 2001. But these discoveries have revealed that genetic factors don’t tell the whole story about how IBD develops.
Dr. Ken Croitoru and Dr. Mark Silverberg, both leaders in the field of IBD research and clinician-scientists belonging to Mount Sinai’s Zane Cohen Centre for Digestive Diseases (ZCC) and senior investigators at the LTRI, are now also looking closely at the environment and microbiome (bacteria) of the gut to try to detect the triggers that cause disease to develop in a person with a genetic predisposition.
“Genetics and family history are important risk factors but alone they’re not enough to explain the incidence of IBD,” says Dr. Croitoru. “So what activates the immune system to produce inflammation and cause disease? Is it the food we eat, the air we breathe, the water we drink?”
Human models of IBD
In a new study, nicknamed GEMINI, Dr. Croitoru, along with co-investigator Dr. Jen Gommerman in the Department of Immunology at the University of Toronto and colleagues, is examining why first-generation South Asian immigrants who have immigrated to Canada have low risk of developing IBD, while their Canadian-born offspring are prone to the disease at rates similar to the rest of the Canadian population.
According to Dr. Croitoru, genetics are likely not the culprit here; genes don’t change dramatically in one generation, and most South Asians and their Canadian-born children lack the genes that have been identified previously as risk factors for disease.
“We know that IBD is more common in certain populations, particularly Caucasians of European ancestry,” adds Dr. Silverberg, who holds the Gale and Graham Wright Research Chair in Digestive Diseases. “But what we can observe in a multicultural city like Toronto is that many immigrants are coming from countries where IBD isn’t very common and are developing IBD at similar rates once they are here.”
Launched in 2015, GEMINI — what Dr. Silverberg terms a “human model of disease” study — leverages the ZCC’s vast IBD patient cohort, which is the largest in Canada. It also makes use of the infrastructure put in place to support the GEM project, an international study established at Mount Sinai in 2008 to study genetic, environmental and microbial factors that impact healthy relatives of Crohn’s disease patients to understand what triggers the disease. Like the GEM project, GEMINI will enable researchers to record and interpret data about the immune system, gut bacteria and genetics of participants in order to identify factors that contribute to triggering disease. And GEMINI goes a step further: By focusing on this narrow demographic, Dr. Croitoru and his colleagues may be able to pinpoint environmental and microbial conditions unique to Canada that elevate disease risk, and also to examine the likelihood that the most compelling environmental triggers for disease occur in early life.
The GEMINI team also plans to investigate the incidence of multiple sclerosis and type 1 diabetes, diseases in which an abnormal immune response plays a role, and which have a similarly lower incidence in South Asian countries. Dr. Croitoru hypothesizes that these diseases will also increase in incidence in Canadian-born children of South Asian descent, suggesting that environmental exposures and/or the microbiome may play key roles in these diseases as well.
The study is currently enrolling participants who are either immigrants or Canadian-born children of immigrants, who will answer questionnaires and provide samples for laboratory analysis as a way to begin exploring differences related to where they were born. From here Dr. Croitoru’s group plans to expand the study, looking more broadly at the whole family of these participants and then focusing on families that have members who develop IBD.
“We want to keep this going long term because in the end that’s what it will really take to get to the bottom of what’s causing this disease and develop a strategy to cure the disease, not just control it,” he explains.
Preventing relapse
Dr. Silverberg is leading another, complementary “human model” of IBD study as part of a large international effort by multiple groups in North America. This study, funded by the U.S. National Institutes of Health, looks at the rate of recurrence of Crohn’s disease in patients who undergo surgery to remove sections of the intestine damaged by disease.
“We know that a high percentage of patients have recurrence of Crohn’s disease after surgery and this study provides an opportunity to gain insight about the factors that lead to inflammation developing again that could ultimately help doctors better protect post-operative patients from an IBD relapse,” Dr. Silverberg says.
As in GEMINI, the study gathers dietary and other personal information as well as biological samples from patients, in this case before undergoing surgery and afterward for a period of three to five years, when recurrence is most likely. Using this information, Drs. Silverberg and Croitoru will eventually be able to compare results from the two studies, maximizing the chances of making meaningful discoveries that will help find cures or preventions for IBD.
In the meantime, Dr. Silverberg says interim results from the post-operative study suggest that certain food groups may lead to a higher risk of recurrence. “Many patients with IBD believe that food and diet are strongly related to the disease,” he says, “and we’re starting to find evidence to support that as well.”