Nature vs. Nurture Microbiome Edition
The CCC-GEM Project explores how genetics and environment affect the gut microbiome — and the development of IBD
By Marcia Kaye
Could our microbiomes be the key to our health? These mysterious communities of microbes that live on and within each of us are a hot topic of research today. Scientists are working to understand the links between our microbiomes and a vast range of illnesses and conditions, from anxiety and asthma to heart disease and obesity.
While these microorganisms reside both on and in our bodies, a major focus of research at Sinai Health System is the gut microbiome and how it relates to inflammatory bowel disease, or IBD. IBD, which includes Crohn’s disease and ulcerative colitis, causes inflammation of the lining of the gastrointestinal tract, which can lead to debilitating pain, fatigue and malnourishment. There is treatment but no cure.
The cause of IBD is unknown, although it tends to run in families. But why do some people develop IBD while others from the same family don’t? Could it have something to do with their microbiomes? That’s what Dr. Ken Croitoru aims to find out.
Dr. Croitoru, a gastroenterologist at Mount Sinai Hospital and scientist at the Lunenfeld-Tanenbaum Research Institute, both part of Sinai Health System, is the project leader on a major global study called the Crohn’s Colitis Canada GEM Project (CCC-GEM Project), which stands for Genetic, Environmental, Microbial determinants of Crohn’s disease. The CCC-GEM Project, funded in part by Crohn’s Colitis Canada, The Leona M. and Harry B. Helmsley Charitable Trust and the Canadian Institutes of Health Research, began in 2008. It has since recruited 5,000 people who were healthy but at risk of developing Crohn’s because they have a parent or sibling with the disease. So far 70 have developed Crohn’s. “The idea is that if you study those individuals before and after they get Crohn’s disease, and you compare their microbiome makeup to someone who does not go on to develop the disease, you’re then in a position to identify what might be the trigger or cause.” The Sinai-led study includes participants in more than 100 sites in Canada, the United States, Israel, the United Kingdom, Australia, New Zealand and Sweden.
And what have the researchers found? “We’re just beginning to peek under the hood,” says Dr. Croitoru. “We already have data that show there is a barrier dysfunction, a leaky gut, that exists before disease starts. And we’ve identified a few individual bacteria that seem to be quite different in people who go on to develop disease compared to people who don’t.” The researchers hope to learn how these important signals relate to the participants’ environmental exposures: their upbringing, diet and lifestyle.
Identifying microbes in stool samples has become easier than ever due to major advances in technological expertise. When the study began 10 years ago, analysis involved putting a sample onto a gel and painstakingly examining bands of DNA fragments to identify a microorganism. But with today’s technology, state-of-the-art sequencers can produce a detailed compositional analysis quickly and cheaply. “It used to cost thousands of dollars to do DNA sequencing, but now we can do it for $70,” says Dr. Croitoru.
The insights gleaned from the CCC-GEM Project are especially relevant in Canada, which has one of the highest rates of IBD in the world. It’s curious that while South Asians who immigrate to Canada continue to have low rates of the disease, their Canadian-born offspring tend to develop the same high rates as other Canadian-born people. “It’s hard to imagine that genetics change in one generation,” Dr. Croitoru says. “It’s got to be something in the environment.” Another study, nicknamed GEMINI, will investigate this phenomenon. The GEMINI study, co-led by Dr. Jen Gommerman, an immunologist at the University of Toronto, and Dr. Croitoru, is currently recruiting healthy first- and second-generation South Asians to compare and contrast their microbiome makeup and study their immune response to their microbiomes.
Understanding the microbiome will improve the ability to treat IBD, says Dr. Croitoru. “It’s conceivable that you could be on a microbiome pill long-term, either to prevent disease or to treat it.” He adds, “I hope we’ll have the funding to continue exploring this very precious goldmine of people who have volunteered for our study because they have a lot to teach us.”
"It’s almost like a fingerprint"
Gastroenterologist Dr. Ken Croitoru answers our most pressing questions about the mysterious microbiome
What is the microbiome?
It’s a term that refers to a very complicated community of microbes that live within our guts or on our skin. Humans depend on these communities for a lot of normal health and physiology.
What kinds of microbes does each person have, and how many?
More than a trillion individual organisms. The focus has been mostly on bacteria, but that’s not to say that viruses and fungi and other microbes are not important. It’s just that our technology in analyzing those is a little less advanced.
How unique is each person’s microbiome?
It’s almost like a fingerprint. There’s probably a core of microbes that you find in everybody, and then there are very subtle differences when compared among individuals.
What diseases are associated with the microbiome?
The strongest links are with metabolic diseases like obesity, diabetes and inflammatory bowel disease, including Crohn’s and ulcerative colitis, which is what we focus on at Sinai Health. There are also links with colon cancer and gut infections like C. difficile. But there are data coming out on heart disease, depression, psychiatric disease, some types of arthritis. People are even looking at eczema, asthma and Alzheimer’s disease, but those are more conjecture right now.
What factors determine each individual’s microbiome?
We think it’s a combination of genetics and environment. The environmental factors may include the air you breathe, the water you drink, the food you eat, the pets you have, the people you live with and the medications you take, especially antibiotics.
Does where you were born make a difference?
Probably, and also how you were born. A vaginal delivery allows you to be inoculated with your mother’s microbiome, and we think that sets the stage for what your microbiome is going to look like. There are studies going on now where obstetricians take vaginal swabs from the new mother and sort of swab the baby after a Caesarean section to see if that makes a difference to their future disease risk.
What should we be eating to keep our microbiome healthy?
Well, that’s the thing — we’re still trying to define what a normal or healthy microbiome looks like. If you take someone who’s a carnivore and put them on a vegetarian diet, you can see major shifts. The question is, is it a shift toward a healthier microbiome? And that we’re not sure of. There are huge differences in the microbiomes of people with disease and people who are healthy, but it’s a chicken-and-egg story. Does the microbiome contribute to disease or just react to disease? We don’t know yet.
Should we be taking probiotics, either in food like yogurt or in supplements?
Very few studies show a true benefit of probiotics supplements. One study showed a benefit of one type of probiotic for irritable bowel syndrome, but that’s a very difficult problem to define. Another study showed that a different type of probiotic worked in a very specific circumstance in patients with inflammatory bowel disease, but those results haven’t been reproduced.
What about prebiotics?
Prebiotics are food substances that are thought to help certain bacteria grow. At the end of the day, it’s not clear whether prebiotics are of any greater benefit than probiotics. What I tell my patients is if you take it and you think it makes you feel better, then fine. There have been no serious side effects other than the fact that it’s costing them money.
Illustration by Jeannie Phan, Portrait by Eden Biggin
Make a gift to support life-changing research at Sinai Health System.