An accurate but less-than-riveting title for Brett Finlay and Marie-Claire Arrieta’s bestselling book for parents published this past September could have been: Enhancing Environmental Biodiversity for Optimizing Pediatric Gut Microbiome Health. Instead, Dr. Finlay, a professor of microbiology at the University of British Columbia, and Dr. Arrieta, an assistant professor of physiology and pharmacology at the University of Calgary, wisely decided on the much snappier Let Them Eat Dirt: Saving Your Child from an Oversanitized World.
Publication of the book and associated media coverage from outlets as prestigious as the Wall Street Journal and the Guardian newspapers are indicators of the growing recognition of the importance of microbiological life in the human gut (the gut microbiome) and how it influences health – as well as the important role played by Canadian researchers and universities in this emerging field.
Once one gets over the “ick” factor of looking at the human digestive tract and all the microbes that call it home – and the messy approaches to treatment such as human fecal transplants – the subject area can be seen as a fascinating and important one.
The incidence of food allergies, asthma and obesity has increased significantly in the last couple of decades in Canada and much of the Western world. In addition, Canada has the highest incidence of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) in the world. Many are now looking at a symbiotic relationship between the gut microbiome and the immune system, mediated by factors such as an increased use of antibiotics, as being responsible for this concerning trend. More importantly, this research is pointing towards new potential preventive therapies involving the gut to help not just digestive diseases, but everything from diabetes to asthma and even autism and mental health issues.
While interest in the bacteria, viruses, protozoa and fungi that inhabit the human gut is of fairly recent vintage, Canadian researchers have been involved for more than a decade in mapping out what some are calling a new human organ. Investment in the area has escalated in recent years as millions of dollars are directed towards funding networks, research chairs and individual researchers – much of it coordinated through the Canadian Institutes of Health Research.
Why Drs. Finlay and Arrieta chose to write their book is explained in the introduction, where they note: “This was such a new field, there was no one source parents could turn to if they wanted to learn more. Even as scientists in the field, we were stunned to discover some of the profound roles … microscopic bugs have in normal childhood development. No doubt many of these findings, and many more to come, will have a profound impact on how we think about raising our children.”
Marc Ouellette is scientific director of the Institute of Infection and Immunity at CIHR and one of two directors (along with Philip Sherman of the Institute of Nutrition, Metabolism and Diabetes) overseeing gut microbiome research at the funding agency. “We have known for a very long time that there were a number of bacteria in our bodies, but we did not recognize the diversity until unique sequencing technology was available,” Dr. Ouellette says.
“Basically, the human is an incubator of bacteria,” he says. The large number of bacteria – mainly in the gut, but found throughout the body – play positive roles in helping digest food and other functions related to the immune system.
What has only become recognized more recently, he says, is that the microbiome is associated with the development of almost all diseases. In addition, says Dr. Ouellette, “there is also a clear link between the microbiome and some of what happens in your brain” through what’s called the enteric-brain, or gut-brain, axis.
He says research interest in Canada really started in about 2008, when a CIHR conference was held to focus on this emerging field. This was held in the context of the ongoing Canadian Microbiome Initiative created a year earlier to provide a framework for microbiome research and set research priorities.
Dr. Ouellette says early work focused on cataloguing the bacteria present in people with conditions such as IBD and asthma versus those in the healthy population – although it was also recognized that there are large variations in the type of bacteria within healthy individuals. “Now we’re more at a stage where we’re starting to try to change the microbiota … either by food intake or probiotics or other approaches, to have some effect on pathology.”
While early CIHR support in this area came through catalyst grants and a large $15.5-million grant to support research teams, Dr. Ouellette says more and more investigators are now being funded through open competitions. Through these open grants, he says, more than $6 million annually in Canada is going towards microbiome research.
The microbiome will continue to be a strategic focus for his institute until at least 2018, adds Dr. Ouellette. Moving forward, he says, prevention is a key priority for CIHR, and maintaining a healthy population of microbes in the gut is an important element of this.
One of the largest current collaborative research projects in Canada focusing on the gut microbiome involves 17 centres, 75 researchers and nearly $12.5 million in funding. The IMAGINE (Inflammation, Microbiome and Alimentation: Gastro-Intestinal and Neuropsychiatric Effects) network was launched in the spring of 2016 and is funded by CIHR under the Strategy for Patient-Oriented Research (SPOR) chronic disease program.
The network of researchers across Canada will study the gut bacteria and diet of IBD and IBS sufferers compared to those of healthy individuals. According to a synopsis on the network’s website, “We will use this information to develop changes in diet, probiotics, fecal transplants or antibiotics to improve IBD, IBS and mental health. With this network we can start to IMAGINE a cure for these diseases.”
“It is vital that we begin a process where we can integrate research from across the country into care,” says McMaster University’s Paul Moayyedi, who is co-lead for the IMAGINE network along with Bertus Eksteen from the University of Calgary. “IMAGINE will bring together patient advocates, provincial health authorities, academic health centres, charities, and others who are dedicated to accomplishing this.”
Dr. Moayyedi, who is also director of gastroenterology in the school of medicine at McMaster, says the network includes gastroenterologists, microbiologists, psychiatrists, epidemiologists and experts in patient engagement, even within each participating centre. “We are connected with a common goal of trying to tease out how the diet and microbiome interact to cause GI disease … and the associated psychiatric comorbidities that go along with those diseases.” He says this involves a number of randomized control trials as well as investigations involving a common cohort of patients.
“Let’s not minimize the task ahead of us,” Dr. Moayyedi says. “We’re looking for the organism or organisms that cause these diseases. It’s a huge undertaking given the thousands of organisms that exist, most of which we haven’t even characterized. A needle in a haystack doesn’t even cover it,” Dr. Moayyedi says. “I do believe a network approach like we are doing is the way to do this and I hope we make big strides over the next five years.”
One of the groundbreaking aspects of IMAGINE is that, as part of the SPOR program, it is involving patients in all phases of the research process. “Researchers and health-care workers in general have been far too paternalistic towards patients for too long,” says Dr. Moayyedi.
Canadian researchers are also involved in international collaborative efforts involving the gut microbiome. Some of Dr. Moayyedi’s colleagues at the Farncombe Family Digestive Health Research Institute at McMaster are recipients of two of six recent grants awarded by the European-based Joint Programming Initiative.
Elena Verdú is the principal Canadian investigator, along with partners in France and the Netherlands, who have been funded to explore the effect of diet and the microbiome on a protein, the aryl hydrocarbon receptor (AhR), recently shown to be crucial for maintaining balance in how the intestines function. Mike Surette and Jennifer Stearns are co-investigators on a grant led by McMaster colleague Eileen Hutton, with international partners, to look at the impact of introducing solid food and stopping breast-milk feeding on the gut microbiome of premature and term babies.
“I think we have some of the best investigators throughout the world working on the microbiome,” says Dr. Ouellette. “Our strategy [at CIHR] has been to create a strong research group and they are internationally competitive.”
Canada is also attracting researchers from overseas to participate in this area. Last summer, it was announced that Université Laval had been awarded a $10-million Canada Excellence Research Chair in the Microbiome-Endocannabinoidome Axis in Metabolic Health, to be held by Italian biomolecular chemist Vincenzo Di Marzo.
Unpalatable though it may seem, the poster child for successful treatment approaches focusing on the gut microbiome has been fecal transplantation. According to Dr. Ouellette, using fecal transplants to treat Clostridium difficile infection has been the most dramatic example of the type of transitional medicine now being attempted as a result of gut microbiome research.
By taking stool samples from healthy individuals and using them to treat patients infected with C. difficile, significant success has been shown in displacing this bacteria with healthy bacteria and eradicating the infection, which in some cases can be life-threatening. “This was the first big success,” says Dr. Ouellette. In their book, Drs. Finlay and Arietta declare: “The simple act of delivering fecal microbes either through a nasal tube to the gut or by enema, cures a potentially fatal disease.”
In Canada, fecal microbiota transplants have also been used with some success to treat ulcerative colitis and obesity. Dr. Moayyedi says preliminary small studies using fecal transplants to treat ulcerative colitis in Canada have induced remission in about 25 percent of patients – a success rate equivalent to that seen with expensive drugs that target specific parts of the immune system.
Herbert Gaisano and Johane Allard are part of the University of Toronto Fecal Microbioata Transplantation Outcomes Program, and they are involved in research to assess the role of the microbiome in obesity and the potential of fecal transplants to treat patients with obesity. Taking another approach, Emma Allen-Vercoe, an associate professor in microbiology at the University of Guelph, and her team are working to produce a defined multi-species probiotic – a synthetic stool treatment called “RePOOPulate” – to overcome the challenges of using regular fecal transplants, which might contain unknown pathogens from donors.
“The stars have aligned,” says Dr. Finlay in an interview, to make Let Them Eat Dirt a success. “If I’d written it five years ago, nobody would have read it and five years from now there will be 50 other books on the subject.” He says professional colleagues in this field have been very supportive and “love” the book. He points out that all of the information in the book is based on peer-reviewed, published data.
But for all the excitement and potential being generated as a result of gut microbiome research here and abroad, there is still a need to be cautious and moderate expectations. As Elisabeth Bik from the department of medicine at Stanford University recently wrote in an article in the Yale Journal of Biology and Medicine: “Disturbingly, the recent large amounts of microbiome articles by popular science media and general news outlets have generated feelings of exaggerated excitement among the public which has led to a belief that the microbiome is connected to all human organs and diseases,” she writes. “Many of these proposed connections are interesting hypotheses, some of which might turn out to be correct, but most of these hypes are not, or only poorly, founded by scientific findings.”
She adds: “Microbiome research has brought us better understanding but yet no clear cause or cure for complex gastrointestinal or other disorders such as IBD, autism, or multiple sclerosis.” However, in the conclusion to her article, Dr. Bik acknowledges the potential with microbiome research by stating, “the microbiome is an important and intricate part of our physiology which appears to be disturbed in a wide range of disease conditions (and) in some instances, microbiome studies have led to treatment options.”
For his part, Dr. Finlay, having spent more than a decade working in the area, says he is gratified that the scientific community is now starting to recognize the importance of the gut microbiome and its relevance to many fields of medicine. “The time is right,” he says.