Emma Allen-Vercoe touts her motto as “My microbes told me to do it”. The phrase captures the essence of her work as a professor in the University of Guelph’s Department of Molecular and Cellular Biology, where she has spent more than a decade exploring the daunting biochemical frontier that makes up the human gut. This all too familiar part of our anatomy — which most of us would prefer to think of as a simple black box that turns food into feces — harbours an anaerobic environment known as the microbiome.
“It’s an incredibly complicated ecosystem with many moving parts,” she explains. “I wouldn’t even suggest that we have made huge inroads into this, because there’s an awful lot to learn.”
What we do know is that the microbiome that each of us carries around in the lower part of our digestive tract is home to a vast array of microbes, estimated to make up just over half of all the cells in our bodies. In other words, more than half of the cells that you think of as “you” are in fact independent agents and not at all human in origin. This discovery has placed the concept of health in an entirely new perspective and opened up exciting research possibilities for Allen-Vercoe and her colleagues.
“We’re not really human — we’re super organisms,” she says. “If we only look at disease from a human angle, we’re missing half of what’s there.”
We would also be overlooking the capabilities of organisms that have an evolutionary history several orders of magnitude greater than humanity’s. Allen-Vercoe suggests that it is no accident that we harbour ancient bacteria that have been alive on earth far longer than us. Over that time they have developed biochemical capabilities that put to shame anything our bodies can do on their own. The physiological commands generated by these bacteria could well turn out to be the underlying framework that determines how well each of us survives and thrives during the course of our lives. But first we have to stop thinking of the gut as a nasty sewer and instead begin to admire it as an on-board repository of billions of years’ worth of genetic information.
“There are about 100 times more genes in the microbiome than there are human genes,” she points out. “That’s where the future of medicine really is. We need to start paying attention to what our microbes are doing and stop thinking of them as things that need to be destroyed.”
Gearing up for the gut
In biochemical terms, “paying attention” to the microbiome means piecing apart the myriad reactions taking place there. Allen-Vercoe’s earliest efforts consisted of stir tanks maintaining an anaerobic atmosphere, with a set of pH probes that could make adjustments as conditions warranted. Samples of human feces were inserted into this setting and specific reactions of interest were teased out.
This arrangement became much more sophisticated after she began dealing with the Swiss-based instrument maker Infors, which offers a bench-top bioreactor that enabled her to reduce the physical footprint of the hardware and allow researchers to focus on specific microbes. She recalls the horror of company reps when she outlined her plans for the equipment, which included a dedicated toilet down the hall where volunteers would offer up stool samples that would be promptly walked to the apparatus and inserted before any oxygen-based reactions could interfere.
The system, dubbed “robo-gut”, has become her laboratory’s workhorse. By the time it had processed around 100 distinct sets of feces, Allen-Vercoe’s team had begun to sort out many of the key bacterial players that feature in everyone’s microbiome, as opposed to the “tourist” bacteria that are just passing through (depending on what you might have had for lunch that day).
“The robot-gut worked out to be a really good selector for the things that actually have a role in the ecosystem and interact with each other,” she says. “It’s not perfect — I’m sure there are some things we have left to discover and everyone has a different microbiome. But we’ve really excelled in the area of defined experimental ecosystems, and over the years we’ve gotten better and better at it.”
Just how good they were getting became evident several years ago when a colleague asked them to look for genetic markers associated with Type 1 diabetes in tissue samples from infants diagnosed with this condition. Although the samples were 20 years old, the robo-gut successfully replicated the environment in which these genes would have thrived, so that the microbes containing these genes could be grown in volumes sufficient for comprehensive study.
Beyond bacteria
While most observers of the robot-gut’s progress are initially struck by the use of feces as a medium of choice, Allen-Vercoe has refined her approach to the task of sorting through the cornucopia of genetic detail it yields. This approach has carried her into the even newer field of the microbiome’s metabolomics, the study of metabolites that are responsible for interactions with the body, which will be the most likely source of insights that can be transformed into therapeutic innovations.
“Working with microbes is obviously a lot harder than working with metabolites,” she says. Unfortunately, little is known about the precise function of these metabolites, so a great deal of work still revolves around bacteria.
Among the most publicly prominent aspects of microbiome-based medicine has been a flurry of work on fecal transplants — the often controversial process of transferring gut samples from healthy individuals into those suffering from particular conditions, such as Crohn’s disease or infection by the notorious c. difficile bacterium. Evidence from these procedures has produced tantalizing hints that altering patients’ microbiomes could utterly eliminate their systemic health problems, but Allen-Vercoe insists that it is just too early to draw any confident conclusions.
“We know that the microbiomes in many diseases are somehow different from the microbiomes of healthy people,” she maintains. “But we don’t even know what health is.”
She also reiterates the observation that a fecal sample is rich with bacterial content, along with the metabolites that might be related to elusive disorders such as Crohn’s. “If you’re putting in a live microbial therapeutic, you’re putting in the factory that makes the metabolites,” she observes, adding that this only makes a thorough assessment of the treatment all the more complicated.
Microbiomes and modernity
For her part, Allen-Vercoe is eager to continuing mapping the microbiome. This summer she was named to the Canada Research Chair in Human Gut Microbiome and Host Interactions, which will provide her with funding to take part in an international effort to collect microbiome samples from the few remaining members of the human race who have not embraced a diet based on cultivate agricultural products.
“If you look at the small pockets of hunter-gatherer peoples around the world, like in Africa or South America, you’ll see microbes that are present in their gut that are never present in the Western gut,” she notes. “The fact that they’re there, and that these populations are so distant from each other, suggests that these are ancestral microbes that we as a Western population have lost.”
She admits that there is no way to predict the value — if any — those microbes might bring to ailments that afflict modern human beings. If nothing else, however, this global survey will serve as a useful baseline for trying to understand the intimate relationship between our contemporary lifestyle and the microbiome we have inherited.
In the meantime, the robo-gut is being put to work in other contexts that are expected to yield specific medical applications. This technology is the backbone of NuBiyota, a small private enterprise established by Allen-Vercoe, which operates alongside her laboratory and just this spring struck a formal collaboration with the major Japanese drug maker Takeda Pharmaceuticals.
“Instead of using fecal transplants, the premise of NuBiyota is to create defined microbial ecosystems therapeutics,” she says, referring to the identification of specific bacteria and metabolites that could introduce desired changes in a patient’s microbiome.
It could take some time to track down such products, but the robo-gut’s entry into another medical research venture could move much more quickly. Thanks to earlier work that Allen-Vercoe had done on an obscure species of bacteria called Fusobacterium, over the past few years she has been swept into the scientific community’s growing excitement around links between this microbe and colorectal tumours. Her longstanding knowledge of this bacterium, along with her laboratory’s ability to replicate its habitat, recently won her a place in Cancer Research UK’s $25 million initiative, called OPTIMISTICC (Opportunity to Investigate the Microbiome’s Impact on Science and Treatment in Colorectal Cancer).
That acronym reflects her own attitude to the work, which will not only help characterize the role of Fusobacterium in cancer but could help to recruit other bacteria that can seek out and eliminate it from the microbiome — which might perhaps remove a primary cause of the disease. That outcome would represent a satisfying culmination of her lifelong commitment to a field that was long regarded as just too unpleasant to be promising.
“My mentors asked me why I would work on microbes that you couldn’t even grow,” she recalls. “Now I’m in a unique position where I can watch my research being translated into medicine.”