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“Robogut” helps Guelph microbiologist hunts for links between the digestive tract and disease
The framework of glass, steel and plastic tubing doesn’t look much like a human gut. Its soft clicks and grinding noises don’t sound like one either.
But there’s one thing this state-of-the art equipment and spotless laboratory cannot disguise: the unmistakable odour.
It’s the first clue to what microbiologist Emma Allen-Vercoe is brewing in her “RePoopulation Station” at the University of Guelph.
This is the home of the Robogut, a unique system of flasks, tubes and high-tech monitors that simulates the lower intestinal tract and, more importantly, cultivates the trillion microbes that inhabit it.
That means the smell is a small price to pay. As the Robogut mimics the human distal gut by taking in food components and breaking them down, it also produces waste full of microbes never before grown in a lab. The end result is in demand around the world, from Harvard University to researchers in the Netherlands and France.
“This is liquid gold,” says Allen-Vercoe, professor of molecular and cellular biology, pointing to a flask of amber fluid. “It allows us to culture a lot of microbes other people have not been able to culture.” That includes 30 novel bacterial species, in addition to an array of bugs that are difficult to isolate and reproduce.
Some of those bacteria have gone to the groundbreaking Human Microbiome Project, an initiative launched six years ago by the U.S. National Institutes of Health to map the genetic sequences of all the microbes that live inside — and on — the human body. Similar to the Human Genome Project, the Microbiome Project will create a benchmark for what’s normal. Allen-Vercoe is one of several Canadians on the team.
The field is still a little like “the wild west,” says Brett Finlay, professor in the Michael Smith Laboratories at the University of British Columbia and a driving force behind the Canadian microbiome initiative, which was launched in 2008 by the Canadian Institutes of Health Research and funds projects across the country.
Finlay says the last decade has seen a major shift away from thinking about the human body in isolation and towards thinking of each person as a “super-organism” that includes the countless microorganisms thriving inside and on the surface.
The Robogut is important because it grows the complex ecosystems of bacteria, viruses and other microorganisms — known collectively as the microbiota — that live in the human intestines. With that, rather than looking at species individually, scientists can study the way they interact in their environment.
Allen-Vercoe says understanding the “communities” of bugs in a healthy gut will help researchers uncover their role in everything from digestion and nutrient absorption to conditions such as inflammatory bowel disease.
It is also leading to new treatments that involve repopulating the intestinal tracts of unhealthy people with beneficial bacteria.
The Robogut has already played a key role in this, by creating a synthetic stool substitute for use in fecal transplants to cure patients with chronic clostridium difficile (c difficile), which causes severe diarrhea and inflammation.
Next week, a study on the synthetic stool, by Allen-Vercoe and Queen’s University medical professor Elaine Petrof, will be published.
Synthetic stool could boost safety and reduce the “ick factor” for fecal transplants, which involve placing small amounts of donor stool in a recipient’s colon, and have shown promising results in studies at McMaster University and in the U.S.
The ability to select and manipulate the bacterial mix to create this “purified” stool could eliminate the risk of disease transmission and improve the chances of transplant success, says Petrof, an infectious diseases specialist at Kingston General Hospital and gastrointestinal diseases researcher who has done these transplants.
“Without the Robogut, a lot of this would not be possible.”
Allen-Vercoe is among the Canadian scientists on the frontier of this exploding field of research into the human microbiome, which refers to the trillions of bacteria that colonize the human body starting at birth and form distinct ecosystems in the mouth, respiratory system, intestines, reproductive tract and on the skin.
UBC’s Finlay notes the importance of these bugs to how we think about health. “We’re Homo sapiens plus all the microbes that inhabit us and that collectively make us who we are,” says Finlay. “And that’s a very different way of thinking.”
One of his current projects involves tracking 3,000 children from birth to age 5 to look for possible correlations between asthma and the evolution of gut bacteria.
Scientists have spent a long time waging a war on germs, and with good reason. Bacteria spread deadly diseases ranging from diphtheria to dysentery and e-coli. But harmful disease-causing bacteria represent only a small fraction of the total. At the same time, researchers are beginning to understand how crucial friendly bacteria are to maintaining health.
Disease is no longer seen as the result of either genes, microbes or the environment, “but the intersection of all three,” says Allen-Vercoe.
She is among those who believe once the gut’s balance is interrupted — by environmental toxins transmitted through the food we ingest, the air we breathe or antibiotics that wipe out the beneficial bacteria — it can lead to a host of conditions.
Allen-Vercoe says tampering with the microbiota is like messing with a rainforest. Strip away one species and the entire ecosystem is thrown off, with potentially disastrous consequences.
“I don’t think people have any idea how important their guts are to their health,” she says.
“These microbes are in all of us but we flush them all away every morning and don’t really give them much thought.”
Researchers are using samples from her lab to try and shed light on how gut dysbiosis (bacterial imbalances) contributes to conditions such as inflammatory bowel disease, asthma, obesity, colorectal cancer and regressive autism.
Allen-Vercoe is among those who suspect that what goes on in the gut may also play a poorly understood role in mood disorders and brain development.
Growing recognition of the importance of the gut’s flora is also part of the reason for the popularity of probiotics, the live bacteria sold in pills or liquids, or added to foods such as yogurt, that promise to improve digestion and promote healthy microflora. But they are transient (they don’t remain in the gut after passing through) and their effectiveness depends on the dosage and type of bacteria.
The hope of scientists like Allen-Vercoe is they will one day make a pill that will replenish unhealthy intestinal tracts with a complete ecosystem of bacteria. In the long term, this may hold promise for treating diseases that appear to be linked to bacteria imbalances in the gut.
The technology to encapsulate live bacteria in a pill has already been developed by the probiotics industry, and Allen-Vercoe says early-stage efforts to convert the Robogut’s “repoopulate” mix into a pill by freeze-drying are promising. She has “no doubt” they will eventually be able to package these targeted “microbial ecosystem therapeutics” in an oral form.
Developing the Robogut, the backbone of such innovations, wasn’t easy, particularly because gut microbes perish when exposed to oxygen. So making an artificial gut required creating an aenorobic (airless) environment just like the colon.
The $300,000 system was set up in 2009. The process begins with the most rudimentary ingredient: a stool sample, typically donated by a student or faculty member who gets a $25 honorarium, but must deliver it to the lab within five minutes to ensure the microbes survive.
It goes straight into an anaerobic chamber, where one of the researchers reaches gloved hands through sealed sleeves and places the stool in a box, where it is paddled and spun into liquid, mixed with a helping of microbe “food.”
The sample is then transferred to one of the Robogut’s six glass beakers, which each hold about 400 millilitres, similar to a real gut. High-tech monitors ensure the soupy contents are kept at the correct temperature (37 degrees) and PH balance, and control the stir rate and feeding levels “so the microbes feel at home and happy,” says Allen-Vercoe.
Allen-Vercoe’s grad students check the Robogut daily and collect samples through needlelike probes that are stored in the minus-80-degree freezer.
Nitrogen bubbles through each beaker to keep the oxygen out, while incoming tubes deliver a steady trickle of chemical components that resemble digested food in the lower intestine.
Meanwhile, waste exits the outbound tubes at the same rate, dribbling into a bottle on the counter. This is the “liquid gold,” a mixture of microbes and their byproducts that is helping unravel the mysteries of how the microbiota contributes to health and disease.
The idea of studying what constitutes healthy microbiota was planted by a professor while Allen-Vercoe was working on her PhD in Britain in 1999.
“I thought, we’ve done it all backwards by looking at the pathogens before we really know what a healthy gut is.”
She soon moved to the faculty of medicine at the University of Calgary and came to Guelph in 2008, lured by its reputation in microbiology. A year later, the Robogut was beginning.
Allen-Vercoe acknowledges a strong stomach and a sense of humour are helpful in this business. Her email signature reads: “Support bacteria, they’re the only culture some people have.”
But she’s serious about her subject matter, even though many people would rather not think about it.
The average person is still grossed out by this important measure of health, she says. They’d rather give blood than consider donating a stool sample. Some would probably rather give a kidney.
“But once you get past the ick factor, it’s fascinating.”