Gut of the matter

Cynthia Morgan-Robson always prided herself on her independence. She raised four kids (her husband died of cancer 45 years ago), including a daughter with Down’s syndrome. She lived on her own in Port Hope, Ont., well into her senior years, and every Sunday night, she’d drop into daughter Linda Harness’s house for dinner. In 2009, following a string of hospital visits related to knee-replacement surgery, Morgan-Robson acquired a vicious Clostridium difficile ( C. diff ) infection. Laid low by crippling diarrhea, she could no longer care for herself. At times, she was incoherent. Vancomycin, a powerful antibiotic prescribed for C. diff , seemed to help, but as soon as she went off the drug, her symptoms returned.

Harness moved her mother, now 75, into a nursing home in early 2012. “Her cognition was completely gone,” says Harness, a nurse. “She couldn’t eat, couldn’t use the toilet, couldn’t walk.” A doctor at the nursing home referred her to infectious diseases specialist Dr. Elaine Petrof, who works with C. diff patients at the Kingston General Hospital. Petrof suggested a fecal transplant—transferring a donor’s stool, by colonoscopy or enema, into the patient’s colon.

Harness, who was tapped to supply her mother’s dose, was initially horrified. “Dr. Petrof said, ‘Go buy a Magic Bullet [blender]. You’re only going to use it once, and it’s not going to be for a drink,” she says. The idea of fecal transplant is that “good” bacteria from healthy stool move in and take up residence, crowding out “bad” bacteria such as C. diff . The donor (typically a patient’s family member) is screened for conditions that could disqualify her, including hidden disease or parasites. She’s instructed to produce a sample at home, put it on ice and take it to hospital for the procedure. “I almost broke into hysterics,” Harness continues. “Even as a nurse, I’d never heard of this.”

The Magic Bullet was spared. Instead of calling for Harness’s sample, Petrof recruited Morgan-Robson into a clinical study using synthetic feces—the first of its kind—produced with the help of the “robo-gut” at the University of Guelph, a bioreactor that approximates the human colon. “Elaine contacted me because she knew I could culture a lot of the bugs found in the human gut,” says Guelph microbiologist Emma Allen-Vercoe. They found a donor who’d rarely taken antibiotics and was thought to have a healthy, diverse communty of gut bacteria, then seeded the robo-gut with the donor’s fecal sample. The scientists chose 33 strains of bacteria they knew could be knocked out with antibiotics (so there would be an “antidote” if anything went wrong), and added them to a saline solution. The synthetic stool, called “Repoopulate,” is “way less gross” than the real thing, says Allen-Vercoe, who adds that it looks a bit like a vanilla milkshake.

Amazingly, it seems to have cured Morgan-Robson and the other C. diff patient who was treated as part of the study. Both received Repoopulate by colonoscopy at Kingston General in May 2012; since then, their symptoms have disappeared. Morgan-Robson, who remains in the nursing home, has returned to her former self. After the treatment, she was able to recognize Harness’s three daughters again. “We were amazed,” Harness says. “She’s back.”

Canada has become a hotbed for C. difficile infection, which can be fatal: Between 1997 and 2005, hospitals saw an almost fourfold increase in associated deaths, according to the Public Health Agency of Canada, partly due to the spread of a more dangerous strain of the bug. Those at risk aren’t just the elderly and hospital-bound. Increasingly, “community-acquired cases” are being reported among young and otherwise healthy people, Petrof says, such as women who’ve received antibiotics prior to Caesarean sections, or patients who get antibiotics from their family doctors for sinus infections. “I have Queen’s University students in my clinic,” says Petrof, who is also an associate professor there. “I see people in their twenties. I’ve been contacted about children [with C. diff ].”

Fecal transplant appears to be a powerful way to treat them, maybe even more effective than antibiotics. Emerging evidence suggests many of the illnesses that plague us today, including asthma, heart disease, diabetes, allergies and even autism, could be related to the billions of bacteria in, on, and around us—and the success of fecal transplant in combatting C. diff hints at potential fixes for a range of conditions.

In a study published in January in the New England Journal of Medicine, a Dutch team found that these transplants (using the real stuff, not synthetic) cured 15 of 16 people with recurring C. diff . Antibiotics cured three of 13, and four of 13, in two separate groups. Fecal transplant was “significantly more effective” than the use of vancomycin, the study concluded. “It’s a proof of principle that restoring a normal intestinal ecosystem can cure an important disease,” says Dr. Martin Blaser, an infectious diseases specialist at New York University’s Langone Medical Center, who was not involved in that study. “It suggests that if the microbial ecosystem is disturbed, and you can [fix] it, you could cure various diseases.” In other words, not just C. difficile.

The world of medicine is always looking for the next high-tech cure: stem cells, mind-controlled prosthetics, a brand-new wonder drug. Yet one of the most talked-about treatments today is extraordinarily primitive. Fecal transplant, which has been practised for centuries (taken through the mouth, it was called “yellow soup” in traditional Chinese medicine), gives scientists a window into the ecosystems of bacteria that inhabit our bodies: a vast, interconnected web called the human microbiome, which remains terra incognita —and our next medical frontier.

Judging from the hand sanitizers, antibacterial soaps and other germ-fighting products that have now become standard nearly everywhere, many people think of all bacteria as pathogens—invisible organisms that cause disease. In fact, even the healthiest among us carry far more bacterial cells than human ones: They outnumber us 10 to one. As Julian Davies, a reknowned microbiologist at the University of British Columbia (now emeritus) puts it, “We are only 10 per cent human and the rest of us is microbes.” That population of microbes is established early in life—starting with a baby’s voyage through the birth canal, when he’s doused in his mother’s bacteria—and remains as unique as a fingerprint. In the gut, microbes extract nutrients from food; they synthesize vitamins, fight off infection and reduce inflammation, to name just a few of their roles.

Our modern microbiomes are thought to look quite different than those of our ancestors. A 2012 study of 1,000-year-old human fecal samples (collected from three archaeological digs in the Americas) shows that ancient-human gut microbiomes looked more like those of non-human primates and rural, non-Western communities than the average Canadian or American, concluding that the last century has seen a seismic shift in our gut bacteria populations, at least in Western cities.

Scientists believe it’s no coincidence that, since the advent of antibiotics, conditions such as inflammatory bowel disease, Celiac disease, childhood asthma and allergies, heart disease, obesity and autism, to name a few, have been on the rise. And while no one doubts the importance of antibiotics in fighting infectious disease, we’re exposed to a lot of them these days. Kids receive 17 courses of antibiotics, on average, before their twentieth birthdays, according to Blaser, who notes that antibiotics are also fed at low levels to the farm animals we eat, to promote growth.

Antibiotics don’t just attack pathogens; they can take out beneficial bacteria, too. That’s why patients with C. diff tend to relapse once they stop taking vancomycin, a powerful antibiotic that wipes out good bugs and bad. Like seeds, C. difficile produces spores. To cause a full-blown infection, these spores must take root and germinate in the gut, which is much more easily accomplished when the microbial ecosystem is diminished—such as after a course of drugs like vancomycin. Allen-Vercoe compares the gut to a rainforest. “If it’s nice and healthy, with lots of different plants and animals, that ecosystem will be resistant to disease.” But if loggers clear-cut the trees, the ecosystem collapses, creating an opportunity for pathogens to take root.

Antibiotics aren’t the only culprit. In developed countries, more babies than ever are born by Caesarean section (in Canada, it’s about 25 per cent), and a recent study in theCanadian Medical Association Journal found that babies born by C-section lacked a type of gut bacteria found in those delivered vaginally, even if they were breastfed. Infants who received formula (and no breast milk) showed big differences in their gut bacteria, too. A baby’s gut microbiota composition is linked to his or her growth rate, noted a recent Norwegian study that examined fecal samples from 218 newborns.

Disorderly microbiomes are being linked to a range of conditions, including obesity. Dr. Jeffrey Gordon of the Washington University school of medicine has shown that obese people and thin people have different microbial populations in their guts. If fat people diet and become thin, their bacterial makeup changes. After transplanting the gut bacteria of an obese person into a germ-free mouse, that mouse becomes overweight; the same thing happens (in reverse) with bacteria from a malnourished subject, producing a malnourished mouse. One of Allen-Vercoe’s projects, with the B.C. Cancer Agency, looks at colorectal cancer. In certain patients, it seems that a bug normally found in the mouth lives instead in the gut, causing problems we don’t yet understand.

One of the biggest surprises has been a potential link between the microbiome and autism. “It’s a disease thought of as behavioural,” says Dr. Derrick MacFabe, director of the Kilee Patchell-Evans Autism Research Group at the University of Western Ontario in London, Ont. But it looks as though metabolic and immune changes could be at least partly responsible for the behaviours involved. MacFabe has found that certain gut bacteria associated with autism spectrum disorders (ASD) produce a waste product, called propionic acid, after eating the carbohydrates we consume, foods that many autistics crave. When lab rats were given this same substance, they started showing behavioural and brain changes seen in ASD, such as repetitive behaviour, decreased social interaction and seizures.

MacFabe is co-author of a recent study that screened 213 kids with ASD. It found that 17 per cent of them had blood metabolic markers predicted by the lab-rat model. At the same time, his team looked for genetic changes in these children, but none was found, suggesting environmental causes, possibly from the gut. He says long-term antibiotic use in mothers or their kids, which alters the microbiome, is “a potential risk factor for autism.” MacFabe believes a product such as Repoopulate could one day help certain autistic patients, although no trials have yet been done.

Allen-Vercoe is working with MacFabe to sample the gut microbes of autistic patients, She’s also studying fecal samples from autistic kids inside the robo-gut, which mimics the distal colon, the end point of our digestive tract and where the greatest diversity of bugs can be found. “We can add vancomycin,” she says, or alter what sort of diet goes into the robo-gut—limiting carbohydrates, casein or gluten, which some parents believe helps their kids’ symptoms—to see how the autism-associated bacteria respond. She’s also using the robo-gut to build microbial ecosystems such as those found in patients with Crohn’s disease or ulcerative colitis, where, as she puts it, the “ecosystem is really out of whack.” Working with McMaster University, she plans to transfer different ecosystems into germ-free mice, creating a model to study each disease.

Beyond these conditions, gut bacteria have even been implicated in heart disease. A recent study from a group led by Dr. Stanley Hazen of Cleveland Clinic’s Lerner Research Institute found that when bacteria in our digestive tracts metabolize a compound called carnitine (abundant in red meat), they make a byproduct called trimethylamine N-oxide, TMAO for short, which is linked to atherosclerosis. The more carnitine we consume, the more these bacteria thrive. Following 4,000 patients over three years, Hazen’s team found that higher blood levels of TMAO were associated with higher risk of death, as well as non-fatal heart attack or stroke.

“Microbes only know how to eat and replicate,” Hazen says. However, as their by-products are pumped through the bloodstream, influencing our bodies in various ways, “they are functioning as hormones,” he continues. “Our gut microbiome is really our largest endocrine organ.” But it’s a flexible one, he notes, because what it’s “fed” can influence over time what this microbiome becomes. “In our future, we will drug the microbiome,” Hazen predicts. “We will give it drugs to treat diseases, like cardiac disease or diabetes or obesity. We just have to work out what the language [the bacteria] are speaking—the chemical Braille.” Then it becomes a druggable target. “That’s our long-term future; it’s so much easier to take a pill. Nobody wants to do a fecal transplant to treat their diabetes.”

Repoopulate represents the future of medicine, one in which the patient’s own microbiome is manipulated to cure or prevent disease. Until we understand and master those techniques, our body’s crudest waste product—which teems with literally millions of bacteria, representing hundreds of different species, many of which are still barely known to science—is gaining recognition as a wonder drug, but one that’s still considered experimental. There’s a powerful “ick” factor associated with working with raw feces, even among doctors and nurses. The ones who do perform the procedure typically find themselves resorting to it when confronted with patients who might not have any other choice.

Dr. Elaine Petrof performed her first fecal transplant only four years ago. Her elderly patient “had an unrelated infection and then got C. diff . She was maxed out; I couldn’t put her on any more antibiotics.” Her desperate family kept coming to the hospital with a “pot of poop” and asking Petrof to try a fecal transplant. “I finally thought, ‘Why not? She’ll die otherwise,’ ” she says. Within three days, the patient dropped from 20 bowel movements to two. She was soon able to return home. Petrof says she performed several more fecal transplants before Health Canada tightened its restrictions in 2011.

Today, Health Canada considers the use of fecal transplant to be “investigational,” meaning it can only be conducted within a clinical trial. (Kingston General partnered with McMaster and continues to perform fecal transplants under the umbrella of a clinical trial.) In the U.S., the Food and Drug Administration (FDA) requires an “investigational new drug application” whenever fecal transplant is used. These are “incredibly burdensome, time-consuming and expensive for an independent practitioner to obtain,” Dr. Judy Stone, an infectious diseases specialist, recently wrote in Scientific American .

Some patients who can’t find a doctor to perform a fecal transplant will take the drastic step of doing it themselves. Jim Hughes, 59, was one of them. About four years ago, after taking antibiotics to fight a sinus infection, he contracted C. diff ; Hughes, who is five feet, eight inches tall, dropped from 160 to 145 lb. He took vancomycin for about a year, but whenever the doctor tried to taper his dose, “the symptoms came roaring back.” Three years ago, Hughes’s doctor put him in touch with Dr. Michael Silverman, an infectious diseases specialist and assistant professor at the University of Toronto, who published a paper describing DIY fecal transplants. “He said, ‘If you’re willing, here’s something,’ ” Hughes says. “I said, ‘Sign me up.’ ”

Hughes’s two daughters and daughter-in-law were screened as potential donors. (Silverman insists on this step before self-administering a fecal transplant, which he says is done with a home enema kit.) Hughes’s daughter-in-law ended up providing the sample. It took three attempts to complete the procedure, but eventually, it worked. Within a day or so, Hughes’s symptoms started to disappear. “Within a week, it was fine,” and he remains healthy today. Patients considering DIY transplants must talk to their doctors first, says Silverman, who believes that at-home transplants can “fill a gap” for patients when local health care providers won’t do it.

Dr. Colleen Kelly, a gastroenterologist with the Women’s Medicine Collaborative in Providence, R.I., cautions against DIY fecal transplants due to the risk of infection. Still, she’s frustrated more doctors won’t perform the procedure. “I was getting annoyed because [patients] were coming from really far away,” Kelly says. “One from North Carolina had to fly to Rhode Island with their donor. I had an 88-year-old drive down from New Hampshire.” She surveyed other doctors about why they weren’t doing fecal transplants and many told her it was because safety and efficacy data were lacking. As a result, she’s leading the first randomized controlled clinical trial of fecal transplant to treatC. diff in the U.S., with funding from the National Institutes of Health. One of several Canadian trials, at St. Joseph’s Healthcare Hamilton, is looking at whether frozen stool works as well as fresh, which could allow for anonymous donor banks. (It would also eliminate the problem of stage fright, when a donor can’t perform the morning of the procedure.)

Now that fecal transplant is increasingly accepted to treat C. diff , severe inflammatory bowel disease, including ulcerative colitis, is a candidate to come next, according to Dr. Ciaran Kelly, a professor of medicine at Harvard Medical School. As our understanding of the human microbiome continues to grow, one day maybe hospitals everywhere will have a bioreactor such as the robo-gut, churning out powerful “super-probiotics” to treat a range of diseases. For doctors and patients, it can’t come fast enough.

Maclean's July 15, 2013