It’s hard to think of a medical term that produces a more immediate cringe than the words “fecal transplant.” The concept of taking the feces from one person and injecting them into the colon of another has “That’s just wrong!” written, if not smeared, all over it. Unless, that is, you are a patient suffering from clostridium difficile, C. diff as it is commonly known, an infection of the gut resistant to all available antibiotics.
Then it might sound like “hope.”
The procedure has produced remarkable recovery rates upwards of 90 percent for patients who had no other choice and can now live as they did before with the donor’s intestinal “ecosystem” repopulating their intestinal track. With such results, the number of clinics offering fecal microbiota transplants, or FMTs, is growing quickly. “In the last couple of years, it’s gone from a couple of people in the world to almost every major hospital now doing it,” says Larry Smarr, a leading voice in the “quantified self” movement and founding director of the California Institute for Telecommunications & Information Technology (Calit2).
The FDA has given a kind of fast-track investigational drug status to the procedure, and a search at ClinicalTrials.gov produces 43 studies, most of them in process now. There is even—get ready to cringe again—a DIY at-home movement with YouTube videos and instructions, summed up by Canadian microbiologist and “robogut” inventor Emma Allen-Vercoe as—“Go to Walmart. Buy a blender and, you know ...”
C. diff to start
The next step, as many see it, is a process with less ick, more precision and less uncomfortably delivered formulas grown in a laboratory or refined from human stool. There may even be an opportunity for a probiotic company willing to invest in hard-to-know science and hard-to-grow microbes.
At this point, FMT is still far more scatological than pharmacological, but the science is solid. Antibiotics take an indiscriminate toll on the teeming trillions of bacteria working tirelessly in our gut, as good bugs and bad bugs fall prey to the chemical onslaught. Science is only beginning to understand the mind-boggling intricacy of the gut microbiome. We don’t know the ideal mix of bugs yet, but we do know that a functioning gut, like that of a fecal donor, has a better chance of thriving than the antibiotic-ravaged gut of a C. diff patient. Colleen Kelly, a gastroenterologist at Brown University, describes the toll of antibiotics on a C. diff patient as “like you’ve dropped a bomb on a rainforest.” It’s a non-functioning blank slate. The solid matter in stool being nearly a third bacteria, transplanted bugs can colonize and repopulate the ailing gut.
The process is effective. The long-term consequences cannot be known, but C. diff can be so severe that for many patients the benefits far outweigh the risks. “They are typically very sick people who have been on many rounds of antibiotics over months or years,” says Mark Davis, a naturopathic physician at the Good Life Medicine Center in Portland and a board member for the Fecal Transplant Foundation. These patients don’t take it lightly. The Centers for Disease Control and Prevention (CDC) estimates 14,000 people die every year of an infection that can lead to kidney failure, ruptured colon and perforated bowel. “They want to be cured before it gets to that severe state,” Davis says.
Risk v. reward
The unknown risks of fecal transplant could include colorectal cancer years later, but doctors note that many patients are old enough—the CDC estimates 90% of C. diff deaths are people older than 65—that cancer 20 years from now might seem a reasonable tradeoff. Allen-Vercoe calls that just one of a host of unknowable possibilities. In clinical studies, donors are carefully screened for diseases, but doctors don’t know what an optimum gut even looks like. “We don’t research health, really. Generally we research disease,” Allen-Vercoe says. “If you don’t know what healthy is, how on earth can you define what unhealthy is?” It’s hard to tell the good bugs from the bad when there are trillions of them in hundreds of species swimming through the human gut and interacting directly or indirectly with every system in the body. “How do you know we’ve got a good strain or a bad strain?”
Robert Orenstein, a doctor performing fecal transplants with the Mayo Clinic in Phoenix, is careful with his cautions for new patients. “I always explain in detail both the risks and the potential benefits of the process, and I inform them that this is investigational,” he says.
Indeed, the FDA has labeled feces in this instance an investigational drug, while some have argued that it is human tissue, a category that includes breast milk. Davis says that puts fecal transplant in a gray zone rare in medicine. “I think they could say, ‘Look, we can all agree that poop is not food,’” he says. But it’s also obviously variable in ingredients, potency and efficacy. “They call it a drug, but it will never be approved as a drug.” It’s bacterial, but it’s not a probiotic either. “It can’t be classed as a probiotic because it’s not a food.”
Right now, it’s just a procedure that works. Kelly calls the current FDA stance “a very fair, happy balance,” though she wonders why adding viable bacteria is more controversial than wiping out the flora with antibiotics. “Some of these antibiotics are really powerful. They are causing extinction in our guts. We worry about adding things when we’ve already messed it up.”
The process would never have become as common as it is without the explosion in C. diff cases. In one six-year period, 2001 to 2007, the number of cases quadrupled. The CDC designates C. diff as “urgent” in the growing constellation of antibiotic-resistant infections.
With such a high success ratio, and a ubiquitous supply of material, nobody should be surprised that a do-it-yourself movement would spring up. The in-the-privacy-of-your-own home would make it difficult to regulate, but fecal transplants outside a clinic can’t be regulated anyway. There is no law against it. Smarr explains the process simply—“You get a turkey baster and you add some stool from a donor and you inject it”—and describes the cautions equally so. What’s true for body fluids is likely true for body solids, he says. “If this were completely safe, then we wouldn’t have sexually transmitted disease,” he notes, adding, “As I tell people in my lectures, ‘Don’t try this at home.’”
Fecal for all
Davis is one of few practitioners who advocates at-home transplants, an opinion he claims is far from prevalent but “not completely radical.” He notes a 2010 paper on six C. diff patients cured by at-home procedures and describes his recommendations as something like a needle exchange program for heroin addicts. People are doing it anyway. They will do it more safely with good information. “Another doctor I talked to compared it to safe sex,” Davis says.
Other sources interviewed for this story were universally opposed to home fecal transplants. Part of the problem, they say, is use for diseases where there are no findings that the process provides a benefit. “I have had people call me who wanted me to do fecal on their kids who were autistic,” Kelly notes. Davis has also seen “crazy things.” “The most extreme things we have heard are people using animal stool for fecal transplant,” he says. Allen-Vercoe describes an “increasing trend to use fecal transplant to fix your microbiota for just about any disease you can think about.”
Without a studied target, fecal transplant carries risk without proven benefit. As Allen-Vercoe notes, an armchair gastroenterologist can’t safely, or even realistically, decide, “I’m just going to fix my dysbiotic gut with a fecal transplant.”
Only recently have amateurs been able to learn anything about their gut makeup. Jessica Richman’s company uBiome provides a genetic census of the gut. What customers do with that information is their own business, she says. Such people tend toward the proactive and informed and convene on message boards to discuss various strategies to optimize their gut. “We give them information to pursue their own theories,” she says, though she notes that those theories may hold little validity. “The average user is not going to go on Google Scholar and read 10 papers,” she says.
For the most part, she notes, the strategies are of little concern. The gut is fairly sturdy for most interventions. “I don’t worry about diet changes,” she says. What worries her more, are supplement companies concocting formulas designed, or at least marketed, to mimic the effects of a fecal transplant. Ineffective treatment could delay clinical intervention. “One real problem is that people who see a business opportunity and are going to sell stuff to desperately sick people,” she says.
NBJ found one company, Bioprosper Labs, offering what they hint to be an “alternative” to fecal transplant. “If you are considering a fecal transplant but are not too eager about it, there may be an alternative,” the marketing copy reads, followed by testimonials from purported C. diff sufferers who found relief with the Nexabiotic, a probiotic product formerly marketed as Benebiotics. Attempts to reach Bioprosper for this story were unsuccessful.
After reviewing the company site, Allen-Vercoe found the suggestive-but-not-stated-outright claims irresponsible and wrote: “All of these bugs are very simple to grow from my perspective, so that (and the FDA’s list of organisms that are GRAS) likely drove the development of their product, not clinical efficacy. Also, no indication of strains used—a big no-no in microbiology—makes it seem to this microbiologist that they don’t really know what they have.”
The challenges would be many for a probiotic company hoping to replicate the effect of a fecal transplant. Davis and Allen-Vercoe note that the common strains found in over-the-counter probiotics are aerobic, meaning they need oxygen, whereas the gut microflora are anaerobic and cannot live in oxygen environments. “Ninety-nine percent of the organisms in our colon are anaerobes,” says Davis, who also looked over Nexabiotic’s ingredients and claims. “This may or may not be a good probiotic, but it’s not comparable to a fecal transplant.”
Smarr describes the “50 billion CFUs” claims on probiotic labels as distracting. “If you are a probiotic, there are 100 trillion microbes waiting for you and their main job is to kill you because they don’t want you coming in to take their niche,” Smarr says. Allen-Vercoe doubts many probiotic companies possess “the expertise” to grow the anaerobic bacterias. “They are not particularly good at growing hard-to-grow microbes.”
There are several companies pursuing a drug-track alternative. Allen-Vercoe is involved in one of them, NuBiotia, based on findings from the RoboGut-brewed RePoopUlate. The NuBiota product will be classified a “biological drug,” she says, and subject to all the standard regulatory hurdles. Other companies include Seres Health, a Massachusetts company attempting to produce refined-from-feces capsules, and Rebiotix, researching an enema-administered “microbiota suspension” of tailored microbes grown in the lab.
The clinical track is expensive, of course. Rebiotix raised $25 million from investors in August. Orenstein wonders and worries if there will be probiotic knock-offs. “My guess is that those companies making probiotics would love to take the group of bacteria that are found to be important and make that into a probiotic pill and then market it,” he says. The over-the-counter result could be either ineffective or dangerous, but it would likely be “unregulated” in his opinion, and thus safety concerns arise. “I think there is a scientific conflict there,” he observes.
Allen-Vercoe says any bacterial cocktail would have to be specifically tailored to the patient and the condition. Every microbiome is different, she says. “You want to look at people’s gut microbe like you are looking at the engine of a car. You might end up replacing the engine of a Fiat with the engine of a Rolls Royce.”
Kelly doubts companies without a pharma product and payout in mind would commit the resources to develop such a product. “I think about the amount of R&D,” Kelly says. “I don’t think any probiotic company would want to put out the money.” The answer is going to come out of pharma-funded labs, she says, and she is looking forward to that option. “We might not be doing whole-stool fecal transplantation the old way for much longer.”
Orenstein is also convinced the era of the cringe will be over before long. “My view is this whole fecal transplant procedure is a bridge to something that will come later and will be safer and more effective,” he says. “I hope we get there soon.”