A little more than a year ago, I wrote a piece in Scientific American about fecal transplants – replacing the stool in someone's colon with stool donated by someone else – as a treatment for the pernicious, recurrent diarrhea caused by *Clostridium difficile * infection.

I have been a journalist for two decades, and some of my stories have won prizes, triggered hearings and legislation, and caused people to change their minds about significant social issues – but I don't think anything I have written has ever proved as sticky with an audience as that 1,500-word column. In the 60 or so weeks since it was published, I have heard from more than 100 people – yes, that's more than 1 per week – who are afflicted with C. diff, believe that a transplant could help them, but cannot find a doctor who agrees that the procedure has merit.

A paper published Wednesday evening in the New England Journal of Medicine may give those patients assistance, and change those doctors' minds. It represents the first report from a completed randomized trial of fecal transplants, and it finds that the treatment worked much better than the powerful antibiotics that are usually given for C. diff infection – so much better, in fact, that the trial was ended early, because the monitoring board supervising the trial's execution could not ethically justify withholding the transplants from more patients.

Here are the details: A group of Dutch and Finnish researchers enrolled patients with severe C. diff (defined as at least one relapse of infection after antibiotic treatment, plus at least three bouts of diarrhea per day or eight over two days) into three groups, who received either a fecal transplant, or one of two comparative treatments: either the standard course of vancomycin, a broad-spectrum, last-ditch antibiotic, for two weeks; or the same antibiotic course with bowel lavage (a high-volume enema that reaches deep into the colon and is used to clean things out before transplanting stool) added on the fourth or fifth day of taking the drugs. The fecal transplant was donor stool, screened for parasites and infectious organisms, diluted and strained, and given by a tube that snaked up through the nose and down through the stomach to the start of the intestine. (Edited to add: I should have said here that, while the nasogastric tube has been the preferred method in Europe, the US and Canadian attempts have all used either a classic colonoscopy/endoscopy set-up, or simply an enema kit.)

The investigators planned to enroll 120 patients, with the goal of judging them cured if they made it to 10 weeks from the beginning of any of the treatments without relapsing. In the end, they stopped the trial after 43 patients had been enrolled over 28 months – 17 for the transplants and 13 for either of the antibiotic-treatment arms – because the transplant patients were doing so much better.

Of 16 transplant patients (one was excluded for reasons unrelated to the trial), 13 were cured on their first infusion, and two more on a repeat round, making the transplant 94 percent effective. In the two drug arms, the rates were 31 percent in the vancomycin-only group (4 of 13) and 23 percent (3 of 13) in the group receiving vancomycin plus lavage.

There are two interesting footnotes to the trial experience. The first is that the investigators analyzed the bacterial content of the transplant patients' stool before and after they received the infusions. Beforehand, their bacterial flora were not diverse, and afterward, they were, indicating the transplants had recreated a healthy, diverse bacterial ecosystem in the patients' guts. The second is that the patients randomized to the drug-treatment arms apparently appreciated how well the patients in the transplant arm were doing: after relapsing, 15 of them subsequently went on to have what the paper calls "off-protocol" fecal transplants, and were cured of their C. diff as a result.

In science, everything always needs to be repeated, and every endorsement is always hedged – but really, I can't see how this can be considered anything but a rousing success. As an accompanying editorial says:

The study is an important confirmation of the efficacy of (fecal microbiota transplantation) for recurrent C. difficile infection... The results ... represent a clear precedent in which planned therapeutic manipulation of the human intestinal microbiota can lead to demonstrable, clinically important benefits, thereby bringing FMT to the mainstream of modern, evidence-based medical practice. (It) will encourage and facilitate the design of similar trials of intestinal microbiota therapy for other indications, such as inflammatory bowel disease, irritable bowel syndrome, prevention of colorectal carcinoma, and metabolic disorders, to name just a few.

It is important to say that this is not the first study to find a high rate of cure – almost always in excess of 90 percent – for fecal transplants, but it is probably the best-designed to be reported to date. (There is a list of some recent case series in my earlier post on this.) At least two other trials are now underway, in Canada and in the United States; that SciAm piece discusses the US one, which will be both randomized and also blinded. Already, leaders in gastroenterology have called on the specialty not only to make fecal transplants mainstream, but to make them the primary treatment for C. diff and other gut disorders – not the last resort after months of relapses, but the first thing they try.

There is huge demand for this procedure, illustrated not just by my anecdotal experience of hearing from readers, but also by asurvey of patients published in *Clinical Infectious Diseases *last September. Researchers at Dartmouth reported on 192 people who responded to a structured survey:

When provided efficacy data only, 162 respondents (85%) chose to receive FMT, and 29 (15%) chose antibiotics alone. When aware of the fecal nature of FMT, 16 respondents changed their choice from FMT to antibiotics alone, but there was no significant change in the total number choosing FMT (154 [81%]; P = .15). More respondents chose FMT if offered as a pill (90%; P = .002) or if their physician recommended it (94%; P < .001)... Most respondents preferred to receive FMT in the hospital (48%) or physician's office (39%); 77% were willing to pay out-of-pocket for FMT.

The main barrier to adoption, in most cases, seems to be physicians' own distrust of the procedure, or distaste for it. Lawrence Brandt, one of the pioneers of fecal transplant in the US, wrote in Clinical Infectious Diseaseslast year:

Patients with (C. diff infection) and their accompanying family and friends who come to see me were highly knowledgeable and not “turned off” by the fecal nature of the fecal reconstitute; rather they were “turned on” by the possibility—indeed the likelihood—of cure. For many the major stumbling block has been the intransient negativism of their physicians, who told them, uninfluenced by any of the positive reported data, that FMT was “quackery,” “a joke,” “snake oil,” or other pithy labels that were discouraging but served only to delay, not dissuade, these perseverant individuals.

A piece of research published just last week addresses that yuck factor. Two patients at Kingston General Hospital in Ontario who had refractory C. diff diarrhea were cured following the administration, not of feces, but of a feces substitute compounded from saline solution and fecal bacteria that were harvested from one donor and cultured. Both women recovered, and the microbial diversity of their colons repopulated as well. The authors called the study a "proof of principle":

A synthetic stool substitute approach has multiple advantages: the exact composition of bacteria administered is known and can be controlled; the bacterial species composition can be reproduced, should a future treatment be necessary; preparations of pure culture are more stable than stool, which some groups recommend should be collected fresh and instilled into the recipient within 6 hours of collection; an absence of viruses and other pathogens in the administered mixture can be ensured, thereby improving patient safety; and the administered organisms can be selected based on their sensitivity to antimicrobials, allowing an enhanced safety profile.

All true; and the existence of a "synthetic stool substitute" could entice more gastroenterologists who now distrust fecal transplants into being willing to perform them. (Though, if you think about it, isn't gastroenterologists being turned off by feces somewhat odd?) And yet: We already know that fecal transplant works, using a substance that is ubiquitous, abundant, and effectively free. Because of those characteristics, feces are also unpatentable, which effectively guarantees that a pharma company will never become interested in backing fecal-transplant research. But if a feces substitute existed, that could be subject to patent – and we might find that a procedure that can be had for the several hundred dollars it takes to use an endoscopy suite (or much less than that, for the home version), has suddenly become prohibitively priced and available to only a few.

Update: NPR's Shots health blog has a great interview with the Canadian team who came up with the synthetic substitute, amusingly dubbed "RePOOPulate."

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