Fecal transplants to treat recurrent gut infections

A clinical trial just published in the New England Journal of Medicine shows that fecal transplants are far more effective than antibiotics at treating recurrent gut infections caused by Clostridium difficile.

Clostridium difficile is a bacterium that causes severe diarrhea, and it is the most serious cause of antibiotic-associated diarrhea. It is the scourge of hospitals and nursing homes, because of its high contagion potential – the bacterium can survive for a long time outside the human body as a spore – and because it’s particularly difficult to treat.

The conventional treatment for a C. difficile infection is a course of antibiotics, however up to 25% of patients treated for a first infection relapse. What is even more worrying is that the efficacy of antibiotic therapy is estimated to be 60% in case of a first recurrence of the infection (which is already lower than the efficacy observed after the initial infection), and then further declines in patients with multiple recurrences.

Fecal transplants – in which feces from one person is infused into another’s intestines – have been reported to successfully treat recurrent cases of C. difficile infection by many physicians. However, until now, these were only case reports (though admittedly representing more than 300 patients), and a proper evaluation of the treatment in a clinical trial was lacking.

A new study published on January 16, 2013, in the renowned New England Journal of Medicine has now filled this gap. Researchers recruited people whose C. difficile infection had relapsed after at least one failed round of antibiotic treatment. The volunteers were then randomly assigned to receive either a standard two-week course of the antibiotic vancomycin or an infusion of a solution of feces from healthy donors (delivered directly to the small intestine via a tube threaded through the nose).

The difference in efficacy of the two treatments was so dramatic that the trial was stopped early: even with fewer patients enrolled than what had been initially planned, the difference in success rates was large enough to reliably establish the superiority of one treatment over the other. Of the 16 patients in the fecal transplant group, 13 were cured after one infusion and of the 3 remaining patients, 2 were cured after a second infusion (overall success rate of 94%). By contrast, only 7 out of 26 patients receiving antibiotics were cured (success rate of 27%). After the clinical trial was stopped, the patients for whom the C. difficile infection had returned received off-protocol donor-feces infusion treatments, and 83% of them were subsequently cured. On the whole, the fecal transplant treatments did not show any adverse side effects, except for mild diarrhea and abdominal cramping on the infusion day.

The striking efficacy of fecal transplants for C. difficile infections is thought to be due to the restoration of a normal population of gut bacteria that usually keeps C. difficile at bay in healthy individuals. The researchers who conducted the clinical trial looked at the fecal microbiota of the patients before and after infusion of donor feces and observed that patients with C. difficile infection had a reduced bacterial diversity compared to healthy individuals, but that this microbial diversity was increased after the fecal transplant. Transferring a solution made from feces of a donor allows the transfer of some of the gut bacteria of the donor, which then settle down in the gut of the recipient and displace C. difficile. This may also explain why a conventional antibiotic regimen often fails at curing recurring infections of C. difficile: each round of antibiotics will not only kill C. difficile but also the harmless bacteria that normally live in the intestine, leaving a clean space ready to be colonized again by the persisting C. difficile spores once the antibiotic treatment is discontinued.

Despite the unappealing nature of fecal transplants as a therapy, its striking effectiveness at curing recurrent C. difficile infections – now demonstrated in a randomized controlled clinical trial – makes it an appealing treatment option. Nevertheless, researchers are also working on developing alternatives to fecal transplants while keeping what most likely makes them so effective, namely the transfer of normal gut bacteria.

In a study published in October 2012 in PLoS Pathogens, a team of researchers in the UK reported isolating 18 types of bacteria from mouse fecal material that had been successfully used to cure other mice infected with C. difficile. The researchers further identified a combination of 6 kinds of bacteria out of these 18 that could also cure the infected mice. Recently, a Canadian team has managed to grow a mixture of 33 bacterial species from the feces of a healthy donor, and successfully cured two patients with recurrent C. difficile infection by infusing this mixture in the colon (via colonoscopy). The study was published on January 9, 2013, in the journal Microbiome. An advantage of using a mix of purified bacterial cultures over a solution of donor feces – beyond the obvious one of taking away the “icky” factor – is that it allows for a better control of the population of bacteria that is being transferred.

Perhaps someday C. difficile infections will easily be treated with a simple suppository of bacteria. In the meantime, more clinical trials are needed to optimize and standardize the fecal transplant technique, but also to address its suitability and safety for other patients (e.g., immunodepressed and critically ill patients).

References

1. Duodenal Infusion of Donor Feces for Recurrent Clostridium difficile. van Nood E et al. N Engl J Med. 2013 Jan 16.
PMID: 23323867

2. Lawley TD, Clare S, Walker AW, Stares MD, Connor TR, et al. (2012) Targeted Restoration of the Intestinal Microbiota with a Simple, Defined Bacteriotherapy Resolves Relapsing Clostridium difficile Disease in Mice. PLoS Pathog 8(10): e1002995. doi:10.1371/journal.ppat.1002995

3. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: ‘RePOOPulating’ the gut. Petrof EO et al. Microbiome 2013, 1:3 doi:10.1186/2049-2618-1-3

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