Poo Transplants: Sniffing Out the Story

In this guest post for Student Voices, PhD student Andrew Swale explains how although Faecal microbiota transplantation is a highly successful treatment for patients with relapsing Clostridium difficile infection (CDI), it remains a long way off becoming a standardized treatment.

CHECKLIST:

• Bottle of saline
• 2-quart enema bag
• 1 standard kitchen blender
• Faeces from a healthy friend/relative

This may seem like a bizarre shopping list, but in reality this is exactly what you would need to carry out a faecal transplant from the comfort of your own living room (or perhaps the bathroom may be more hygienic).

Why on earth would someone be carrying out a faecal transplant you ask? To prevent this:

Faecal microbiota transplantation (FMT) is the process of transplanting faecal bacteria from healthy individuals into a recipient-most commonly as a treatment for patients suffering from Clostridium difficile infection (CDI). First described in 1958, the technique has a reported average cure rate of >90% for relapsing CDI (1). Despite this, the treatment is still a long way off from becoming a standardised therapy.

Clostridium difficile is a hospital superbug, which results in a wide variety of symptoms ranging from mild diarrhea to pseudomembranous colitis (severe inflammation of the colon) and in some cases, death. There were 17,414 reported cases of CDI in England in 2011, responsible for 2,053 deaths. In the US, CDI infects 250,000 individuals and is linked to 14,000 deaths each year. It is estimated that 13 out of every 1,000 patients that enter hospital will pick up the superbug (2).

A rise in levels of antibiotic resistance, as well as the emergence of hypervirulent strains of the superbug have resulted in this disease becoming much more difficult to manage. Standard treatment is a 14 day course of the antibiotic vancomycin. However, 20-30% of patients develop the disease again (relapse) within four to twelve weeks, with some patients relapsing multiple times. It is in these patients, where all other treatment options have been exhausted, that FMT has been deemed a ‘last resort' and has started to slowly gain momentum.

"The Proof is in the Poo-ding"

In January, this all changed when a randomised study published in the New England Journal of Medicine (NEJM) reported a 94% cure rate via FMT administration for pseudomembranous colitis caused by CDI, compared to 31% via standard vancomycin treatment (3). In fact, the study was stopped prematurely as it was deemed unethical not to offer FMT to all of the study participants due to the outstanding results.

Surprisingly, clinicians and other medical staff still find the procedure distasteful-perhaps because of the undeniable ‘ick' factor. Or it may be the complicated procedure of finding and subsequently screening a donor. Donors need to be tested for a wide array of bacterial and parasitic infections and their faeces must be transplanted within 24 hours. And despite all the success FMT has had, there is still a lack of peer reviewed research.

The lack of peer-reviewed evidence for this technique is a delicate situation. Due to a lack of funding for large-scale clinical trials, drug or medical device companies usually foot the bill. It is at this point that the issue of ‘patentability' arises. As evidenced by the recent decision by the US Supreme Court to rule that no human genes may be patented, FMT could remain a natural, patent-free treatment and therefore no company stands to make a major profit. And this technique would likely cost the pharmaceutical companies money: in the US a single pill of vancomycin costs ~$55 with patients usually taking four pills daily over a two week period. Excluding manpower costs, strictly speaking a faecal donation costs nothing at all.

The U.S. Food and Drug Administration (FDA) has recently put up more barriers to FMT use. The administration announced that as FMTs are not an approved biologic therapy, they would require an Investigational New Drug application to be submitted for each proposed use. These applications are extremely time-consuming, involving hours of paperwork and can take up to 30 days for approval to be granted. That's time that a patient suffering from debilitating bouts of severe diarrhea can't wait.

However, there does seem to be a small amount of light at the end of this dark tunnel in the form of synthetic faecal substitute. Researchers in Ontario took a stool sample from a proven healthy individual, grew the bacteria and then sequenced the bacterial DNA to determine varying species. They then selected 33 species known to be healthy to produce a synthetic faecal cocktail aptly named ‘RePOOPulate' (4).

The faecal substitute is produced by a mechanical device (the ‘Robogut'), which mimics the conditions present in a healthy colon. Proof of principle has already been validated in two patients who had relapsing CDI (4), cured after administration of the faecal substitute. The bacteria present in their colons slowly grew and displaced the Clostridium difficile, repopulating the microbial diversity of both patients' colons, which remained stable six months post-transplantation.

A fecal substitute has major advantages that could become a frontline treatment in the near future. The exact composition of the bacteria involved is known and controlled and thus can be reproduced if future treatment is required. Perhaps most importantly in terms of future viability, a synthetic substitute would be eligible for patent and therefore gives scope for the pharmaceutical industry to invest in major trials. The technique is also a lot safer than FMT (4), therefore FDA approval would be much more easily obtained.

The development and validation of a synthetic faecal substitute will not only be a huge benefit for CDI-sufferers, but may also help other conditions such as colitis, constipation, irritable-bowel syndrome, and even some neurological conditions such as multiple-sclerosis and Parkinson's disease, in which the microbiome has recently been implicated (5).

Hopefully, that awkward moment when a CDI-sufferer has to ask a ‘friend' for a ‘sample' will soon become a thing of the past.

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Andrew Swale is an NIHR doctoral research fellow from Liverpool, working on a PhD focused on Clostridium diffcile infection (CDI). He has a healthy interest in all things poo-related and can often be found discussing the Bristol Stool Chart over a family meal. You can follow Andrew on Twitter here.

References:

(1) Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol 2012 Nov;5(6):403-20.

(2) Jarvis WR, Schlosser J, Jarvis AA, Chinn RY. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. Am J Infect Control 2009 May;37(4):263-70.

(3) van NE, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med 2013 Jan 31;368(5):407-15.

(4) Petrof EO, Gloor GB, Vanner SJ, Weese SJ, Carter D, Daigneault MC, et al. Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. Microbiome 2013 Jan; 1(3)

(5) de Vos WM, de Vos EA. Role of the intestinal microbiome in health and disease: from correlation to causation. Nutr Rev 2012 Aug;70 Suppl 1:S45-S56.

Image Credit:

Low magnification micrograph of colonic pseudomembranes in Clostridium difficile colitis by Nephron