By Bernat Olle, PureTech Ventures
The NEJM's recent publication of the first randomized, controlled trial of fecal transplantation (FT) is a big deal for research of the human microbiome, which is the community of microbes that colonize the body and impact infection, immune reactions and other aspects of our health. I can't think of a better response to the warnings of hype for this new field of research than convincing clinical data validating microbiome modulation as a therapeutic approach.
Like hitting 'reset' on your computer
Some background first. FT involves obtaining a stool sample from a healthy donor and administering it to a recipient by enema, via a nasogastric tube, or via a colonoscope. The procedure has been used primarily as a last-resort treatment for patients with Clostridium difficile infections (CDI) that stop responding to antibiotic courses. CDI is a major problem in hospital settings. Just in the U.S., where diagnosis rates have increased four-fold since 2000, it causes 14,000 deaths a year. Often the FT donor is a relative who has been prescreened to rule out carriage of certain enteric pathogens, parasites, and viruses, and usually the recipient is prepared for the transplant with a gut lavage, and then given one or more stool infusions. There isn't much science yet to rationalize the donor screening criteria (it is unclear whether relatives and nonrelatives are equally desirable), the preparation steps (e.g., it is still unclear whether pretreatment with antibiotics helps the transplant "graft"), the administration route (all three mentioned above seem to work), the dose, dose frequency, and numerous other aspects of the procedure. But it works. Sort of like when you hit "reset" when something is wrong with your computer and 90% of the time it does the trick.
FT also seems to do the trick around 90% of the time. As of a few months ago, there were over 300 published cases showing 90% resolution. Gastroenterologists and infectious disease specialists have been aware of the growing anecdotal evidence of efficacy. Still, combine the fact that published cases did not include well-controlled, randomized trials with disbelief around the notion that anything good can come from feces and the result has been a mixture of surprise, amusement, and some skepticism.
This is why this first randomized, controlled trial with FT is a key development for the field. Van Nood and colleagues compared infusion of donor feces after vancomycin with vancomycin alone in CDI patients and found an 81% response after one FT infusion vs. 31% for the vancomycin arm. With a second infusion, the cure rate with FT was 94%. The trial was terminated early after an interim efficacy analysis when only 30% of the recruitment was completed because the data and safety monitoring board deemed it would be unethical to withhold FT from the remaining patients. When you take into account this trial as well as the previous accumulated clinical studies, the track record with the procedure is very impressive.
This time it is not just correlation
The most frequently heard cautionary warning around microbiome-related work has been that the numerous emerging associations between microbiome alterations and human disease reflect correlation, not necessarily causation. This is often a fair criticism, and press releases that ignore the difference are doomed to be demolished by @phylogenomics, the official Twitter policeman of microbiome-related press blunders. As I've noted previously, I too think that some of the correlative connections emerging in the literature will turn out to have no role in driving disease. But the evidence that alterations in the microbiome in CDI aren't just correlatively associated to the pathology, but are actually a driver of the pathology, is now very compelling. A randomized-placebo controlled trial is not absolute proof, but it ranks among the most reliable forms of scientific evidence when it comes to ruling out issues of spurious causality. Perhaps most importantly, it is this type of evidence that affects policy and clinical practice. If you weren't taking this field of research seriously, after the NEJM paper, you have to.
…Or not. See the reaction on social networks
Of course, there is something deeply fascinating about jokes involving feces that no NEJM paper is ever going to change. The reactions on Twitter following news of the paper were hilarious. Here are some pearls of wisdom in 140 characters or less (see the full conversation here):
@adamfeuerstein: NEJM study: Infusion of shit from a healthy donor works better than vancomycin in treating c. diff. Um, I'd rather have c. diff, thx.
Matthew Herper @matthewherper01/16/2013 5:32pm
@adamfeuerstein You would not rather have c. diff. Tell you what: we'll anesthetize you and not tell you what happened.
Adam Feuerstein @adamfeuerstein01/16/2013 5:34pm
@matthewherper Can i pick my healthy shit donor? Maybe i'd feel better about it then.
Matthew Herper @matthewherper01/16/2013 5:36pm
@adamfeuerstein you really DONT want to know whose shit they're squirting into you. Be at peace with the shit. Better than losing your shit.
Kevin Chow @kevintoshio01/16/2013 6:33pm
Ryan McBride @ryanmfierce01/17/2013 8:35am
This isn't crap. Well, yes it is. Fecal transplants beat antibiotic in treating C. diff in 1st randomized trial www...
carlzimmer @carlzimmer01/16/2013 6:58pm
Ed Yong @edyong20901/16/2013 6:56pm
In the media frenzy following the NEJM paper there has been plenty of lighthearted commentary. Just about every imaginable play on words that could be tweeted or printed has been. Embedded among the puns, however, are a few of the issues that will determine whether FT becomes a mainstream procedure. In short, The Good: credible science and good track record of clinical efficacy and safety. The Bad: patient and physician perceptions of the procedure ("ick factor"), the inability to get broad IP protection on the approach, lack of standardization (donor-selection protocols, patient pretreatment protocols, mode of delivery), and uncertainty around the regulatory route that will apply to FT. Science writers @marynmck (Wired, Scientific American), @edyong209 (Nature), and @carlzimmer (NYTimes) are among a few who have been discussing the topic in depth for some time now and highlighted some of these issues.
Follow-on indications and a word of caution
The publication of the first randomized, controlled trial with FT has lent credibility to FT and to the prospects of manipulating the human microbiome for treating human disease. Some experts are starting to wonder out loud if FT should become first line of treatment for CDI. The clinical success in CDI is already leading to experimentation with the procedure in other diseases. CDI was a natural starting point for the procedure because the role of microbiome dysbiosis in driving pathology in CDI is unambiguous, doctors run out of options to treat desperate patients that relapse after first-line antibiotic treatments, and published case reports of FT in CDI going back decades made it easier for investigators to get institutional review board approval for clinical studies. A natural follow-on indication which we will now see pursued more vigorously is IBD. A search on Clinicaltrials.gov shows 13 ongoing FT trials worldwide, 7 of which are recruiting IBD patients. IBD shares common mechanisms of pathology with CDI (a subset of CDI patients develop colitis); among gastroenterologists, the role of microbiome dysbiosis in driving IBD pathology is well accepted; and perhaps most importantly, several small human studies have already shown promising results of FT in IBD (e.g., here).
As it often happens, increased attention begets quackery and snake oil salesmen as well. Claims of astonishing results in unproven applications such as depression, multiple sclerosis, or what have you will crop up. People will try FT at home. And somebody may drop the ball and transplant a contaminated sample. This is something to be concerned about. It only takes one self-taught cowboy passing as a physician to poison the well for the rest of reputable clinical researchers. Unsupervised FT outside of the hospital setting should be discouraged.
Clinicians working on FT are getting some long-overdue respect. It's time to take FT seriously and it's time for regulators, payers, and the biotech industry to join the conversation. It remains to be seen whether anyone can make a business out of FT, but it's worth starting a discussion about it.
Watch this space for more on who will try to figure out the business opportunities in fecal transplants, publishing next week.
Other contributions from Bernat Olle:
Industry Voices: Designing Probiotics - You Get What You Select For
Industry Voices: Microbiome Therapies - Coming to a Clinic Near You