Shitstorm! That’s what the recent weather’s been like at the Fecal Microbiota Transplantation (FMT) Facebook Group ever since Tracy Mac, the group’s founder and host of The Power of Poop website, posted a link to a blog post written by Matt Wood of Science Life (a University of Chicago promotional blog) called Taking the Scientific Approach to Fecal Microbiota Transplantation. Matt Wood’s blog post summarizes an editorial called Curbing our Enthusiasm for Fecal Transplantation in Ulcerative Colitis written by the co-director of the Inflammatory Bowel Disease Center at University of Chicago, David T Rubin. Rubin’s editorial is written about a journal article which appeared in The American Journal of Gastroenterology called Temporal Bacterial Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota Transplantation. If you’re still following, the members of the FMT Facebook Group immediately expressed outrage for what Mr. Wood’s article said. The shitstorm was enough for Science Life to end the ability of users to post new comments after only 3 days even though it’s the blog’s most commented post ever. Mr Wood decided he’d force the last word upon us with links to the journal article and editorial. The comments here will remain open: My skin is thick, this is an important topic, and I hold no sword pointed out.
My outrage isn’t so much that Rubin had negative comments about the efficacy of FMT and questioned its safety but that he ignored the dangers of conventional therapies, cherry picked negative evidence, ignored recent work in his field, misrepresented the original journal article he chose to editorialize, and makes a medical recommendation to his colleagues based on a pilot study regarding a treatment he has no experience performing. The FMT Facebook Group, on the other hand, was outraged by his comments.
FMT is a very sensitive subject for patients with Inflammatory Bowel Diseases. Us patients aren’t given the option of FMT by our physicians. If patients get a choice at all it can be between Humira and go find a new gastroenterologist — one that will command you take Remicade or Cimzia or Tysabri or Simponi or maybe just an impressive dose of prednisone. Informed patients know that FMT has a death rate of zero. There are no reports of it causing cancer. There’s no pending litigation over FMT. There are cases of FMT completely curing Ulcerative Colitis. And there are actually lots of them. As a contrast, Humira and The Others, can kill, cause cancer, and antagonize latent infections among many other serious side effects. (Please see rxisk.org for side effect information on each of the above mentioned drugs.) The conventional commercial therapies are prohibitively expensive unless insurance is paying, FMT, by contrast, is inexpensive and the side effects aren’t any more dangerous than the disease. There’s also an uncountable and uncomfortable amount of litigation over Humira, for example. And this is all besides the fact that pharmaceutical companies won’t release clinical trial data. No one will argue that the world needs to know more information about FMT, especially the FMT Facebook Group. That’s what it’s there for.
Informed patients can be more sensitive to the risk/reward of trying a treatment than physicians. The potential harm of the conventional commercial treatment should at least be acknowledged in any FMT discussion. In the editorial Rubin ignores the dangers of the conventional commercial treatment which FMT subverts. If you’re a physician trying to minimize your iatrogenic death rate, you’d always start with the least harmful treatment, as opposed to what’s advertised as the most effective. But minimizing harm is not how physicians tend to think or behave. They tend to believe the marketing which often, and sometimes exclusively, comes in a form of appearing like science. Marketing will always downplay side effects. How many ghostwritten articles are there featuring Humira and The Others? We have no quantitative clue of the duplicitous influence pharmaceutical marketing has had on the likes of Rubin, his colleagues, and the University of Chicago department he’s co-directing, much less the entire medical educational culture. So against an industry which seems to always confront opposition to the status quo with all its swords pointing out, and because there’s no broader shareholder interest to profit, the only people promoting FMT are us patients.
I will not cover all the expressions of outrage from the FMT FB group but they’re worth reading. What I will cover are some facts which will lead us to some serious questions about Rubin’s agenda. There are dangerous double standards and incorrigible ethical issues which Rubin’s editorial illustrate.
The academic paper at the center of the shitstorm, remember, is called Temporal Bacterial Community Dynamics Vary Among Ulcerative Colitis Patients After Fecal Microbiota Transplantation. The paper is a write-up of a pilot study. It only has five participants receiving FMT but it has 10 authors (Rubin is not one of them). It’s a working prototype. It’s a dry rehearsal for more work to come. They’re workin’ out some kinks, gettin’ feedback, gearin’ up to do some deeper diggin’… Pilot study. I do not fault Rubin for writing an editorial about a pilot study. In fact here’s my own mini editorial about the same study:
Necessary FMT Pilot Study Needs Design Input from Patients for Future Success
Five patients with active Ulcerative Colitis were give FMT both by enema and nasojejunal once a day for three days. None of the patients died but they had a noticeable fever and diarrhea and there was a temporary increase of C-reactive protein. Donor material was responsibly screened for communicable diseases. One patient got better and stayed better for more than the duration of follow up (1 yr). The distribution of gut bacteria after FMT tended toward the distribution of the donor. The donor material was not all from the same donor and one patient received FMT from two different donors. Four of the patients were given metronidazole before FMT. Four patients were given probiotics before FMT. The paper acknowledges the long term efficacy and safety of FMT for Clostridium difficile infection. It does not do a review of Ulcerative Colitis patients trying the procedure at home.
This pilot study is a necessary contribution to the FMT literature. The study is unintentional in terms of the patients chosen, the administrative inconsistency of the antibiotic, the mixing the donors, and the dual FMT administration (pick one, enema or nasojejunal). In a bigger study the researchers should work to keep as many variables the same as possible. The statistics will bare fruit when the sample size is bigger. The researchers seem aware of the shortcomings of the work and should do fine to run a larger trial.
My suggestion is to do a review of what Ulcerative Colitis patients have done with self administered FMT. Patients (of all flavors of gut dysbiosis) have generated a lot of literature about FMT. Here’s a reference, Analysis of Crohnology’s FMT Users: An Open Source Peer-to-Peer Observational Treatment Study. In reviewing the literature generated by patients, the authors should note that one FMT per day for three days is not enough. Ulcerative Colitis is not Clostridium difficile infection. Be more aggressive. These researchers might also do well to find a patient consultant with extensive FMT experience. Someone like Michael Hurst would likely happily advise you.
End mini editorial.
In a pilot study the results should largely be ignored and the methods critiqued. If I wanted to further an agenda or create a news worthy headline I would’ve called my mini editorial: “Empirical Evidence Suggests FMT Can Cure 1 in 5 Cases of Ulcerative Colitis in Only Three Treatments!” Even though the pilot study may have set an unofficial record for the least number of FMT used to get an Ulcerative Colitis patient into remission it would be irresponsible of me to push this result. Irresponsible.
What I fault Rubin for doing is misrepresenting the article to create his own negative evidence for FMT. Let’s dissect what he says in the editorial. But first you should know that Rubin’s editorial is intended to influence his colleagues. I found his tone condescending and I imagine to some extent he’s acting out against patients who question him and don’t comply with his expectation of paternalistic authority. Also, the editorial exists behind an academic paywall so he’s not expecting patients to ever read it. (Surprise!) We know he has an agenda and wants to curb enthusiasm for FMT in Ulcerative Colitis. Mostly we know this because of what he named his editorial: Curbing our Enthusiasm for Fecal Transplantation in Ulcerative Colitis.
The first problem is in the bold type of the abstract:
This editorial accompanies a prospective series of five patients with ulcerative colitis who underwent FMT, but did not achieve remission.
Rubin’s interpretation of the pilot study’s results is presented differently on the next page:
However, none of the five patients in this study achieved clinical remission during the formal 12 weeks of follow-up, and only one had some clinical improvement.
Rubin backpedaled towards honesty but still wasn’t representing the facts or spirit of the study. This is what the pilot study actually says:
In our pilot study, however, only patient 3 responded clinically to FMT, whereas two other patients a clinical deterioration of UC was observed. One reason for the poor response rate might be patient selection…More than 1 year after FMT, patient 3 continues to be in stable clinical remission without need of immunosuppressive therapy.
Rubin’s abstract presents more than a gross misrepresentation.
Here’s a longer excerpt from Rubin’s editorial and I will break it down in the next few paragraphs (the quotes and parenthesis are his):
Similarly, there is fervent interest in “fecal transplantation” (or fecal microbiota transplantation, FMT) for IBD by patients, who believe it to be a “natural” treatment. Many are certain this will be their cure, and will go to great lengths to find the treatment (and to pay out of pocket for it). Given the availability of the raw materials (stool from a donor), websites have sprouted (some with at-home FMT recipes and kits), weblog accounts of anecdotal success are multiplying, and patients are seeking providers who can deliver this treatment to them or just doing it themselves in their bedrooms and kitchens. Given this exuberance, there is a clear need for more research of FMT in IBD, and an even more pressing priority to ensure the safety of patients who are desperate and forgoing available standard of care medical or surgical therapies in favor of this unproven approach. To accomplish these goals, we need scientifically valid studies that answer important questions about the role of the microbiome in IBD, while simultaneously rigorously assessing the safety and limitations of transferring an entire community of organisms from one human being to another.
Why be pejorative about a patient looking for a natural treatment? What’s a treatment more natural than poop? Human fecal transfers to cure diarrhea date back to ancient China. And by the way it’s a well established technique in the veterinary community. FMT for cows is called transfaunation. Dogs ingest poop all the time. So do baby elephants. (Is that enough animal testing?) FMT is so common in nature it usually goes by the name of coprophagia. In fact nasojejunal FMT is exactly human coprophagia.
It appears as if “natural” presents a problem because patients will “pay out of pocket for it”. FMT is a tiny fraction of the cost of commercial IBD treatment. Imagine, patients not using their insurance for $500 appointments, $2,000 a month Humira treatments, $6,000 Remicade infusions every six weeks, and $50,000 colectomies. I sense that Rubin feels a threat to his department’s revenue stream. If FMT works decently in even a small fraction of IBD patients then a ton of money will be saved (never mind the intestines). Perhaps the editorial was a business decision necessary to justify his department’s antiquated treatment protocols. Defending a revenue stream under the guise of patient safety is not uncommon in contemporary medicine, but that doesn’t make it any less deplorable.
Along the lines of double standards, Rubin sites as a reference, a case study of a single Ulcerative Colitis patient who underwent FMT for Clostridium difficile infection and then had a flare. Rubin uses this as more evidence that FMT may be bad. It’s a double standard how a physician’s report about one patient is evidence when it’s convenient for an editorial’s agenda, but a bunch of patients attesting to FMT bringing relief are looked down upon as mere anecdotes. It’s also an ironic reference because some Ulcerative Colitis patients have realized that FMT helped their Ulcerative Colitis symptoms after FMT was administered for their Clostridium difficile infection. Please see Dr Carl V Crawford explaining his experience with FMT in Ulcerative Colitis patients.
The editorial states:
Despite the lack of data, theories of bacterial causes of IBD have “face validity” to many … we need scientifically valid studies that answer important questions about the role of the microbiome in IBD…
So I’m assuming Rubin means studies which would use metagenomic sequencing to catalogue the human gut microbiota and then relate the finding to Inflammatory Bowel Diseases. That would be difficult. You’d likely need an Illumina Genome Analyzer, hundreds of patients, and about 53 collaborative researchers to figure that out. You’d also have to do some fairly difficult statistics work, like principle component analysis, to see if the distribution of gut bacteria of Crohn’s and Colitis patients separate distinctly from the general population. If the world were so kind as to get that done some day, wouldn’t it be great if the research was published in a journal out from behind the academic pay wall so the entire world could see it for free? Something like Nature, perhaps? Until then I guess we’ll have to rely on this silly little paper published in an obscure journal 3 years before the editorial was written: A human gut microbial gene catalogue established by metagenomic sequencing. The above quote from Rubin continues with:
…while simultaneously rigorously assessing the safety and limitations of transferring an entire community of organisms from one human being to another.
Please notice that under that logic Rubin is also suggesting that FMT, with its 90% cure rate for Clostridium difficile infection, also be “curbed”. That’s unmistakable nonsense. Additionally, understanding the entire microbiome before administering FMT is unnecessary and an absurd standard. Scientists don’t even understand the mechanism of action behind acetaminophen and that’s available over the counter. What physicians should be charged with is figuring out if a treatment is worth its risks.
To continue, for only a moment more, the defense of my claim that evidence was ignored, it’s likely that Rubin’s editorial is the only piece published on FMT lately which left out references to Thomas J Borody’s work on FMT for IBD. Borody’s work goes back about 25 years. The earliest reference in western medicine I can find for FMT used to treat IBD is called Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis (Eiseman, Silen, and Bascom). It was published in 1958.
The editorial also states:
…pressing priority to ensure the safety of patients who are desperate and forgoing available standard of care medical or surgical therapies in favor of this unproven approach.
Unproven approach? Not so much anymore, but fine, I’ll stop picking that scab, it’s bleeding enough. Here’s where I get angry. If Rubin was genuinely interested in patient safety, and science, he’d demand that AbbVie release its clinical trial data on Humira. Likewise for Janssen Biotech, the makers of Remicade, and all the rest of the pharmaceutical companies. Where’s his signature on the AbbVie petition that went around last fall? This same argument goes for Matt Wood’s blog post. If these two are interested in safety and doing science they need to redirect some energy to obtaining data on the conventional commercial therapies. Sharing data and replication of results are pieces of the scientific method you can’t leave out just because data is stamped “proprietary” by ferocious commercial interests. And where’s the outrage that clinical trial data trumps public health? There’s likely no greater threat to the revenue of pharmaceutical companies than the scientific method. And there’s likely no greater threat to public health than pharmaceutical companies. So here’s a suggestion for University of Chicago’s Inflammatory Bowel Disease Center: Make like the Mayo Clinic did with the Remicade patients and follow the progress of your patients who take Humira. Take a look at Infliximab for Crohn’s Disease: The First 500 Patients Followed Up Through 2009. You’ll likely see the efficacy of Remicade (when it works at all) decreases with each infusion, and patients can end up in a worse place than where they started. If that hypothesis ends up true the “wonder drug” panacea that gastroenterologist see as the commercial biologics is nothing more that a very dangerous, and expensive, false crutch which delays the inevitable next treatment. But you won’t know unless you follow up and look at the data. Read the accounts of patients taking Humira from sites like Crohnsforum, and Crohnology. Adam from IhaveUC.com did a poll of his users who have experience with Humira. Start there. A separate and highly necessary idea is to survey of all the physicians who have written Humira prescriptions for IBD and what their perception of the outcome data looks like. You could then compare physician’s perception about patient outcomes and the actual outcomes. That way you could see how wrong or right you all are about the outcome data you should be tracking anyway. I once had a physics professor who would give a short lecture on the importance of being able to predict your exam score before handing back our exams. His point was about awareness of what you don’t know. How good are you at predicting, Dear Doctor, what you get wrong? On this point I hear a deafening silence from the medical industry. There’s an institutionalized denial for self assessment.
My second to last point from Rubin’s editorial regards this quote:
… and we certainly need additional careful studies like this one to inform us about how this may or may not be a path forward for our patients. Patient desperation is not the reason to provide patients with this treatment, and based on these results, the patient with moderate to severe colitis failing our current medical therapies and facing surgery may not be the best candidate for FMT.
It’s not a careful study, it’s a pilot study, but let me be clear about what he’s saying here: Cut out colons and bowels without exhausting all the known therapies. And please realize he’s making this recommendation based off the evidence of a pilot study of five people. Five. Based on a much larger breadth of evidence I wouldn’t be surprised if Rubin’s recommendation is exactly wrong. And please, please notice that Rubin does not say his recommendation is in addition to his years of experience performing FMT. Rubin has no recorded or acknowledged experience performing FMT. None.
At what point does an editorial become dangerous agenda riddled sophistry? At what point is it just a physician who thinks he’s the entire boxoftricks himself desperately attempting to uphold the status quo? What is the retraction policy at The American Journal of Gastroenterology?
In case you read the editorial and think I’m being too critical, Rubin has likely fooled you with generalist heartfelt righteous posturing (and this is not a lonely example):
In addition, we must remember that it is our first responsibility to protect our vulnerable and sick patients.
That sounds so sweet, but I’ll defer to the more eloquent William Blake:
He who would do good to another must do it in Minute Particulars:
General Good is the plea of the scoundrel, hypocrite, and flatterer,
For Art and Science cannot exist but in minutely organized Particulars.
This quote is from the beginning of Rubin’s editorial:
…and modern day charlatans make enthusiastic claims of the effectiveness of their supplements, probiotics, and dietary plans, and prey on the desperate and suffering patient looking for answers.
POT. KETTLE. BLACK.