Fecal Microbiota Transplantation: Beyond the treatment of Recurrent Clostridium Difficile

Do your patients ask you a lot of strange questions? Since I’ve begun doing fecal transplants (FMT), here are some of the typical questions I’ve been getting:

• “Is the FMT donor fat?”
• “Was the FMT donor breastfed?”
• “I have two great FMT donors and don’t want to hurt anybody’s feelings. Could you mix their stools?”
• “How do you extract the stool from the FMT donor?”
• “What if it doesn’t agree with my own poop?”

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Today, FMT has one approved use: the treatment of recurrent Clostridium Difficile colitis. For that use, the success rates are extremely high. Of all the things we prescribe as doctors, this is one we can feel unambiguously proud of. It’s fast, effective, and inexpensive. This is no small matter: about 30,000 Americans die every year of Clostridium Difficile . Millions of dollars are spent treating this infection, which can be devastating. One can administer FMT though the upper GI tract or directly into the colon. Since Clostridium Difficile colitis affects the colon, today most gastroenterologists administer it via colonoscopy.

As a result of this success, now some patients will try anything to convince you that they need a fecal transplant to cure a whole host of maladies. Others will refuse one even when they have been debilitated by years of infectious colitis and multiple hospital admissions.

But will there be other clinical uses for fecal transplant?

To do justice to this question, it is important first to consider the topic of the microbiome. Recently, FMT has inspired the medical community to look at this “newly discovered organ” we had been ignoring for so long. The “organ” is our microbiota: an enormous number of cells living in an organized dynamic ecosystem and playing so many roles in virtually every aspect of our health and disease. Our gut microbes interact with each other and with us, the host. We have coevolved and developed a mutually beneficial relationship: we provide them with food and shelter and they help with our nutrition, our ability to fight infections, our metabolism, and even our neurologic development. Their study is particularly fascinating because it brings together medicine, ecology, and evolution.

To better understand the microbiota, we have used several tools that have allowed us to gather an enormous amount of information: more information than we can actually interpret. In a sense one could say that technology is ahead of science. Today, for example, we have the ability to sequence the genetic material of the organisms that live in the gut instead of culturing them.

We have observed that the microbiota of patients with IBS, IBD, metabolic syndrome, obesity, autoimmune diseases, and even autism is different from the “normal” microbiome, but association and causation are of course two different things.

Moreover, it has become clear that in order to understand the effects of the microbiota, we need to not only identify these microorganisms, but also measure the products of their metabolism. The mere presence of a particular microbe or a group of microbes may not be as important as what they are doing.

FMT has also helped to advance our understanding of the microbiome and its role: If for example a disease or a trait can be transmitted though FMT, that could support at least some role of the microbiota in causing that disease or trait.

But studying the effects of stool transplant is a lot more complicated than studying the effects of a regular drug. Even though stool (when used for FMT) is now considered a drug, there are many unknowns: dose, ideal route of administration, mechanism of action, etc. Also, each individual person’s stool is different, like a fingerprint. And it may therefore interact in a unique way with the recipient’s microbiota.

A few months ago we started to enroll patients in a multicenter study with doctors at Montefiore, Yale, and Concorde Medical Group to investigate the possible use of FMT in IBS-D (diarrhea predominant IBS).

IBS-D, especially when it is moderate to severe, can be a debilitating disease and very frustrating to treat. Most patients have typically tried conventional therapies like special diets, probiotics, antidiarrheals, antispasmodics, and sometimes antibiotics like rifaximin, which was recently approved for this use.

Why are there currently so many different conventional therapies prescribed for IBS? Likely this is because the pathogenesis of IBS is so little understood. Visceral hypersensitivity, low-grade inflammation, and dysbiosis have been thought to play a role.  Regarding dysbiosis, we know that there is an abnormal microbiota: the numbers of lactobacilli and bifidobacteria, for example, are lower in patients who suffer from IBS than in those who don’t. Also their microbiota seems to be less diverse. Replacing “good bacteria” is the idea behind the use of probiotics, which seem to help some patients. But why are they not sufficient to cure IBS in most patients? The answer is not clear today. Perhaps the numbers of bacteria that survive the passage through the GI tract are not sufficient. Or maybe in order to change that whole ecosystem that is our microbiota in a permanent way, one has to modify it more radically instead of just adding a few specific strains of bacteria.

Despite the unanswered questions about IBS-D, we hypothesize that IBS-D is a condition that occurs secondary to an altered microbiota in the small bowel. Therefore, instead of administering the FMT via colonoscopy as we would do for recurrent Clostridium Difficile colitis, we are using “poop capsules.” It’s a 6-month, randomized, placebo-controlled trial and at 3 months there is a crossover so by the end of the study 100% of the patients will have received the active drug.

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As doctors and investigators, we are eager to help our patients with this very debilitating disease. In the process, we also hope to learn more about the microbiota, its effects on our health, and how this new knowledge will lead to exciting new therapies.

To learn more about this trial, go to clinicaltrials.gov

Caterina Oneto, M.D. (@caterina_oneto) | Twitter