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FDA Scrutinizes Fecal Transplants

On Monday November 5, officials at the FDA listened for three hours to arguments for and against “fecal microbiota transplants” – mostly for. Speakers reported that the procedure has saved thousands of lives.

The technique of “FMT” is highly effective in treating infection with Clostridioides difficile (“C diff“). This infection is usually hospital-acquired, causes life-threatening diarrhea, and tends to recur. It is terrifying.

FMT introduces a healthy donor’s gut microbiome (the population of microbes in the intestines) and is in clinical trials for a variety of ills. But microbiomes are highly individualized entities, and so variations on the fecal transplant theme, in terms of what’s actually being delivered, haven’t been well documented.

A Death

The FDA meeting came, coincidentally, just days after The New England Journal of Medicine (NEJM) published a report about two patients who’d contracted rare, antibiotic-resistant E. coli bloodstream infections from fecal transplants. One patient responded after he switched to the appropriate antibiotic; the other died of pneumonia and sepsis within days.

Fecal material is usually taken in capsule form.

The capsules that the patients had swallowed had been frozen (for preservation) before the FDA began requiring further testing that would have revealed the E. coli. The researchers matched patients to donor by comparing the genomes of the microbes in the feces to those of the bacteria swarming in the men’s bloodstreams.

Others who’d received material from the donor had been infected with the E. coli but hadn’t gotten sick. The two men had probably been vulnerable because they had unusual underlying conditions – liver cirrhosis and a stem cell transplant, not the typical C diff infection that most of the 10,000 or so FMT recipients last year in the US had. Clinical practice guidelines have allowed FMT for “recurrent or refractory” C. diff  infection since 2013 and for new cases since 2018.

A letter-to-the-editor in the same NEJM issue intrigued me even more than the editorial or report. The letter spelled out how stool banks screen potential donors: about 97 percent don’t make the cut. But first, a short recounting of this ages-old therapeutic approach.

A Brief History of FMT

Fecal transplants treat a “dysbiosis,” or condition caused by a disrupted microbiome. The delivery route is from either end, via capsule or enema. Microbiome alteration has become big business; here’s a list of companies.

One of the first known incarnations of a fecal transplant was “yellow soup.” Fourth century Chinese doctor Ge Hong administered the broth of dried or fermented stool from a healthy person, to treat diarrhea from food poisoning. It worked.

Cattle have received stool enemas for a century.

When German officials noted during World War I that North African natives weren’t succumbing to dysentery, but the Germans were, they zeroed in on the fact that the Africans ate the camel dung that was abundant in the region  That worked, too.

Camel dung

People unwilling to wait for the medical profession to catch up with history have tried it on their own. My favorite media account: Marie Myung-Ok Lee’s “Why I Donated My Stool,” describing a doctor-guided experience that helped a desperate friend with ulcerative colitis.

But DIY can be dangerous. Wrote Martin J. Blaser, of Rutgers University in the editorial, “Despite its seemingly innocuous, if unpleasant, aspect and possibility to do it oneself at home, FMT carries a risk of infectious hazards that needs to be taken seriously.”

Stool for Sale

It isn’t as easy to donate stool as it is blood or sperm. (None of these are really donations if the person is paid). Stool is a varied mixture, even within an individual, unlike the easily defined components of blood or the single cell type in a semen sample. Perhaps the complexity is why “you can earn $13,000 a year “selling your poop,” according to an article in the Washington Post, to OpenBiome, a “nonprofit stool bank” that is “expanding safe access to fecal transplants and catalyzing research on the human microbiome.” It’s in Cambridge, Mass.

OpenBiome’s clinical program director Majdi Osman told FDA on Monday that the bank has provided material for more than 50,000 treatments to 1200 hospitals and clinics, and for dozens of clinical trials. The bank estimates that 98% of the US population lives within a 2-hour drive of an FMT provider.

A potential donor to OpenBiome has to leap over four hurdles, which Zain Kassan, MD, PhD, from Finch Therapeutics, and three colleagues describe in their letter to the NEJM.

  • Stage 1 is online prescreening. Smokers, those with a BMI greater than 30, and those who can’t make regular donations need not apply.
  • Stage 2 poses 200 clinical questions and requires a meeting with a trained nurse or doctor, who weeds out people who reveal risk factors for infectious disease or conditions associated with altered microbiomes. These include certain metabolic, gastrointestinal, autoimmune, neurological, and psychiatric illnesses, as well as allergies.
  • Stage 3 probes the nasal and gut microbiomes, looking for key antibiotic-resistant microorganisms.
  • Stage 4 is blood work to check further for infection.
The OpenBiome logo

Dr. Kassan and colleagues considered the 15,317 donor candidates who showed up from 2014 through 2018. Their numbers fell sharply as the weeding out process progressed: 10,046 were out at stage 1, 4,700 eliminated at stage 2, 166 more at stage 3, and 19 at stage 4 whose blood work turned up hidden infections. Only 386 of the original 15,317 applicants remained – about 3%.

“This experience highlights the point that healthy, screened donors are not easy to find,” conclude the letter-writers.

Perspective

I thought I’d put the 3% chance of having one’s stool accepted for a transplant into a random sort of perspective.

Somewhat relevant is the probability that a blood donor will be accepted: about 38%.

Less releveant is the chance of getting into Harvard among those qualified enough to apply: 4.6%

The likelihood of being accepted as a flight attendant for Delta airlines is under 1%.

If more stringent requirements are set for stool donations, perhaps the acceptance rate will approach that of a child being accepted into kindergarten at a ritzy Manhattan private school: 0.066%.

Anatomy of a BM

For now, stool donation must be selective, because the stuff is so complex and variable. All 3 NEJM articles – report, editorial, letter – stress the importance of better defining exactly what is in a bowel movement.

It’s something I’ve often pondered.

A BM has a lot of stuff in it: bacteria, archaea, protozoa, fungi, intestinal lining cells, viruses, cytokines, and metabolites. Here’s a nice review of poo, with illustration:

(Diana P. Bojanova and Seth R. Bordernstein, from “Fecal Transplant: What Is Being Transferred?” in PLOS Biology)

 

The FDA meeting generally gave high marks to FMT.

A speaker from the American Gastroenterological Association presented new, unpublished findings showing that most patients receiving fecal transplants do just fine – with no adverse events. A speaker from the National FMT Registry showed data indicating sustained cure for three-quarters of patients treated since 2011. Companies asked that the FDA require stricter requirements, while stool banks and physicians urged the agency to stick to present guidelines.

Meanwhile, clinical trials forge ahead, with 202 entries at ClinicalTrials.gov listing the obvious inflammatory bowel disease, but also anorexia, Alzheimer’s, various cancers, autism, peanut allergy, and obesity.

I can envision stool banks of the future sorting out the product according to composition, a little like the way the cannabis industry seems headed. But the ick factor persists. The biological source of CBD oil or a THC product is more palatable than that of an FMT.

Herbert DuPont, from the University of Texas Health Science Center at Houston, who is conducting a clinical trial using FMT for the company Rebiotix, perhaps said it best at the FDA meeting: “All of us want to remove the F from FMT.”

 

 

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