Faecal microbiota transplantation (FMT)

What it is and how it works

Trillions of bacteria, viruses and fungi live in the gut, the gut flora or microbiota. A diverse gut flora occupies niches and nutrients and thereby keeps pathogens in check. Antibiotics can disturb this balance; specialists call it dysbiosis. In this gap, Clostridioides difficile can spread, a bacterium that produces toxins and causes severe, sometimes life-threatening diarrhoea. In almost a third of those infected the infection comes back, and every further course of antibiotics weakens the gut flora again (Minkoff 2023).

The faecal transfer targets the cause: instead of killing the pathogen over and over, it restores a complete, healthy community of gut bacteria. The donor stool is processed and, depending on the centre, given by colonoscopy, enema, a tube into the small intestine or as a capsule. The two US products are standardised further developments of this: Rebyota is a microbiota preparation obtained from donor stool, and Vowst contains live bacteria from screened stool donations in capsules taken by mouth.

Established medicine: recurrent C. difficile infection

Here the transfer is not an experiment but part of the guidelines. Since its 2021 update, the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) prefers faecal transfer or the antibody bezlotoxumab, each in addition to standard antibiotic treatment, for the second and every further recurrence. What decides the choice of treatment is the risk of recurrence, not the severity of the disease alone (van Prehn 2021).

In Germany, according to the BfArM, the transfer is used in a very large number of hospitals, mainly for exactly this indication. In the US, the Food and Drug Administration (FDA) approved Rebyota on November 30, 2022 and, on April 26, 2023, Vowst as the first faecal microbiota product taken by mouth, both to prevent a further recurrence in adults after antibiotic treatment of a recurrent infection. These approvals are the strongest evidence that a targeted replacement of the gut flora can be a real, measurable therapy.

The idea of microbiome rejuvenation

It is understandable why the longevity scene is paying attention: if a donor’s gut flora can end a stubborn infection, perhaps it could also reverse age-related changes in the gut flora. The best-known basis is a study in Nature Medicine. Two mouse models of progeria, a hereditary disease with strongly accelerated ageing, had an altered gut flora, with more Proteobacteria and fewer Verrucomicrobia. In people with progeria the researchers also found dysbiosis, whereas centenarians had strikingly many Verrucomicrobia. When the progeria mice received the gut flora of healthy mice, they lived longer and healthier; giving the single bacterium Akkermansia muciniphila was already enough for beneficial effects (Bárcena 2019). More on this bacterium under Akkermansia.

The second line is metabolism. In 2012, a Dutch research group transferred the gut flora of lean donors to 18 men with metabolic syndrome; six weeks later, insulin sensitivity was higher than after transfer of their own stool. A meta-analysis has pooled this and other small randomized trials (Qiu 2023). If you are more interested in measuring your own gut flora or in bacterial preparations, see microbiome tests and probiotics.

What the studies show

Minkoff 2023 (Cochrane) – recurrent C. difficile infection

Six randomized trials with 320 adults from Denmark, the Netherlands, Canada, Italy and the US, almost exclusively without a weakened immune system. The transfer was given by tube, enema or colonoscopy; the comparison groups mostly received vancomycin. The infection resolved almost twice as often with transfer (relative risk 1.92), number needed to treat 3, moderate certainty. Serious adverse events (relative risk 0.73) and deaths (0.57) tended to be less frequent, with few events and wide confidence intervals. The data allow no conclusion for people with weakened immunity.

Vowst – pivotal trial

In the randomized, placebo-controlled trial, 89 adults received Vowst and 93 placebo, each after antibiotic treatment of a recurrence. Within eight weeks, the infection came back in 12.4 percent with Vowst and in 39.8 percent with placebo. Side effects more frequent than with placebo were bloating, fatigue, constipation, chills and diarrhoea (FDA 2023).

Qiu 2023 – metabolism and overweight

Meta-analysis of nine randomized trials with 303 people with overweight or metabolic syndrome, compared with placebo or their own stool. Up to six weeks after the transfer, fasting glucose (minus 0.12 mmol/l), HbA1c (minus 0.37 mmol/mol, roughly 0.03 percentage points) and insulin were lower and HDL cholesterol slightly higher. From twelve weeks on, there was no difference in any value, except for a slightly lower HbA1c in a single study. There was no difference in weight at any time. No serious adverse events occurred; the certainty of the results was mostly low.

Bárcena 2019 – mice with accelerated ageing

In two mouse models of progeria, the gut flora of healthy mice extended healthspan and lifespan; giving Akkermansia muciniphila alone also had beneficial effects. The researchers saw the restoration of secondary bile acids as a possible mechanism. The model is a rare hereditary disease, not normal ageing, and the approach has not been tested in humans.

What users report

The following figures come from surveys and are self-reports, not proof of efficacy. In a long-term follow-up from five US centres, 77 patients with recurrent C. difficile infection answered a questionnaire, on average 17 months after transfer by colonoscopy. They had, on average, five unsuccessful courses of antibiotics behind them. In 74 percent, the diarrhoea was gone within three days at most, and 53 percent said they would choose the transfer as the first treatment if the infection recurred (Brandt 2012).

An online survey reached 84 people who had done a faecal transfer on their own, 80 percent on themselves. The most common reasons were inflammatory bowel disease (35 percent) and irritable bowel syndrome (29 percent), conditions for which there is little evidence. 82 percent reported an improvement, 12 percent side effects. Respondents had been reached via foundation and social media pages; people with bad experiences are probably under-represented (Ekekezie 2020).

Where the data stop

For the longevity promise, there is not a single human study that targeted ageing, lifespan or markers of ageing. The mouse data come from a model with pathologically accelerated ageing, and whether the gut flora of a young or healthy donor takes hold in healthy older people and changes anything is an open question. For metabolism, the randomized trials tend to argue against a lasting effect: the improvements were small and gone after twelve weeks, and weight did not change.

The established part also has limits. The Cochrane review included almost only people with an intact immune system; randomized data for people with weakened immunity are lacking. In the Cochrane authors’ assessment, long-term effects have not been studied sufficiently, and large registries would be needed for that. In Brandt’s follow-up, four patients developed conditions after the transfer whose relationship to it is unclear. For inflammatory bowel disease and irritable bowel syndrome, the reasons for most self-experiments, there is little evidence according to the survey authors.

Status, approval and legal

In Germany, donor stool for treating humans is a medicinal product under Section 2(1) of the German Medicinal Products Act (AMG). It is prepared in the hospitals under the direct professional responsibility of the treating physician; this licence-exempt preparation must be notified to the competent state supervisory authority under Section 67 AMG. Clinical trials with faecal transfer are approved by the BfArM, and only with comprehensive, multi-stage donor selection and testing, including multidrug-resistant pathogens and SARS-CoV-2.

According to the BfArM in 2023, there was no ready-made medicinal product based on stool authorised in the EU. In the US, Rebyota and Vowst have been approved since 2022 and 2023, exclusively to prevent further recurrences of C. difficile infection in adults. There is no approval for metabolism, weight or longevity in either the EU or the US.

Safety

In the controlled trials on C. difficile infection, the most common complaints were mild and affected the gastrointestinal tract; serious adverse events were not more frequent than with comparison treatments. The fundamental risk lies in the material itself: bacteria, viruses and parasites can be transmitted with the stool. In 2019, two recipients from two different trials in the US developed a bloodstream infection with multidrug-resistant, ESBL-producing E. coli; genome sequencing traced both cases to the same donor, whose stool had not been tested for such pathogens. One patient died (DeFilipp 2019). For the approved product Vowst, too, the FDA points out that despite tested donors it may transmit infectious agents and may contain food allergens.

The BfArM therefore requires multi-stage donor screening with a detailed questionnaire and repeated blood and stool tests for bacteria, viruses, parasites, fungi and multidrug-resistant pathogens. It also names the possible risk of triggering unwanted immunological, metabolic or tumour-related processes in the recipient. Self-experiments at home bypass exactly this protection: in Ekekezie’s survey, 92 percent knew their donor, and most relied on information from the internet. If you are considering a faecal transfer, discuss it with a gastroenterology or infectious diseases clinic.

Sources

• Minkoff NZ et al., Cochrane Database Syst Rev 2023 – 6 randomized trials, 320 participants, recurrent C. difficile infection (PMID 37096495)
• van Prehn J et al., Clin Microbiol Infect 2021 – ESCMID guidance on the treatment of C. difficile infection in adults (PMID 34678515)
• FDA – REBYOTA (fecal microbiota, live-jslm), approval of November 30, 2022
• FDA, April 26, 2023 – approval of Vowst, the first orally administered faecal microbiota product
• BfArM – risk information: faecal microbiota transplantation (FMT, stool transplantation), risk of transmitting multidrug-resistant pathogens (as of June 26, 2023)
• DeFilipp Z et al., N Engl J Med 2019 – bloodstream infection with ESBL-producing E. coli after faecal transfer, two cases, one death (PMID 31665575)
• Qiu B et al., PLoS One 2023 – meta-analysis, 9 randomized trials, 303 participants, metabolic syndrome (PMID 37471410)
• Bárcena C et al., Nat Med 2019 – gut microbiota transfer extends healthspan and lifespan in mice with accelerated ageing (PMID 31332389)
• Brandt LJ et al., Am J Gastroenterol 2012 – long-term follow-up of 77 patients after colonoscopic faecal transfer (PMID 22450732)
• Ekekezie C et al., Am J Gastroenterol 2020 – online survey of 84 people who did a do-it-yourself faecal transfer (PMID 31972620)