Faecal microbiota transplantation: past, present and future

Beyond its role in therapy, FMT is providing insights into the importance of intestinal microbiota in health and disease

As physicians and scientists, we live in exciting times! Bacteria are no longer viewed solely as pathogens, but also as key partners in the maintenance of health. It is conceivable that altering the microbiota in our gastrointestinal tract may either predispose us to disease or ameliorate conditions we already have. Faecal microbiota transplantation (FMT) has captured the attention of the lay press and professional journals since 1958, when faecal enema was reported to have cured four patients near death from severe Micrococcus pyogenes colitis.1

The rationale for treating recurrent Clostridium difficile infection (rCDI) with FMT is the recognition that a diverse population of microbiota is needed to protect our intestines from colonisation by pathogens. The underlying mechanisms are complex, but may include competition for nutrients; enhancement of epithelial barriers; modifying bacterial adherence, reproduction and virulence; niche exclusion; and modulation of inflammation and the host immune system.

It is currently thought that CDI begins with disruption of the normal balance of colonic microbiota, usually as a consequence of antibiotic use. Phylogenetic richness is reduced in the stools of patients with rCDI, including diminished dominance by the Bacteroidetes and Firmicutes phyla, when compared with healthy controls or patients after a single episode of CDI.2 The therapeutic benefit of FMT was therefore thought to derive from its re-establishing a balanced microbiota, with its attendant colonisation resistance. In fact, the microbiota of the recipient’s stool evolves to closely resemble that of the donor about 2 weeks after FMT, a change that persists for at least 4 months.3

A more specific mechanism by which FMT might prevent rCDI involves secondary bile acids, which inhibit the germination and growth of C. difficile.4 The concentrations of primary bile acids in faecal samples from patients with rCDI are high, whereas post-FMT faecal samples and non-CDI faeces mostly contain secondary bile acids. Indeed, one research group identified secondary bile acid-producing bacteria — including members of the genera Holdemania and Clostridium XIVa (eg, C. scindens) — in the stools of patients with rCDI who, as part of a double blind, randomised placebo-controlled trial of therapeutic FMT, received their own stool as an autologous placebo,5 yet experienced a surprisingly high symptomatic cure rate (63%).6

It was recently reported that a jejunal infusion of culture-sterile faecal filtrates restored normal stool habits to five patients with rCDI.7 Bacterial cell wall components or DNA fragments that stimulate host responses via pattern recognition receptors may have induced alterations in ecologic niches needed for the survival of “good” bacteria or colonisation by bacteriophages or viruses that favourably alter microbiota community dynamics. Perhaps not all bacterial species are needed for successful FMT, but rather certain metabolic products or functionally critical taxa, or even non-bacterial members of the intestinal biome, such as viruses.

As detailed in the article by Moayyedi and colleagues in this issue of the MJA,8 the first systematic review of randomised controlled trials of FMT for treating rCDI, there is moderate quality evidence that FMT is effective, with cure rates ranging between 60% and 100%, depending on the method and route of FMT. FMT is currently recommended for rCDI after treatment with vancomycin or fidaxomicin has failed (American College of Gastroenterology, European Society of Clinical Microbiology and Infectious Diseases, Australasian Society for Infectious Diseases), or when rCDI is severe or complicated (Australasian Society for Infectious Diseases).9

In the article by Moayyedi and his co-authors,8 as in other systematic reviews, no serious adverse effects (AEs) were definitely attributed to FMT for rCDI, even in immune-compromised patients, although exacerbation of pre-existing inflammatory bowel disease (IBD) has been reported.10 About 30% of FMT recipients experience bloating, flatulence, cramping, diarrhoea, constipation or nausea after FMT, and severe AEs are noted following 2.0% and 6.2% of upper and lower gastrointestinal FMTs respectively.10 Definitely or probably related severe AEs include bacteraemia, diverticulitis, and norovirus infection, as well as exacerbation of pre-existing ulcerative colitis.10 Possibly related severe AEs include appendicitis, peritonitis, urinary tract infections, and auto-immune diseases such as peripheral neuropathy, Sjögren syndrome, idiopathic thrombocytopenic purpura, and rheumatoid arthritis.10 Procedural complications, including death from aspiration, have also been reported.10

Perhaps more important than short term AEs are the unknown long term consequences of FMT. Is it possible that, by altering the intestinal microbiome, we are setting the stage for diseases not currently recognised as being associated with known organisms? Association is not the same as causation, and establishing causation requires a great deal of data and time. A national registry was recently established for this purpose by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health in the United States. It expects to enrol 4000 patients over a 10-year period, and will facilitate studying patient outcomes and short and long term AEs associated with FMT.

FMT is but the first step in the long journey to curing CDI. Practice has already evolved from using stool provided by a recipient-selected donor to employing cryopreserved stool donated by screened healthy donors. Success with thawed material and experience with stool banking has been positive, as documented by Razik and colleagues in this issue of the Journal.11 The time is not far off, however, when whole stool, whether fresh or preserved, will no longer be used; instead, a designer infusion or capsule of selected microorganisms, either alone or combined with a microbiotic metabolic product, will be given to restore a balanced microbiota. FMT has also been used to treat many other gastrointestinal diseases, including IBD, chronic constipation, and irritable bowel syndrome with diarrhoea. The list of non-gastrointestinal diseases with an abnormal faecal microbiome profile is long and growing, and, for some, FMT is reported to achieve symptomatic improvement or even a cure, including obesity, metabolic syndrome, childhood autism, chronic fatigue syndrome, fibromyalgia, Parkinson disease, and multiple sclerosis.

We bear witness to a sea change in the way that microorganisms and disease are viewed. Patient safety must remain paramount, and we will need to confirm or refute new implications by properly designed clinical trials, but the prospect of progress is tantalising. What an exciting time!