Faecal microbiota transplantation: a review

Faecal microbiota transplantation (FMT) is not a new concept, being first described in traditional Chinese medicine over 1000 years ago¹. FMT delivered by faecal enema was successfully used in the treatment of pseudomembranous enterocolitis in 1958². A timeline for FMT over the years is shown in Figure 1. FMT is now accepted to be the most effective treatment for recurrent or refractory Clostridioides difficile infection (CDI). Clinical trials have also been conducted using FMT in primary sclerosing cholangitis, non-alcoholic steatohepatitis, type II diabetes mellitus, irritable bowel syndrome, inflammatory bowel disease, hepatic encephalopathy, and eradication of multiresistant organisms³.

Perturbations in the composition of intestinal microbiota occur after administration of antibiotics, other medications, dietary changes and travel. Antibiotic exposure decreases the alpha diversity with reduction in Firmicutes and Bacteroidetes phyla and proliferation of Proteobacteria including Enterobacteriaceae⁴. Following FMT there is reduction in Proteobacteria and expansion of Firmucutes, Ruminococcaceae, Lachnospiraceae, Clostridiaceae and Bacteroidetes⁴. Recipient microbiota engraftment has been demonstrated by day three after FMT⁵. This microbial community correlates with that of the donor’s microbial community and has been observed to be stable for 4 months and up to one year^4–6. Complete donor engraftment may not be necessary if functionally effective taxa are present and bacteria associate with secondary bile acid metabolism to provide resistance to recurrent infection⁴.

C. difficile is a Gram-positive anaerobic, spore forming and toxin-producing bacillus¹. Spores are transmitted via the faecal–oral route and are an important cause of hospital-acquired infection. Between 15–70% of infants and 5% of adults are colonised, being more frequent in hospital and nursing home residents¹.

Antibiotic exposure, older age and hospitalisation are major risk factors for CDI¹. Clinical spectrum spans diarrhoea, ileus and toxic megacolon, with severe CDI presenting with fever, haemodynamic instability and peritonitis. Recurrent CDI is classified as recurrence of CDI within 8 weeks of successful treatment and refractory CDI is defined as absent clinical improvement after 3–4 days of appropriate treatment⁷.

FMT has been shown to be the most effective treatment for recurrent CDI and has repeatedly demonstrated superiority to comparators since the first randomised trial in 2013^8,9. In a meta-analysis of seven randomised controlled trials and 30 case series, FMT was more effective than vancomycin (RR: 0.23) for recurrent and refractory CDI with clinical resolution rates of 92%¹⁰.

The Australasian Society for Infectious Diseases published guidelines for management of CDI that includes FMT⁷. Australian therapeutic guidelines recommend FMT as preferred treatment for second and subsequent recurrences or ongoing refractory disease¹¹. This is similar to American, European and British guidelines^12–14.

In general, FMT is considered a safe procedure with rare adverse events. Some of the common adverse effects include fever, abdominal pain, bloating and alteration to bowel habits^15,16. Procedural complications include bowel perforation and mucosal tears^15,16. Infectious complications including transmission of norovirus, Gram-negative bacteraemia and transmission of multiresistant organisms have been reported¹⁵. Deaths have been due to polymicrobial bacteremia in the setting of toxic megacolon, aspiration pneumonia as a complication of anaesthesia during colonoscopic FMT and regurgitation of faeculant material during endoscopic FMT^15–18. Donor stool screening for multiresistant organisms is now mandatory following two cases of donor derived Escherichia coli Extended Spectrum Beta-Lactamase bacteraemia, resulting in the death of one patient¹⁹. The United States Food and Drug Administration (FDA) have recently issued a safety alert regarding FMT after cases of enteropathogenic E. coli (EPEC) and Shigatoxin-producing E. coli (STEC) infection in recipients possibly linked to a stool bank (www.fda.gov).

Food allergy with anaphylaxis is a contraindication to FMT¹². FMT should be offered with caution in patients with decompensated chronic liver disease or immunosuppression and special consideration to donor screening (for CMV, EBV and Strongyloides) should be given for immunosuppressed recipients¹². Elderly and debilitated patients have been treated with FMT for CDI with success, however they may have a lower primary cure rate and higher recurrence rate compared to a younger cohort^18,20. Adverse events in the elderly population have included aspiration; therefore the colonoscopy route has been suggested as the preferred route of administration¹⁸.

Limited data exists on long-term adverse effects. Jalanka et al.²¹ found no difference in incidence of severe diseases or weight gain after 3.8 years of FMT and improved bowel habits and mental health were reported.

Traditionally, donors known to the patient were selected, however this could result in ethical and confidentiality issues if identifying a disease in the donor or a transmission event to recipient²². Alternatively, FMT is best sourced from a centralised stool bank from healthy unrelated donors¹². Donors should be between 18 and 60 years of age and BMI between 18 and 30 kg/m^3 12,23. Donors are screened with a questionnaire followed by blood and stool testing with recommendations in Table 1. Woodworth et al.³ recommend screening for carbapenem resistant Enterobacteriaceae, vancomycin resistant Enterococci and those with frequent contact with health care should be excluded. The risk of transmission of non-communicable diseases remains unknown; therefore, donors with cardiovascular disease, stroke, diabetes mellitus, obesity, metabolic syndrome and malnutrition are excluded³.

Table 1.  Example of donor questionnaire and donor blood and stool testing.

Stool should be processed within 6 hours of defaecation. FMT material prepared in aerobic conditions has been effective for the treatment of recurrent C. difficile associated diarrhea⁸. However, ambient air exposure impacts on viable bacterial composition particularly for oxygen sensitive species²⁴. Processing stool in an anaerobic chamber allows preservation of commensal species²⁴. Freezing reduces the overall viability but the microbiota composition is not significantly different to fresh specimens²⁴, with viable bacteria remaining after 6 months of frozen storage in 10% glycerol^22,25 and no difference in FMT efficacy observed when used for CDI¹⁰.

There are a number of preparations for FMT including fresh, frozen and encapsulated faecal suspensions. Encapsulated freeze-dried preparations had 88% clinical success (49 patients) with no recurrence over two months²⁶. In a randomised study of 72 patients with recurrent CDI, cure rates were highest for fresh faeces (100%), lowest for lyophilized product (78%; P = 0.022 vs fresh) and intermediate for frozen product (83%; P = 0.233 vs fresh)²⁷. CDI recurrence was prevented in 84% receiving oral lyophilized microbiota capsules compared to 88% with FMT by enema (P = 0.74)²⁸. In a non-inferiority randomised trial there was no difference after single treatment with capsule or colonoscopy delivery (both 96.2% without recurrent CDI at 12 weeks)²⁹.

Bowel lavage is administered prior to FMT particularly for the lower gastrointestinal route. There should be minimum 24 hours free from antibiotics before FMT and at least 72 hours after FMT¹². FMT can be delivered to upper (nasogastric, nasoduodenal or nasojejunal tube or upper endoscopy) or lower gastrointestinal tract (colonoscopic administration to caecum or terminal ileum or enema if not possible). Ianiro et al.³⁰ conducted a systematic review and meta-analysis of fifteen studies on different protocols of FMT for CDI. Multiple infusions increased efficacy compared to single infusion (93% vs 76%)³⁰. Duodenal delivery had lower efficacy (P = 0.039) and colonoscopy had higher efficacy rates (P = 0.006). Lower faecal amount (≤50g) and enema had lower efficacy rates after single infusion³⁰. Another meta-analysis also demonstrated administration by lower gastrointestinal route was more effective (95%) compared to upper gastrointestinal delivery (85%) with no difference between fresh or frozen FMT¹⁰. Consecutive courses after failure of first FMT showed incremental effect¹⁰.

Historically, FMT has been performed with varying levels of sophistication across Australia, ranging from the ad hoc and infrequent preparation of fresh FMT material for recurrent CDI to specialised centres operating stool banks, such as the Biomebank (Adelaide, SA) and the Centre for Digestive Diseases (Sydney, NSW). In September 2019, the Australian Minister for Health determined that supply of faecal microbiota transplant products be regulated by the Therapeutic Goods Administration (TGA). The new regulatory model classifies most FMT products as class 1 or 2 biologicals depending on the extent of manipulation and whether manufactured in a hospital and used onsite. A Draft Standards for Faecal Microbiota Transplant Products is available with finalised FMT regulatory requirements expected in early 2020 (www.tga.gov.au). The American Gastroenterological Association (AGA) has proposed an FMT National Registry to collect outcomes to assess short- and long-term safety and effectiveness and current practices³¹. An international consensus on stool banking for FMT in clinical practice is available³². There are now Australian consensus statements for the regulation, production and use of FMT in clinical practice²³.

Small sample studies have shown that FMT was effective in reducing the number of antibiotic resistance genes in patients’ resistome³³. Huttner et al.³⁴ hypothesised that decolonisation could be achieved with oral antibiotics (colistin and neomycin) followed by recolonisation to restore intestinal microbiota. The results were only slightly in favour of the intervention group (OR 1.7). Nine uncontrolled studies with heterogeneity have evaluated the use of FMT for multidrug resistant Gram-negative bacteria decolonisation. However, the European guidelines suggest there is insufficient evidence for or against FMT in this context³⁵. Similarly, UK guidelines do not recommend FMT as treatment for inflammatory bowel disease or other gastrointestinal or non-gastrointestinal disease¹². Australian guidelines suggest FMT has been shown to be successful in induction therapy for mild to moderate ulcerative colitis however more studies are required before it can be implemented into standard care²³. This is a developing research field and future treatment of conditions with FMT will be seen in the future.

The authors declare no conflicts of interest.

Figure 1.  Timeline for faecal microbiota transplantation.