What else do we need to know about faecal microbiota transplantation?

Recently, I’ve had the pleasure of working on an upcoming UEG online course on faecal microbiota transplantation (FMT). The use of FMT has resulted in remarkably high treatment success rates in the management of recurrent Clostridium difficile infections (CDI). However, many central questions remain unanswered: for instance, why and how does FMT work, and how personalized does FMT need to be? In addition, the procedure from donor selection and screening to successful infusion of donor stool is cumbersome, and steps towards developing and implementing simpler and more standardized FMT protocols are warranted.

FMT has a success rate of 87–90% in the treatment of severe or recurrent CDI (infections that do not respond to treatment with vancomycin or metronidazole, for example).¹ Such infections are typically nosocomial, arising after extensive exposure to broad-spectrum antibiotics, for example as treatment for urinary tract infections. CDI is one of the most common healthcare-associated infections, with up to 40% of patients suffering from disease recurrence following standard antibiotic therapy.² FMT typically leads to C. difficile eradication and helps restore intestinal gut microbiota diversity in the recipient. Research performed with a view to extending the applicability of FMT to other diseases, including inflammatory bowel disease, irritable bowel syndrome and metabolic disorders, is ongoing; however, the results so far do not appear as promising as for recurrent CDI.¹

The FMT procedure involves identification of a donor, screening of donor stool for pathogens, stool preparation (including cryopreservation if necessary), preparation of the recipient (antibiotic treatment and enteric cleansing), infusion of the donor stool and post-procedural management of the patient, including the monitoring of adverse events. Hence, the treatment is somewhat unwieldy compared with antibiotic treatment alone.

If more was known about the elements in stool that make FMT work, it might be possible to develop a simpler FMT procedure. For instance, if only certain faecal bacteria are needed for successful FMT, the production of synthetic bacterial suspensions could be standardized, scaled up and potentially commercialized. Such a system would also reduce the risk of transferring potential pathogens such as enteric viruses and parasites that might be difficult to detect during routine microbiological screening of donor stool. In fact, such products are already on the market (e.g. RBX2660 and SER-109). SER-109 capsules contain fractionated and encapsulated spores, and when given orally, they prevented recurrent CDI in 29/30 patients included in a clinical trial.³ By using the spores only (and not live microbes), donor stool could be treated with ethanol to inactivate any pathogens present in the faeces.

Speaking of pathogens, while there are some guidelines as to what donors and donor stool specimens should be screened for,¹ there seems to be no consensus on what organisms are actually allowed in donor stool. Some yeasts (Candida, Saccharomyces etc.) and protists (Blastocystis, Dientamoeba) are extremely common long-term colonizers of the human intestinal tract, and some are more common in healthy individuals than in patients with gastrointestinal disorders.^4–6 Some of these organisms are not usually detected by standard microbiological methods, and we know very little about the fate and clinical impact of such organisms when transferred from a donor to a recipient. Obviously, when donor stool is cryopreserved (for stool banking) or treated with ethanol, these organisms probably do not survive.

Perhaps isolated spores or other stool elements (live organisms, metabolites etc.) can be confirmed to work just as well as crude stool. However, a study by Li et al.⁷ indicates that stool from one donor may work differently when administered to different recipients. As such, establishment of the donor microbiota may rely on whatever bacterial genera, species and strains are already present in the recipient prior to infusion.

Obviously, future FMT regulations will directly reflect scientific progress. Is stool—or components thereof—to be considered a drug or a tissue? Which disease or diseases can be cured by a standardized approach using, for example, microbial suspensions/synthetic preparations, and which may require a more individual approach, potentially involving a specific donor?

While we know more about why some patients develops severe disease² and the microbiota changes that occur in the recipient upon FMT,^2,8 we still know very little about the exact mechanism underlying successful FMT. A more detailed understanding of the effect of each individual stool component and the interplay between these and the host will inform further research into the use of FMT for the treatment of diseases other than recurrent CDI.

References

1. Kelly CR, Kahn S, Kashyap P, et al. Update on fecal microbiota transplantation 2015: Indications, methodologies, mechanisms, and outlook. Gastroenterology 2015; 149: 223–237. http://www.gastrojournal.org/article/S0016-5085%2815%2900680-0/abstract
2. Seekatz AM, Aas J, Rubin TA, et al. Recovery of the gut microbiome following fecal microbiota transplantation. MBio 2014; 5: e00893-14. http://mbio.asm.org/content/5/3/e00893-14.abstract?related-urls=yes&legid=mbio;5/3/e00893-14
3. Khanna S, Pardi DS, Kelly CR, et al. A novel microbiome therapeutic increases gut microbiota diversity and prevents recurrent Clostridium difficile infection. J Infect Dis Epub ahead of print 8 February 2016. DOI: 10.1093/infdis/jiv766. http://jid.oxfordjournals.org/content/early/2016/02/04/infdis.jiv766.abstract
4. Krogsgaard LR, Engsbro AL, Stensvold CR, et al. The prevalence of intestinal parasites is not greater among individuals with irritable bowel syndrome: a population-based case-control study. Clin Gastroenterol Hepatol 2015; 13: 507–513. http://www.cghjournal.org/article/S1542-3565%2814%2901324-X/abstract
5. Andersen LO, Bonde I, Nielsen HB, et al. A retrospective metagenomics approach to studying Blastocystis. FEMS Microbiol Ecol 2015; Pii: fiv072. http://femsec.oxfordjournals.org/content/91/7/fiv072.long
6. Petersen AM, Stensvold CR, Mirsepasi H, et al. Active ulcerative colitis associated with low prevalence of Blastocystis and Dientamoeba fragilis infection. Scand J Gastroenterol 2013; 48: 638–639. http://www.tandfonline.com/doi/abs/10.3109/00365521.2013.780094?journalCode=igas20#.Vyr-Bnp35sM
7. Li SS, Zhu A, Benes V, et al. Durable coexistence of donor and recipient strains after fecal microbiota transplantation. Science 2016; 352: 586–589. http://science.sciencemag.org/content/352/6285/586
8. Seekatz AM, Rao AM, Santhosh K, et al. Dynamics of the fecal microbiome in patients with recurrent and nonrecurrent Clostridium difficile infection. Genome Med 2016; 8: 47. https://genomemedicine.biomedcentral.com/articles/10.1186/s13073-016-0298-8