The Ins and Outs of Fecal Microbiota Transplantation Administration

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Fecal microbiota transplantation is proving to be an effective treatment for many patients with specific disorders associated with dysbiosis.

Trillions of living microbes and their “theater of activities” collectively form the gut microbiome, in which a consortium of commensal microbes work synergistically to maintain overall health.1 Preserving phylogenetic richness and promoting the growth of beneficial bacteria, such as Bacteroidetes and Firmicutes, is implicit for holistic well-being.2-4

Disruptions to the microbial community composition can result in dysbiosis,3 a situation that enables potential intestinal colonization by opportunistic pathogens, such as Clostridioides difficile (C. difficile).5 Dysbiosis is associated with both intestinal and extra-intestinal disorders.6

Some causes and risk factors include antibiotics, advanced age, hospitalization, presence of comorbid conditions, or the use of proton pump inhibitors.7 Although fidaxomicin and vancomycin are the current recommended standard-of-care antibiotic treatments for an initial or recurrent C. difficile infection (rCDI),8 these antibiotics may inadvertently worsen the underlying dysbiosis.

Fecal microbiota transplantation (FMT), the process of introducing fecal material from a screened, healthy donor into a patient’s gastrointestinal (GI) tract to restore microbial diversity, is proving to be an effective treatment for many patients with specific disorders associated with dysbiosis.9 FMT was first reported in Western medicine in 1958, yet the procedure was first documented in China in the 4th century AD, when Ge Hong used human stool to treat food poisoning and severe diarrhea (Fig. 1).10-27

Figure 1. FMT through the ages10,12-27

Click image to enlarge.

Alongside the accumulation of epidemiologic evidence linking dysbiosis and multiple disease states, FMT has been investigated as a potential therapy for various disorders, including inflammatory bowel disease, ulcerative colitis, and rCDI.11,28 Although FMT is an established approach to microbiome restoration, a standard approach to its use is lacking and it is associated with significant safety alerts.8

Limitations include the risks associated with administering living microbes into the intestine of patients with impaired immunity and dysregulated intestinal epithelial barrier function, as well as the possible transmission of multidrug-resistant organisms.29,30 FMT may be administered through various routes, including rectal administration, colonoscopy, nasogastric tube, and oral capsules, with each modality associated with varying clinical success.31,32

FMT preparation, including whether it is used in the form of fresh or frozen samples, as well as donor relation, is not believed to affect the clinical outcome.32 FMT introduces healthy and diverse bacteria, as well as viruses, fungi, protozoa, microbial peptides, metabolites, and bacterial components, which contribute to its beneficial effects.11

As of 2012, pharmaceutical products containing live microorganisms that are “applicable to the prevention, treatment, or cure of a disease or condition in human beings” have received the FDA classification of live biotherapeutic products (LBPs).33,34

LBPs are not intended to reach the systemic circulation, but rather exert their effect through direct interactions with native microbiota and/or the modulation of host-microbiota relation, indirectly leading to biologic effects within the recipient. Clinical studies evaluating the use of LBPs as a potential option for rCDI treatment have consistently reported positive results.35-37

Novel LBPs with regulated and standardized production, such as those from Ferring (RBX2660), Finch (CP-101), and Seres (SER-109), are currently in development.36,38,39 RBX2660 is a potential first-in-class, microbiota-based LBP being developed to reduce recurrence of CDI in adults.37,39,40

RBX2660 contains a consortium of bacteria from the Bacteroidetes and Firmicutes phyla,39,41 and is administered as a single dose by a health care provider (HCP) via rectal administration, without the need for sedation, colonoscopy, or bowel preparation before administration. In a phase 2 clinical trial, RBX2660 treatment, when given after a standard course of antibiotics, was well tolerated in patients with rCDI and correlated with a shift toward a healthy gut microbiome.37

Due to the extensive range of variables influencing the role of route administration on treatment efficacy, the consensus regarding the superiority of one approach over another remains elusive.42 Factors to consider include the potential for interactions with other medications, convenience, the ease of administration, a patient's comfort, any requirements for pre-treatment, hospitalization, and the need of subsequent FMTs.

The role of the route of administration becomes significant when considering the disease being treated. For example, rCDI is a localized colonic infection that would most directly be treated by the rectal administration of FMT, whereas a disorder such as Crohn disease affects both the upper and lower GI tract, and a different approach may be more suitable.31

Rehorova et al. (2022) have developed a standard operating procedure for administering FMT to critically ill patients, and propose that administration through the lower GI routes (colonoscopy or retention enema), is the most efficient approach to restoring the microbiome.11 Concerns surrounding the upper GI routes include the risks of endoscopy in patients with active colitis and anesthesia, as well as logistic issues with the availability of endoscopists.11

The oral administration of FMT may pose a challenge to patients who have an aversion to taking capsules, are unable to take larger capsules or multiple capsules at once, or who have concerns over the risk of capsule aspiration or potential drug interactions.31

FMT using rectal administration has a lower risk of complications than colonoscopy (risk of perforation with colonoscopy and complications from anesthesia),does not require any specific administration environment, and is less expensive and time-consuming, making it convenient for both patients and HCPs.43

Moreover, the rectal administration of LBPs facilitates microbiota colonization in the colon, as the outer mucus layer of the colon provides a niche for intestinal bacteria and the mucus oligosaccharides expedite their adhesion.44 It is important to realize that there are minimal head-to-head trials comparing FMT administration modality, and every assumption that has been made to date is inferential from clinical trials that vary in structure.

The composition of the gut microbiome is intrinsically linked to overall health and well-being. A lack of microbial diversity is related to dysbiosis and a variety of associated disorders, including CDIand its recurrence. The re-emergence of FMT and the development of novel LBPs offer patients and HCPs a promising array of therapeutic options.

Notably, the convenient rectal administration of therapies such as RBX2660 have shown encouraging and consistent results, supporting its use in the treatment of rCDI.

About the Authors

Glenn Tillotson, PhD, GST Micro, North, VA.

Kerry LaPlante, PharmD, FCCP, FIDSA, The University of Rhode Island, College of Pharmacy, RI.

Paul Feuerstadt, MD, FACG, AGAF, PACT Gastroenterology Centre, Hamden, CT.

References

1. Berg G, Rybakova D, Fischer D, et al. Microbiome definition re-visited: old concepts and new challenges. Microbiome. 2020;8(1):103. doi:10.1186/s40168-020-00875-0

2. Sorbara MT, Pamer EG. Interbacterial mechanisms of colonization resistance and the strategies pathogens use to overcome them. Mucosal Immunol. 2019;12(1):1-9. doi:10.1038/s41385-018-0053-0

3. Thursby E, Juge N. Introduction to the human gut microbiota. Biochem J. 2017;474(11):1823-1836. doi:10.1042/BCJ20160510

4. McBurney MI, Davis C, Fraser CM, et al. Establishing what constitutes a healthy human gut microbiome: state of the science, regulatory considerations, and future directions. J Nutr. 2019;149(11):1882-1895. doi:10.1093/jn/nxz154

5. Goldberg E, Amir I, Zafran M, et al. The correlation between Clostridium difficile infection and human gut concentrations of Bacteroidetes phylum and clostridial species. Eur J Clin Microbiol Infect Dis. 2014;33(3):377-83. doi:10.1007/s10096-013-1966-x

6. Buford TW. (Dis)Trust your gut: the gut microbiome in age-related inflammation, health, and disease. Microbiome. 2017;5(1):80. doi:10.1186/s40168-017-0296-0

7. Depestel DD, Aronoff DM. Epidemiology of Clostridium difficile infection. J Pharm Pract. 2013;26(5):464-75. doi:10.1177/0897190013499521

8. Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044. doi:10.1093/cid/ciab549

9. Khoruts A, Staley C, Sadowsky MJ. Faecal microbiota transplantation for Clostridioides difficile: mechanisms and pharmacology. Nat Rev Gastroenterol Hepatol. 2021;18(1):67-80. doi:10.1038/s41575-020-0350-4

10. Zhang F, Luo W, Shi Y, Fan Z, Ji G. Should we standardize the 1,700-year-old fecal microbiota transplantation? Am J Gastroenterol. 2012;107:1755-1756.

11. Řehořová V, Cibulková I, Soukupová H, Duška F. Multi-donor fecal microbial transplantation for critically ill patients: rationale and standard operating procedure. Future Pharmacol. 2022;2(1):55-63. doi:10.3390/futurepharmacol2010005

12. Lewin RA. More on Merde. Perspect Biol Med. 2001;44:594-607. doi:10.1353/pbm.2001.0067

13. Eiseman B, Silen W, Bascom GS, Kauvar AJ. Fecal enema as an adjunct in the treatment of pseudomembranous enterocolitis. Surgery. 1958:854-859.

14. Cutolo LC, Kleppel NH, Freund HR, Holker J. Fecal feedings as a therapy in staphylococcus enterocolitis. NY State J Med. 1959;59:3831-3833.

15. Bowden TA, Mansberger AR, Lykins LE. Pseudomembraneous enterocolitis: mechanism for restoring floral homeostasis. Am Surg. 1981;47(4):178-183.

16. Schwan A, Sjolin S, Trottestam U, Aronsson B. Relapsing Clostridium difficile enterocolitis cured by rectal infusion of homologous faeces. The Lancet. 1983;322(8354):845. doi:10.1016/S0140-6736(83)90753-5

17. Tvede M, Rask-Madsen J. Bacteriotherapy for chronic relapsing Clostridium difficile diarrhoea in six patients. The Lancet. 1989;333(8648):1156-1160. doi:https://doi.org/10.1016/S0140-6736(89)92749-9

18. Borody TJ, Warren EF, Leis SM, Surace R, Ashman O, Siarakas S. Bacteriotherapy using fecal flora: toying with human motions. J Clin Gastroenterol. 2004;38(6)

19. Byrne B, Ward L, Louie M, Louie T, Krulicki W, Louie TJ. Home-based fecal flora infusion to arrest multiply-recurrent Clostridium difficile infection (CDI). presented at: 46th Annual Meeting of the Infectious Diseases Society of America; 2008; Session Epidemiology and Treatment of C. difficile.

20. Aas J, Gessert CE, Bakken JS. Recurrent Clostridium difficile colitis: case series involving 18 patients treated with donor stool administered via a nasogastric tube. Clin Infect Dis. 2003;36:580-585.

21. van Nood E, Vrieze A, Nieuwdorp M, et al. Duodenal infusion of donor feces for recurrent Clostridium difficile. N Engl J Med. 2013;368(5):407-15. doi:10.1056/NEJMoa1205037

22. Youngster I, Russell GH, Pindar C, Ziv-Baran T, Sauk J, Hohmann EL. Oral, capsulized, frozen fecal microbiota transplantation for relapsing Clostridium difficile infection. JAMA. 2014;312(17):1772-1778. doi:10.1001/jama.2014.13875

23. Allegretti JR, Fischer M, Papa E, et al. Su1738 Fecal microbiota transplantation delivered via oral capsules achieves microbial engraftment similar to traditional delivery modalities: safety, efficacy and engraftment results from a multi-center cluster randomized dose-finding study. Gastroenterol. 2016;150(4):S540.

24. Kelly CR, Khoruts A, Staley C, et al. Effect of fecal microbiota transplantation on recurrence in multiple recurrent Clostridium difficile infection. Ann Intern Med. 2016;165(9):609-616. doi:10.7326/M16-0271

25. Jiang ZD, Ajami NJ, Petrosino JF, et al. Randomised clinical trial: faecal microbiota transplantation for recurrent Clostridum difficile infection - fresh, or frozen, or lyophilised microbiota from a small pool of healthy donors delivered by colonoscopy. Aliment Pharmacol Ther. 2017;45(7):899-908. doi:10.1111/apt.13969

26. Hota SS, Sales V, Tomlinson G, et al. Oral vancomycin followed by fecal transplantation versus tapering oral vancomycin treatment for recurrent Clostridium difficile infection: an open-label, randomized controlled trial. Clin Infect Dis. 2017;64(3):265-271. doi:10.1093/cid/ciw731

27. Dubberke ER, Lee CH, Orenstein R, Khanna S, Hecht G, Gerding DN. Results from a randomized, placebo-controlled clinical trial of a RBX2660—a microbiota-based drug for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;67(8):1198-1204. doi:10.1093/cid/ciy259

28. Choi HH, Cho YS. Fecal microbiota transplantation: current applications, effectiveness, and future perspectives. Clin Endosc. 2016;49(3):257-65. doi:10.5946/ce.2015.117

29. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381(21):2043-2050. doi:10.1056/NEJMoa1910437

30. US Food and Drug Administration. Information pertaining to additional safety protections regarding use of fecal microbiota for transplantation – screening and testing of stool donors for multi-drug resistant organisms. US Food and Drug Administration. Updated 06/18/2019. Accessed 11/29/2021. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/information-pertaining-additional-safety-protections-regarding-use-fecal-microbiota-transplantation

31. Gulati M, Singh SK, Corrie L, Kaur IP, Chandwani L. Delivery routes for faecal microbiota transplants: available, anticipated and aspired. Pharmacol Res. 2020;159:104954. doi:10.1016/j.phrs.2020.104954

32. Ramai D, Zakhia K, Fields PJ, et al. Fecal microbiota transplantation (FMT) with colonoscopy Is superior to enema and nasogastric tube while comparable to capsule for the treatment of recurrent Clostridioides difficile infection: a systematic review and meta-analysis. Dig Dis Sci. 2021;66(2):369-380. doi:10.1007/s10620-020-06185-7

33. Cordaillat-Simmons M, Rouanet A, Pot B. Live biotherapeutic products: the importance of a defined regulatory framework. Exp Mol Med. 2020;52(9):1397-1406. doi:10.1038/s12276-020-0437-6

34. US Department of Health and Human Services. Early clinical trials with live biotherapeutic products: chemistry, manufacturing, and control information (guidance for industry). Published February 2012. Updated June 2016. Accessed April 21, 2022. https://www.fda.gov/files/vaccines,%20blood%20&%20biologics/published/Early-Clinical-Trials-With-Live-Biotherapeutic-Products--Chemistry--Manufacturing--and-Control-Information--Guidance-for-Industry.pdf

35. Blount KF, Shannon WD, Deych E, Jones C. Restoration of bacterial microbiome composition and diversity among treatment responders in a phase 2 trial of RBX2660: an investigational microbiome restoration therapeutic. Open Forum Infect Dis. 2019;6(4):ofz095. doi:10.1093/ofid/ofz095

36. Feuerstadt P, Louie TJ, Lashner B, et al. SER-109, an oral microbiome therapy for recurrent Clostridioides difficile infection. N Engl J Med. 2022;386(3):220-229. doi:10.1056/NEJMoa2106516

37. Orenstein R, Dubberke ER, Khanna S, et al. Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial. BMC Infect Dis. 2022;22(1):245. doi:10.1186/s12879-022-07256-y

38. Gonzales-Luna AJ, Carlson TJ. Follow your gut: microbiome-based approaches in the developmental pipeline for the prevention and adjunctive treatment of Clostridioides difficile infection (CDI). Curr Infect Dis Rep. 2020;22(8)doi:10.1007/s11908-020-00729-8

39. Rebiotix announces first patient enrolled in phase 3 clinical trial of RBX2660 for the prevention of recurrent clostridium difficile infection. 2017.

40. Bancke L. Efficacy of investigational microbiota-based live biotherapeutic RBX2660 in patients with recurrent clostridioides difficile infection: Data from five prospective clinical studies. presented at: IDWeek 2021; 2021; Virtual.

41. Jones LA, Jones CRS, M.K., inventors; Microbiota restoration therapy (MRT), compositions and methods of manufacture. United States 2017.

42. Kassam Z, Lee CH, Yuan Y, Hunt RH. Fecal microbiota transplantation for Clostridium difficile infection: systematic review and meta-analysis. Am J Gastroenterol. 2013;108(4):500-8. doi:10.1038/ajg.2013.59

43. Dowle C. Faecal microbiota transplantation: a review of FMTas an alternative treatment for Clostridium difficile infection. Biosci Horiz. 2016;9:1-14. doi:10.1093/biohorizons/hzw007/2526818

44. Sicard JF, Le Bihan G, Vogeleer P, Jacques M, Harel J. Interactions of intestinal bacteria with components of the intestinal mucus. Front Cell Infect Microbiol. 2017;7:387. doi:10.3389/fcimb.2017.00387