The Ins and Outs of Fecal Microbiota Transplantation Administration

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 ages^10,12-27

^{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.

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