Advancements in Novel Live Biotherapeutic Products for Clostridioides difficile Infection Prevention

Abstract

The profound impact of the human microbiome on health and disease has captivated the interest of clinical and scientific communities. The human body hosts a vast array of microorganisms collectively forming the human microbiome, which significantly influences various physiological processes and profoundly shapes overall well-being. Notably, the gut stands out as an exceptional reservoir, harboring the most significant concentration of microorganisms, akin to an organ in itself. The gut microbiome's composition and function are influenced by genetics, environment, age, underlying conditions, and antibiotic usage, leading to dysbiosis and pathogenesis, such as Clostridioides difficile infection (CDI). Conventional CDI treatment, involving antibiotics like oral vancomycin and fidaxomicin, fails to address dysbiosis and may further disrupt gut microbial communities. Consequently, emerging therapeutic strategies are focused on targeting dysbiosis and restoring gut microbiota to advance CDI therapeutics. Fecal microbiota transplantation (FMT) has demonstrated remarkable efficacy in treating recurrent CDI by transferring processed stool from a healthy donor to a recipient, restoring gut dysbiosis and enhancing bacterial diversity. Moreover, 2 newer Food and Drug Administration (FDA)-approved live biotherapeutic products (LBP), namely, Fecal Microbiota Live-JSLM and Fecal Microbiota Spores Live-BRPK, have shown promise in preventing CDI recurrence. This review explores the role of the gut microbiota in preventing and treating CDI, with an emphasis on gut-based interventions like FMT and fecal microbiota-based products that hold potential for gut restoration and prevention of CDI recurrence. Understanding the microbiome's impact on CDI prevention and treatment offers valuable insights for advancing future CDI therapeutics.

microbiome, dysbiosis, probiotics, FMT, live biotherapeutic products

REVIEW ARTICLE

The human body harbors a diverse range of microorganisms throughout the gastrointestinal tract, skin, saliva, and oral mucosa. Although microorganisms are found throughout the body, the greatest concentration of microorganisms are found in the gastrointestinal tract. The human gut hosts approximately 2000 bacterial species and 200 000 phages [1]. The gut microbiome refers to the genomes of these microorganisms, which exist in complex and diverse microbiological communities. Understanding the composition and functions of these microbial communities in the gut is crucial to our understanding of human physiology. Exploring the intricate roles played by the gut microbiome can provide valuable insights into the interplay between microorganisms and their impact on human health and disease.

The composition and function of microbial communities in the gut are influenced by genetics, environment, age and underlying disease, medication use, and diet [2]. The administration of antibiotics is one of the most well-known factors impacting the bacterial composition of the gut microbiome. Antibiotic use leads to disruption of the gut microbiome composition, which is known as dysbiosis or imbalanced microbial communities. Dysbiosis can cause the body to more susceptible to certain diseases, such as Clostridioides difficile infection (CDI) and further recurrences of CDI (known as recurrent CDI [rCDI]). Standard CDI treatment with antibiotics such as oral vancomycin and fidaxomicin does not address dysbiosis but rather can further disrupt gut microbial communities. There has been growing interest in therapeutic strategies for CDI and CDI recurrence that target dysbiosis and restore the gut microbiota. This review aims to discuss the role of the gut microbiota in the prevention and treatment of CDI. We will review various gut-based interventions that may allow for gut restoration and prevention of CDI recurrence.

DYSBIOSIS AND CDI PATHOGENESIS

The gut microbiota is crucial in maintaining colonization resistance against Clostridioides difficile [3]. A healthy and diverse gut microbiota is important for protecting against C. difficile spore germination and vegetative growth [3]. Disruption of the gut microbiota composition and functionality can lead to the reduction of colonization resistance against C. difficile, allowing for C. difficile spore germination, vegetative outgrowth, and toxin production, resulting in clinically overt disease [3, 4]. Dysbiosis characterized by low microbial diversity is a crucial factor in CDI pathogenesis [5]. Previous work has shown that the composition of the microbiota, with fewer Bacteroides and Firmicutes phyla, plays a pivotal role in C. difficile pathology [6, 7]. In a cohort of adults aged 65 years and older, patients diagnosed with CDI had a marked reduction in fecal microbial diversity as compared to healthy individuals [8].

Risk factors for developing CDI are related to gut microbiota disruption. Antibiotic use is one of the strongest risk factors for developing CDI [9]. Antibiotics can cause a profound and rapid decrease in microbiota diversity and the effects of antibiotics on decreased gut diversity can be long-term lasting years after treatment ends [10, 11]. All antibiotics can have effects on the microbiome, but clindamycin, cephalosporins, and fluoroquinolones have been associated with the greatest risk for CDI [9]. Other risk factors for CDI that also are associated with disruption of the microbiome include advance age, the use of gastric acid suppressants including proton lump inhibitors, and presence of underlying diseases such as inflammatory bowel disease [3, 9].

GUT MICROBIOME-BASED INTERVENTIONS WITH DIET, PREBIOTICS, AND PROBIOTICS

Given the importance of the gut microbiome in the pathogenesis of CDI, interventions that target the gut microbiome and attempt to increase or restore the diversity of the gut microbiome are evolving for the management of CDI and to prevent disease recurrence. Here we will discuss more traditional gut-based interventions, including diet, prebiotics, and probiotics, as shown in Table 1.

Table 1.

Traditional CDI Interventions

Intervention	MOA	Microbiome Impact	Place in CDI Therapy
Metronidazole [21]	Nitroimidazole prodrug with broad anaerobic bactericidal activity	Broad depletion of gut flora	Oral use is limited to initial non-severe episodes when other options not available. IV formulation is used for combination therapy in severe CDI
Vancomycin	Glycopeptide antibiotic with broad spectrum activity against G+ organisms through binding of D-ala-D-ala	Broad depletion of gut flora	Alternative option for the treatment of non-severe CDI. High dose therapy is used in combination with metronidazole in severe CDI
Fidaxomicin [56]	Macrolide antibiotic that inhibits bacterial RNA synthesis	More sparing than vancomycin or metronidazole with respect to intestinal bacteria	Preferred option for the treatment of non-severe CDI. Benefits may be lessened as recurrent episodes increase in number
Bezlotoxumab [21]	Human IgG1 monoclonal antibody that binds C. difficile toxin B	No appreciable impact	Not indicated for the treatment of CDI. May be considered in certain populations to prevent CDI recurrence
FMT	Transfer of healthy donor feces into the GI tract	Restores microbiome diversity	May be considered after three episodes of CDI
Diet and prebiotics	Prebiotics act as substrates used by microbiota	Prebiotics, plant-based, and Mediterranean diets may promote beneficial bacteria and overall diversity	No data to support use for prevention or treatment of CDI. However, lifestyle modifications may be considered in adjunct to treatment without clear evidence
Probiotics [21]	Colonization of intestinal microbiota	May impede normal recolonization of the colon after antibiotic use	Recommend against the use for both primary and subsequent prevention of CDI

Abbreviations: C. difficile, Clostridioides difficile; CDI, Clostridioides difficile infection; FMT, Fecal microbiota transplantation; G+, xxx; GI, gastrointestinal; IV, intravenus; MOA, mechanisms of action.

DIET'S ROLE IN MICROBIOME DIVERSITY

There presently are no clinical data to definitively define the role of diet in CDI; however, diet does play an important role in overall health and disease, and the intake of dietary fibers from foods are beneficial for a diverse microbiome [12]. Whole plants foods, including fruits, vegetables, whole grains, legumes, and nuts, are the main source of naturally occurring dietary fibers [13]. Fermentable dietary fibers are converted into metabolites such as short-chain fatty acids (SCFAs) by the intestinal microbiota [14]. SCFAs, such as propionate, acetate, and butyrate, are crucial mediators for the interaction between the gut microbiome and immune system and influence the balance between pro- and anti-inflammatory mechanisms [14, 15]. Regular consumption of dietary fiber protects against erosion of the intestinal mucus barrier by the gut microbiome, which protects against pathogen infection and the incidence of colitis [16]. The intestinal mucus barrier is critical for health and is the primary defense against enteric pathogens [16]. Alternatively, when diets are low in fiber, the gut microbiota uses host-secreted mucus glycoproteins as a nutrient source, which degrades the mucus barrier and enhances pathogen susceptibility [16]. Fermented foods may aid in restoring microbiome balance by introducing beneficial bacteria and enhancing microbial diversity [12, 13]. The fermentation process generates organic acids that create an environment unfavorable to harmful bacteria. Consuming fermented foods like yogurt, kefir, sauerkraut, kimchi, kombucha, and miso introduces live probiotics that colonize the gut temporarily [14]. These probiotics may contribute to a healthier gut microbiota, improving digestion, nutrient absorption, immune function, and reducing inflammation [15]. Additional research is needed before any actionable dietary interventions become a part of a clinical course.

Western diets can be characterized by a high intake of processed foods, animal products, refined carbohydrates, saturated fats, and sugar and a low intake of whole plant foods [13]. Western diets may negatively impact the gut microbiota through dysbiosis and weakening of the intestinal mucus barrier, leading to inflammation and metabolic disturbances [14]. Unlike the Western diet, diets high in fiber, fruit, vegetables, and whole grains have positive effects on the microbiome and promote the diversity of bacterial species in the gut [14]. In vitro data suggests a potential role for prebiotics in preventing CDI [16]. Higher adherence to Mediterranean-style or vegetable-based diets may be associated with beneficial effects on the gut microbiota [17]. However, at this time there are no human data to support the use of diet alteration alone to in preventing CDI. Further studies are warranted.

PROBIOTICS ROLE IN MICROBIOME DIVERSITY

Probiotics are live microorganisms that, when administered in sufficient quantities, may provide health benefits [18]. Probiotics may also be consumed through diet or as supplements and may consist of a single strain or a mixture of multiple strains and species, such as Lactobacillus, Bifidobacterium, Lactococcus, Streptococcus, Enterococcus, Bacillus, and Saccharomyces [19]. The lack of standardization in commercially available probiotics can lead to variability in manufacturing and microbial contents. There is insufficient evidence to support the use of probiotics for the prevention or treatment of CDI [18–20]. The American College of Gastroenterology and the American Gastroenterological Association no longer support the use of probiotics for CDI prevention or treatment [21].

PREBIOTICS ROLE IN MICROBIOME DIVERSITY

Prebiotics are non-digestible food components that promote the growth and activity of beneficial bacteria in the gut. They serve as a source of nutrition for probiotic bacteria, which are live beneficial microorganisms that colonize the intestines. Prebiotics can be found in certain types of foods or dietary supplements. Some fermented foods also contain prebiotic fibers that nourish beneficial bacteria. Prebiotics are compounds selectively utilized by host microorganisms and may provide health benefits [22]. They are often found in dietary fibers, which are fermented by the intestinal microbiota, promoting the growth of beneficial bacteria, and enhancing bacterial diversity for improved host health. Fermented foods may provide a natural way to restore microbiome balance, but data are limited.

FECAL MICROBIOTA TRANSPLANTATION (FMT) INTERVENTIONS IN MICROBIOME DIVERSITY

Fecal microbiota transplantation (FMT) involves the transfer of processed stool collected from a healthy donor to the intestinal tract of a diseased recipient with the goal of treatment of the pathology. FMT has become an increasingly intriguing option for the prevention of rCDI following 2 or more failed courses of antibiotic treatment. The transplantation aims to reverse gut dysbiosis by replacing or replenishing the disrupted gut microbiota with a diverse and healthy microbial community. The patient's disrupted microbiota is supplemented with a mixture of live microbes, bioactive compounds, dietary components, phages, and metabolites, working together as a symbiotic community to facilitate colonization of the intestinal tract [1, 22, 23]. The replenished gut flora enhances bacterial diversity and reintroduces missing strains or species reestablishing the ability to mitigate overgrowth and colonization of C. difficille [23].

FMT has demonstrated high efficacy in treating rCDI [24]. A meta-analysis of 36 studies, including 7 randomized controlled trials and 30 case series, involving over 51 000 patients, reported an average clinical resolution rate of 92% (95% confidence interval [CI] 84%–84%) [24]. The success of FMT depends on factors such as the frequency of transplants and the method of transplantation [24, 25]. A more recent meta-analysis of 45 studies revealed that the clinical effect rate was highest when delivered via lower gastrointestinal endoscopy (96.4%), although enema had the lowest rate (50.2%) [25]. Repeat administration of FMT significantly improved its effectiveness through continued supplementation of healthy flora.

FMTs are generally safe, with mild and self-limiting gastrointestinal side effects, such as abdominal discomfort, transient diarrhea, bloating, flatulence, and constipation [26, 27]. The largest published systematic review and meta-analysis to date has demonstrated a low rate of serious adverse events (<1%) related to FMT [28]. However, FMT is associated with a risk for infection transmission, particularly for severely immunocompromised patients, highlighting the importance of effective donor and sample screening [29]. Although potential pathogens may be harmless in donors, they can pose a threat to immunocompromised recipients, a group that has been excluded from many LBP studies [30, 31]. Minimizing this risk involves careful selection of FMT candidates and thorough screening of prospective donors, something that is now more regulated and requires various quality control measures [27, 29]. Despite screening and rigorous selection processes, FMT contains large quantities of unidentified microorganisms, the risk of transmission of harmful pathogens persists [27]. Adverse events have been reported, such as cases of infection with Shiga toxin-producing Escherichia coli and extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli after FMT [32, 33]. Norovirus gastroenteritis has also been reported after FMT despite asymptomatic donors [34]. The FDA has issued safety alerts regarding FMT and the potential for transmission of pathogenic and multi-drug resistant organisms [35, 36].

LIVE BIOTHERAPEUTIC PRODUCTS AND MICROBIOME DIVERSITY

Currently there are 2 FDA-approved microbiome-based treatments, as shown in Table 2. Both of these treatments are fecal microbiota-based products indicated for the prevention of recurrence in patients with 2 or more episodes of CDI [30, 31]. Coined live biotherapeutic products (LBP), Fecal Microbiota Live-JSLM (FMBL-jslm; brand name Rebyota^TM) and Fecal Microbiota Spores Live-BRPK (FMSL-brpk; brand name Vowst^TM), act through the process of gut flora engraftment [30, 31]. FMBL-jslm (Rebyota^TM) is a rectal suspension, and FMSL-brpk (Vowst^TM) is an oral suspension [30, 31]. Although the focus of this review pertains to presently FDA approved LBP, there are other products such as VE303, which has shown promising results from phase 2 clinical trials using a defined bacterial consortium, differing from the 2 approved fecal extract products [37].

Table 2.

FDA Approved Live Biotherapeutic Products

Prescribing Information	Fecal Microbiota, Live—jslm (RebyotaTM)	Fecal Microbiota Spores, Live-brpk (VowstTM)
Indications	Prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 y of age and older, following antibiotic treatment for recurrent CDI [30]	Prevention of recurrence of Clostridioides difficile infection (CDI) in individuals 18 y of age and older, following antibiotic treatment for recurrent CDI [31]
Limitation of use	Not indicated for the treatment of CDI should be used after a completed course of standard CDI treatment	Not indicated for the treatment of CDI should be used after a completed course of standard CDI treatment
Preparation	Prior to use, thaw completely by placing carton in a refrigerator (2°C to 8°C) for approximately 24 h [30]	Prior to taking the first dose: (1) Complete antibacterial treatment for rCDI 2 to 4 d before initiating treatment. (2) Drink 296 mL (10 oz) of magnesium citrate on the day before and at least 8 h prior to taking the first dose* [53]
Dosage	Single dose of 150 mL is rectally [41]	4 capsules, once daily for 3 consecutive days *In clinical studies, participants with impaired kidney function received polyethylene glycol electrolyte solution (250 mL GoLYTELY, not approved for this use) [31]
Route	Rectal enema	Oral capsule
Administration	Administered 24 to 72 h after the last dose of antibiotics for CDI [30]	Take capsules on an empty stomach prior to the first meal of the day [31]
Efficacy	Treatment success defined as the absence of CDI diarrhea within 8 wks of treatment Bayesian analysis estimated rate of treatment success of 70.6% compared to 57.5% in the placebo group [39]	Primary efficacy endpoint was CDI recurrence through 8 wks CDI recurrence occurred in 12.4% of Vowst-treated participants through 8 wks compared to 39.8% of placebo-treated participants [42]
Adverse reactions	Most commonly reported (≥3%) adverse reactions were abdominal pain (8.9%), diarrhea (7.2%), abdominal distension (3.9%), flatulence (3.3%), and nausea (3.3%) [39–41]	Most commonly reported adverse reactions (≥5%) were abdominal distension (31.1%), fatigue (22.2%), constipation (14.4%), chills (11.1%), and diarrhea (10.0%) [42, 44, 45]
Description	Opaque fecal microbiota suspension manufactured from human fecal matter sourced from qualified donors. The fecal microbiota suspension is the filtrate generated by processing the fecal matter in a pre-defined ratio with a solution of polyethylene glycol (PEG) 3350 and saline. Each 150 mL dose contains between 1 × 108 and 5 × 1010 CFU per mL of fecal microbes including >1 × 105 CFU/mL of Bacteroides and contains not greater than 5.97 grams of PEG3350 in saline	Bacterial spore suspension in capsules manufactured from human fecal matter sourced from qualified donors. The spore suspension is generated by treating fecal matter with ethanol to kill organisms that are not spores, followed by filtration steps to remove solids and residual ethanol. Each capsule contains between 1 × 106 and 3 × 107 Firmicutes spore CFU in 92 ± 4% (w/w) glycerol in saline
Donors	Human fecal matter is tested for a panel of transmissible pathogens. Donors do not have any dietary restrictions with respect to potential food allergens [54]	Human fecal matter donations are routinely tested for a panel of transmissible pathogens. Donors do not have dietary restrictions with respect to potential food allergens [55]
Storage and handling	Store in an ultracold freezer (−60°C to −90°C). Alternatively, store in a refrigerator (2°C to 8°C) for up to 5 d (including thaw time). Do not freeze after thawing [30]	Store in original packaging at 2°C to 25°C (do not freeze) [31]

Abbreviations: CDI, Clostridioides difficile infection; CFU, colony-forming units; rCDI, recurrent CDI.

RECTAL LIVE-JSLM FECAL MICROBIOTA SUSPENSION (REBYOTA^TM)

FMBL-jslm (Rebyota^TM) is the first FDA-approved (November 2022) microbiota suspension indicated for the prevention of rCDI. It consists of a rectal suspension derived from healthy human stool samples, containing a diverse mixture of trillions of live microbes, including Bacteroides, specifically targeting the gut microbiome [30]. The stool undergoes a panel screen for transmissible pathogens before being suspended with a solution of polyethylene glycol (PEG) 3350. Unlike standard FMT, this therapeutic provides an option to restore microbiome diversity utilizing a consistently defined potency and uniform route of administration that has been evaluated in long-term placebo-controlled trials [38]. Formulated in a pre-defined ratio, the resulting product is a 150 mL single dose suspension abiding by preset measures. A single dose of FMBL-jslm (Rebyota^TM) consists of fecal microbes composed of ≥1 × 10⁵ colony-forming units (CFU)/mL of Bacteroides and PEG contents not exceeding 5.97 g in saline. The refrigerated preparation is administered by a healthcare professional rectally to a patient in a supine position following bowel excavation. The single dose process should take place 24–72 hours after the last dose of CDI antibiotics and spans approximately 45 minutes [30].

FMBL-jslm (Rebyota^TM) was approved utilizing data from the PUNCH CD trials in a Bayesian analysis. This analysis was composed of a randomized, double-blind, placebo-controlled, multicenter phase 3 study that incorporated treatment success from the prior phase 2 study [39, 40]. The extrapolation and interpretation of data was conducted in adults experiencing diarrhea with a positive stool test for C. difficile and at least 2 prior episodes of CDI within a 12-month period. Initially patients were randomized to placebo groups, those receiving 1 dose of FMBL-jslm (Rebyota^TM), and those receiving 2 doses of FMBL-jslm (Rebyota^TM), suggesting the potential for multiple-dose treatments [40]. After failing to meet preset measures for non-inferiority, the single dose group was extrapolated into a Bayesian analysis. With this extrapolation, a higher recurrence-free rate was observed at 8 weeks (70.6% vs 57.5% for placebo) [39]. Furthermore, over 90% of those who achieved treatment success remained recurrence-free after 6 months of follow-up [39].

Adverse events across the five preliminary clinical studies were reported through patient journals and were monitored up to 24 months following treatment. The standardized stool-based product is well tolerated, with mild gastrointestinal side effects being most frequently reported [30, 39, 40]. The most frequent adverse reactions in recipients of FMBL-jslm (Rebyota^TM) were abdominal pain (8.9%), diarrhea (7.2%), abdominal distention (3.9%), and flatulence (3.3%). Although most adverse events during studies occurred within 2 weeks of treatment, the full extent pertaining to the potential of transmissible pathogens and food-allergen reactions lacks complete elucidation. Like other approved live biotherapeutic products, the widespread use should confer a brief pause due to the uncertainty extrapolating the available data to a large group of patients [30, 41].

ORAL FECAL MICROBIOTA SPORES LIVE-BRPK CAPSULES (VOWST^TM)

FMSL-brpk (Vowst^TM) is a newly FDA-approved bacterial spore suspension and the first orally administered microbiome-based product [31]. This capsulated live biotherapeutic product is manufactured through purifying the human fecal matter from screened donors. The fecal matter undergoes an ethanol treatment to kill non-sporulated organisms, followed by filtration to remove residuals and isolate Firmicutes spores. Although this process removes several potential pathogens, non-spore-forming organisms, and residual solids, it does not exclude the possibility for commensal fecal flora to be infectious. The resulting product is a standardized consortium of Firmicutes spores able to resist gastrointestinal acids, allowing for oral administration. The ubiquitous generated capsules are provided in packages of 12 capsules, with the daily dose being 4 capsules taken orally on an empty stomach prior to a patient's first meal [31]. The treatment duration spans 3.

days and begins 2–4 days after the completion of CDI treatment with antibiotics. Magnesium citrate should precede the initiation of treatment to properly expel any residual antibiotics lingering in the patient's gastrointestinal system and prevent unintentional harm to the administered live biotherapeutic product.

The recent FDA approval of FMSL-brpk (Vowst^TM) was largely based on the results of the ECOSPOR trials, including 1 randomized, double-blind, placebo controlled and 1 randomized, open-label trial. Within these trials, adults were included if they met the criteria of having rCDI being defined as 3 or more episodes of CDI within 12 months. The blinded phase three trial compared three daily doses of FMSL-brpk (Vowst^TM) against placebo in a group of patients with 3 or more CDI episodes within 12 months and established a primary efficacy endpoint of no rCDI episodes in the 8 weeks following treatment. The trial showed that engraftment of the Firmicutes spores consortium occurred as early as 1 week after administration and continued for up to 8 weeks. Additionally, the active treatment group exhibited higher concentrations of secondary bile acids. At 8 weeks after treatment, the recurrence rate of CDI was 12% in the active group compared to 40% in the placebo group [42]. Subsequent studies confirmed a sustained decrease in the risk of recurrence compared to placebo, with extended follow-up through 24 weeks after treatment. FMSL-brpk (Vowst^TM) was protective against rCDI in patients receiving either vancomycin or fidaxomicin as primary therapy [43].

Safety data reported from the ECOSPOR trials predominantly were limited to gastrointestinal adverse effects consisting of abdominal distention (31%), constipation (14.4%), and diarrhea (10.0%). As with other live biotherapeutic products and FMT procedures, FMSL-brpk (Vowst^TM) does carry the warning of risk of transmissible infectious agents [42, 44, 45]. This risk is certainly noteworthy, and the FDA has subsequently highlighted the importance of rigorous screening for these products. The presence of food allergens and the potential reactions that may precipitate following the administration of live biotherapeutic products are important considerations as these live biotherapeutic products continue to be approved since they originate from human fecal matter.

PROJECTED PLACE IN THERAPY

FMBL-jslm (Rebyota^TM) and FMSL-brpk (Vowst^TM) are FDA approved as a therapeutic to treat those at risk of rCDI. Other agents, such as bezlotoxumab, have recently been approved for a similar indication, but unlike bezlotoxumab, these treatments additionally offer an option to those with active congestive heart failure or previously treated with bezlotoxumab. In the absence of comparative studies, further research is needed to compare efficacy of LBP and bezlotoxumab, with data also needed to analyze any added benefits possibly achieved through microbiome restoration. These products also possess several benefits over traditional FMT therapies, mainly attributable to their respective standardized manufacturing and modes of delivery. Both products have a diminished risk of containing transmissible pathogens and FMSL-brpk (Vowst^TM) even has the theoretical added benefit of ethanol removal of pathogens.

The antibiotic selected for the treatment of CDI is not expected to impact the efficacy of either LBP. Fidaxomicin and vancomycin treated patients had similar results in the aforementioned studies; however, FMBL-jslm (Rebyota^TM) trials included significantly less patients treated with fidaxomicin. The role of LBP in patients needing concomitant antibiotic treatment is not known. Expectedly there would be diminished efficacy when any LBP is used concomitantly with antibiotics, but future studies are needed to determine the significance.

Although LBP are approved for the treatment of rCDI, their benefits may expand beyond infection prevention. An interesting finding related to quality of life was observed in secondary analyses of phase 3 clinical trial data for this purified Firmicutes spore based-product [46]. It is well understood that CDI is a debilitating disease causing severe and uncomfortable gastrointestinal symptoms and that it can lead to reductions in quality of life and longstanding negative physical consequences for effected patients, such as lack of energy, sleep disturbances, irritable bowel syndrome, and psychological consequences, such as anxiety, depression, and post-traumatic stress disorder [47]. Secondary analysis of phase 3 clinical trial data demonstrated rapid and steady improvement in health related quality of life in patients treated with orally administered fecal microbiota product [46]. In the placebo group, improvements in health-related quality of life were mostly observed in patients with non-recurrent CDI; however, in the treatment group, improvements were noted independent of the clinical outcome, being whether or not patients had CDI recurrence. The significance of these results is presently uncertain but rather detail an area for further exploration to better interpret these observations. These data suggest that improvements in health-related quality of life in patients who received live purified Firmicutes spores may be mediated by effects on the gut-brain axis. Future studies should be conducted evaluating potential roles for microbiome treatments in mood disorders, targeting the gut-brain axis.

Another intriguing outcome necessitating future research is LBP mediated resistome alteration. Both FMBL-jslm (Rebyota^TM) and FMSL-brpk (Vowst^TM) have been shown to reduce the presence of antibiotic resistance genes across several organisms [48, 49]. The clinical implications following treatment with one of these LBP have not yet been determined, including the potentially negative effects resulting from introducing new antibiotic resistant genes to recipients [50]. The ability to demonstrate consistent taxonomic shifts through LBP administration to manipulate the resistome should be further studied.

CONCLUSION

The therapeutic possibilities appear numerous as we gather more information about the microbiome's role in human health despite the first US FDA therapies being approved just at the end of 2022. Currently FMBL-jslm (Rebyota^TM) and FMSL-brpk (Vowst^TM) are the only FDA-approved microbiome products [30, 31]. Although the microbiome interventions in CDI are currently at the forefront, interventions for other disease sates may soon follow [51, 52]. As novel methods to research and utilize the microbiome as a therapeutic target emerge, we must be diligent in interpreting how generalizable published results truly are. Patient-specific interventions may be the future of microbiome therapy as everyone's is truly unique, because there really is no place like a microbiome.

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. The views expressed are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs. This material is based upon work supported, in part, by the Office of Research and Development, Department of Veterans Affairs.

Supplement sponsorship. This article appears as part of the supplement “The Microbiome and Human Health Perspective,” sponsored by Ferring Pharmaceuticals Inc., Seres Therapeutics Inc., and Nestlé Health Science.

Financial support. This work is supported by Seres Therapeutics Inc. and Ferring Pharmaceuticals Inc.

Author notes

Potential conflicts of interest. K. L. L. reports receiving research funding from Pfizer Pharmaceuticals, Gilead, Abbvie, Ferring Pharmaceuticals, Inc., Melinta Therapeutics, Seres, Basilea Pharmaceutica, Merck, Paratek, Entasis and Shionogi. H. J. A. reports funding from Pfizer—Antiviral Therapy in coronavirus disease 2019 (COVID-19) infection; VA HSRD CDA number 15-260 in the development of a stewardship intervention for CLC pharmacists to improve urinary tract infection (UTI) treatment; VS HSRD Merit Award number 15-12 improving antimicrobial stewardship in Veteran Affairs community living centers (CLC's); Shionogi Antibiotic resistance rates, and treatment of Acinetobacter baumanii and stenotrophomonas in the national VA healthcare system; and honoraria payments for attending the Antimicrobial Stewardship forum. T. L. has no conflicts to report.

All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.