Microbiome-Based Therapies for Clostridioides difficile Infection

Primary and recurring Clostridioides difficile infection (CDI) continues to afflict patients worldwide.¹ In the United States, C. difficile causes about half a million infections and 29,000 deaths per year (which is approximately 2/3 of the number of people who die in car accidents each year), while in Europe, about 152,905 CDI cases and 8,382 associated deaths occur every year.² The target population for CDI is the elderly, the immune-depressed, and hospitalized patients, or those under antimicrobial treatment, which is the main risk factor for infection.²

Although CDI is generally healthcare-associated, the number of community-acquired infections is increasing.³ In addition, the SARS-CoV-2 infection has significantly impacted CDI, with some research suggesting that CDI may worsen the course and prognosis of COVID-19.^4,5 Researchers are also seeing high rates of CDI recurrence.^6,7 Over the last several years, treatment options for CDI have been evolving with the emergence of fecal microbiota transplantation and probiotic therapies. What is the state of the research on the latest treatments for CDI?

Fecal Microbiota Transplantation

Following antibiotic treatment (with vancomycin, fidaxomicin, or metronidazole), the use of fecal microbiota transplantation (FMT) is indicated for recurrent CDI.^8,9 It is a promising therapy for recurrent CDI, with one trial demonstrating recurrent CDI resolution in 90% of 20 patients treated with FMT and vancomycin vs 26% of 19 patients treated with vancomycin alone (P < 0.001).⁸

In 2021, Sandhu et al, writing in Therapeutic Advances in Gastroenterology, review the clinical successes and challenges of FMT, which has become a common treatment modality as part of a two-pronged approach to prevent recurrent CDI.¹⁰ FMT, a process of harvesting stool from a healthy donor and transplanting it into the colon of the patient, is a treatment option to counteract intestinal imbalance.¹⁰ The donor stool microbiota competes with C. difficile bacteria in the patient’s gut, allowing for the restoration of secondary bile acids and the stimulation of the mucosal immune system to help reinstate a healthy microbiome in the patient.¹⁰ A 2020 prospective study reported significant change in microbiota toward eubiotic status at all time points analyzed pre- and post-FMT at one week and six and 12-24 months.^10,11 Specifically, there was a decrease in protobacteria, which is related to dysbiosis, as well as normalization of Faecalibacterium prausnitzii one year post-FMT—again favoring the eubiotic state achieved by FMT.^10,12 (The eubiotic state or eubiosis refers to microbiota that provide the host with health benefits. The dysbiotic state or dysbiosis is defined as changes in the proportion and/or taxa of microorganisms that deviate from a eubiotic profile).¹² A 2022 retrospective observational cohort using 38,396 patients with CDI suggests that FMT is strongly associated with a decrease in CDI recurrence compared to traditional care (antibiotics), with generally mild complications, for up to two years.¹³

FMT has also demonstrated survival benefit in severe cases when compared with standard oral antibiotic treatment.¹⁰ The results of a prospective cohort study demonstrated a higher, 90-day overall survival in the FMT group, with a 32% increase in overall survival compared to the antibiotic group (pulsed oral vancomycin, oral metronidazole plus pulsed oral vancomycin, fidaxomicin, or oral metronidazole).^10,14

Several adverse and serious events with FMT have also been reported, from self-limiting abdominal pain to death due to severe sepsis.¹⁵ To this end, for patients with SARS-CoV-2 infection, Yadav et al outline the safety of FMT for CDI and indicate that COVID-19 is a potential pathogen that could be transmitted via FMT.¹⁵

Probiotic Therapies

To address dysbiosis of the gastrointestinal microbiota, one of the most researched non-antibiotic therapeutic options is the use of live commensal microorganisms, probiotics.¹⁶ A 2022 review by Pal et al published in Critical Reviews in Microbiology highlights the probiotic strains that have been proposed as plausible interventions for CDI based on findings from in vitro cell culture studies and some in vivo models, including (but not limited to) the following:¹⁶

• Lactobacilli: Limosilactobacillus reuteri 17938 is one of the most studied probiotics in clinical trials for different applications, including inhibiting growth of difficile. L. reuteri converts glycerol into a potent broad-spectrum antimicrobial compound, reuterin, that inhibits the growth of both Gram-positive and Gram-negative bacteria. A recent study suggested that reuterin inhibits the growth of metabolically active C. difficile by inducing reactive oxygen species (ROS) production. This results in a shift in carbon metabolism, followed by reduced toxin synthesis. Researchers suggest that reuterin may also inhibit C. difficile outgrowth from spores. Furthermore, L. reuteri is resistant to the antibiotics used for CDI treatment, including vancomycin, fidaxomicin, and metronidazole. The susceptibility of the pathogen to these antibiotics was also enhanced by L. reuteri.^16,17
• Bifidobacterium spp: Evaluated for their ability to reduce the cytotoxic effect of clostridial toxins, Bifidobacterium longum and Bifidobacterium breve reduced the toxic effect of difficile supernatant when exposed to a human intestinal epithelial cell line (HT-29) in a 2016 study by Valdés-Varela et al.^16,18 Specifically, B. longum IPLA20022 demonstrated the strongest ability to counteract the cytotoxic effect of clostridial toxins. B. bifidum CIDCA 5310 and L. plantarum CIDCA 83114 also antagonized the biological activity of C. difficile.^16,18
• Non-pathogenic Clostridium spp: Clostridium butyricum is a non-pathogenic butyric acid-producing Clostridium found in human intestines. It has been used clinically to prevent human gastrointestinal diseases like antibiotic-associated diarrhea. When co-cultured with C. difficile, it resulted in a complete loss of C. difficile toxicity. Clostridium scindens is a bile acid 7alpha-dehydroxylating intestinal bacterium that possesses potent anti-clostridial activity.¹⁶
• Enterococcus spp: Enterococcus spp are a component of the human gut microflora; specifically, Enterococcus faecium and Enterococcus faecalis have recently been studied for their ability to inhibit difficile growth. In a mouse model, in vitro, a screening assay identified the cell-free supernatant (CFS) of three isolates from infant fecal samples, E. faecalis NM815, E. faecalis NM915, and E. faecium NM1015, that exhibited more than 50% inhibition of C. difficile growth.^16,19

Several meta-analyses have been conducted on the use of probiotics in preventing CDI, with diverging conclusions, also outlined by Pal et al, some of which include:

• A 2021 study suggests that a three-strain probiotic preparation of acidophilus CL1285, L. casei LBC8OR, and L. rhamnosus CLR2, commercially known as Bio-K+ 50 Billion (50 billion CFU per capsule), may lower the incidence of healthcare-associated CDI for at least half of the patients on multiple-antibiotic regimens. Similarly, patients on more than one high-risk antibiotic regimen had a lower incidence of infection when on Bio-K+ during the intervention.²⁰ Contrary to this study, another finding from 2021 did not support the use of the Bio-K+ probiotic formulation for the prevention of primary CDI in hospitalized adults greater than 50 years old receiving antibiotics in a setting that has low baseline CDI rates.^16,21 Based on this evidence, the three-strain probiotic may be helpful in settings with high rates of CDI infections.

Functional Medicine Considerations

Although research continues to evolve,²² FMT and probiotics may be considered as adjunctive therapies for CDI treatment and prevention under certain circumstances. A balanced symbiosis of the gut microbiota is closely associated with human health, and as a clinician, you can help your patients restore a healthy, diverse microbiome at any stage of their life.

From intestinal pathogens and allergens to intestinal permeability and imbalances in colonic microbiota, gut dysfunction compromises a patient’s health and diminishes vitality. The functional medicine model takes a whole systems approach to evaluating and treating not only local gastrointestinal disease but many systemic diseases that are linked to GI dysfunction.