March 8, 2021

Perfect probiotics for C. difficile: what’s your gut telling you?

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Perfect probiotics for <i>C. difficile:</i> what’s your gut telling you?

Kelly R. Reveles, Pharm.D., Ph.D., BCPS

Assistant Professor, The University of Texas at Austin College of Pharmacy, Adjoint Assistant Professor, The University of Texas Health Science Center, San Antonio, Texas

Kelly R. Reveles is an Assistant Professor at The University of Texas at Austin College of Pharmacy and an Adjoint Assistant Professor at The University of Texas Health Science Center at San Antonio School of Medicine. She received her Doctor of Pharmacy degree from UT Austin and UT Health Science Center San Antonio in 2010. She also completed a multi-disciplinary, multi-institutional Translational Science PhD degree from UT Austin, UT Health Science Center San Antonio, and UT San Antonio in 2014. Dr. Reveles’ long-term research goal is to reduce the incidence and improve the outcomes of healthcare-associated infections by designing, testing, and implementing effective clinical strategies. Her current research focus is the prevention and treatment of Clostridioides difficile infections and innovative methods to improve the translation of clinical research findings into practice. Her research approach emphasizes multi-disciplinary, collaborative research in the areas of large database design and analysis, pharmacoepidemiology, comparative-effectiveness research, and human and animal microbiome studies.

Financial Relationship Disclosure

  • Merck, Inc., AstraZeneca: Principal/Co Investigator or named investigator for a research grant

All other planners, presenters, reviewers, ASHP staff, and others with an opportunity to control content report no financial relationships relevant* to this activity.

*As defined by the ACCME definition of commercial entity.


In what patient populations do you most recommend probiotic use?

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The human microbiome contains trillions of microbial cells in and on the body, with about 95% inhabiting your gastrointestinal tract. While the human microbiome may weigh as much as five pounds, those are pounds you don’t want to lose. The microbiome plays a critical role in human health by resisting pathogens, aiding in digestion and metabolism, modulating the immune response and endocrine function, and providing for energy and nutrients.1 Because of these extensive functions, disruption of the healthy gut microbiome (i.e., dysbiosis) has been associated with many diseases, including gastrointestinal disorders, obesity, metabolic syndrome, immune disorders, cancer, and cardiovascular disease.1 One of the most well-studied microbiome-associated conditions is Clostridioides difficile infection (CDI). Disruption of the gut microbiota allows for C. difficile to colonize the gut, then spores can germinate and produce toxins when conditions become favorable, most commonly after antibiotic use.2

Rationale and evidence for probiotic use in CDI

Since the microbiome plays an important role in CDI pathogenesis, there has been significant interest in using microbiome-targeted therapies, notably probiotics, to prevent CDI. Probiotics are live microorganisms intended to confer a health benefit.3 But are probiotics the magic bullet? And anyone who’s walked through a grocery or drug store knows there are many to choose from. The most common probiotics belong to the bacterial genera Lactobacillus and Bifidobacterium and the yeast Saccharomyces boulardii. Probiotic health benefits are proposed to be mediated through competition for resources with pathogens, improvement of gastrointestinal barrier function, and immune system modulation.4 Several meta-analyses have evaluated the effectiveness of probiotics for CDI primary and secondary prevention. A 2017 meta-analysis of 31 randomized controlled trials found that probiotics significantly reduced incident CDI risk compared to placebo or no treatment.5 In post-hoc analyses, probiotics were only effective in populations with a high (>5%) baseline CDI risk. Another meta-analysis stratified trials by primary and secondary prevention and reported that four strains significantly reduced primary CDI: S. boulardii, L. casei, a mixture of L. acidophilus and B. bifidum, and a mixture of L. acidophilus, L. casei and L. rhamnosus. Interestingly, probiotics did not significantly improve secondary prevention of CDI.6

While evidence is promising, prior studies have had inconsistency in findings and potential for bias due to study design, populations studied, CDI definitions, and probiotic formulations, doses, and durations used. There are likely patient- and probiotic-specific characteristics that influence probiotic effectiveness, but little is known in this area. Next, although most clinical studies have found probiotics to be safe, they are not without risks. Gastrointestinal side effects, unfavorable metabolic profile, immune stimulation, and systemic infections in hospitalized patients are reasons probiotics are not recommended for immunocompromised or severely debilitated individuals.7 Lastly, most probiotics are available as dietary supplements that are not subject to FDA approval or good manufacturing practices. Notably, the current CDI clinical practice guidelines do not recommend routine administration of probiotics for primary or secondary prevention.8

Alternative microbiome-targeted therapies for CDI

One important limitation of probiotics is that supplementation is often with one or few bacterial species; however, dysbiosis may involve a deficiency in several important bacterial taxa. Fecal microbiota transplantation (FMT) addresses this limitation. FMT, an unapproved biological agent, refers to the administration of healthy donor feces into the intestinal tract of a recipient. Prior studies documented increased diversity and restoration of important bacteria and metabolites following FMT in patients with CDI9 while safely improving patient outcomes. In a meta-analysis of 37 studies, FMT was more effective than vancomycin in resolving recurrent and refractory CDI, regardless of administration route.10 Prior studies have noted short-term adverse events (e.g., bloating, diarrhea, constipation) following FMT; however, FMT is still human feces which may not be the most pleasant intervention for some and could pose a risk for serious adverse events. Recent reports indicate potential transmission of pathogens (multidrug resistant E. coli and SARS-CoV-2) to FMT recipients, prompting FDA warnings.11,12 There are also many logistical issues surrounding FMT acquisition (e.g., donor selection and screening), storage, administration, and billing.

So how do we get around the poo issue? Rationally designed combinations of microbes are now being developed to target known microbial deficiencies. Many microbiome-based products are currently in phase 1-3 trials for CDI and non-infectious indications, including inflammatory bowel disease and cancer. SER-109 is an investigational product that holds FDA Breakthrough Therapy designation and Orphan Drug designation for CDI. This oral formulation contains a collection of purified bacterial spores that compete with C. difficile for nutrients and convert the microenvironment from C. difficile growth-promoting to growth-inhibiting. It’s manufactured by fractionating bacteria from healthy donor stool while inactivating potential pathogens, an advantage over FMT. Although the data are not yet published, a recent press release by the company indicated promising results from the phase 3 clinical trial (ECOSPOR III); SER-109 prevented CDI recurrence in 89% of patients at 8 weeks compared to 59% in the placebo group (p<0.001).13

While microbiome-targeted therapies are an exciting next step in CDI prevention and treatment, simple strategies can help improve our microbiome. Diets rich in vegetables and fruit and low in meat are associated with high gut microbial diversity.14 Additionally, prebiotics have been used to support the nourishment of our healthy gut microbes.3 Diets that are mostly plant-based contain resistant starch (a fiber component) and oligosaccharides that positively affect microbiome diversity and abundance of certain good bacteria.15 In fact, one small randomized controlled trial found that supplementation with oligofructose decreased CDI recurrence risk.16 Given the potential health benefits and limited side effects (primarily flatulence and bloating), dietary fiber can be recommended as part of a healthy diet.

In summary, the “perfect probiotic” is not yet available, but I think we are getting closer. The ideal probiotic will likely be a combination of microbes that successfully outcompete C. difficile, confers other health benefits, is easy to administer (e.g., oral) and affordable, and has low risk for adverse effects even in high-risk individuals. In the meantime, eat your fruits, veggies, and fiber – when you toot, it’s just your microbiome saying “thank you!”

More Information


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  11. U.S. Food and Drug Administration. Important Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Risk of Serious Adverse Reactions due to Transmission of Multi-Drug Resistant Organisms, 2019 June 2013.
  12. U.S. Food and Drug Administration. Safety Alert Regarding Use of Fecal Microbiota for Transplantation and Additional Safety Precautions Pertaining to SARS-CoV-2 and COVID-19, 2020 March 23.
  13. Seres Therapeutics Announces Positive Topline Results from SER-109 Phase 3 ECOSPOR III Study in Recurrent C. difficile Infection. Available at: Accessed Feb 25, 2021.
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