Point/Counter

Which probiotics or combination of probiotics hold the most promise for C. difficile prevention?

Click here to read the Cover Story, Probiotics: An unproven answer to prevent C. difficile infection

POINT

Research has shown that multistrain and single-strain probiotics may have an effect on CDI.

CDI — a battle we must fight in the war on antibiotic resistance — is uniquely complex and multifactorial. Several tactics are required to keep this deadly disease in check, and the use of probiotics is but one offensive strategy aimed at CDI prevention. Regardless of continued opposition related to insufficient data required for clinical recommendation, the use of probiotics as a preventive strategy persists.

Jennifer K. Spinler

Inherent in the nature of C. difficile susceptibility is the breakdown of a healthy gut microbiome. Antibiotic treatment for an unrelated illness diminishes the natural microbial barrier required to keep C. difficile at bay, and adjunct probiotic therapy could replenish the microbiota and fend off C. difficile. Multistrain probiotics are favored to maintain a diverse microbiota capable of inhibiting C. difficile growth, whereas single-strain probiotics with specific activity against C. difficile are also promising.

Bio-K+, a multistrain lactobacilli probiotic currently implemented as standard adjunct therapy in Canada, has been credited with decreased incidence and severity of CDI in participating hospitals. Additionally, the use of this formulation has been tracked for over a decade and has not been associated with downstream negative effects in adult patients regardless of comorbidities in these settings. Recent findings in a United States hospital counter this claim with data showing Bio-K+ had no impact on CDI in their hospital, highlighting our need to strive for rigor and reproducibility in probiotic clinical trials.

Alternatively, a single-strain probiotic potent enough to inhibit C. difficile growth without broadly impacting the gut microbiota has potential as a preventive strategy. Under the right conditions, the well-studied probiotic Lactobacillus reuteri produces a natural antimicrobial compound that directly impedes C. difficile growth with minimal effects on the residual bacterial community. Formulations critical for translating this finding to human trials have yet to be defined, but it lends promise to the potential that a single-strain probiotic may have in fighting CDI.

The plethora of available probiotics combined with an increasing public awareness and demand for functional applications toward disease treatment and prevention puts added pressure on clinicians to reliably recommend specific probiotics as options to their patients. Based on current literature, we can only suggest probiotic formulations that may be useful in the fight against C. difficile. However, as the field of microbiome science continues to sharpen its cutting edge and regulatory agencies revisit regulations surrounding the use of live microbes as drugs, it is only a matter of time before next-generation probiotics become standard therapy in treating C. difficile among other important diseases.

Jennifer K. Spinler, PhD, is a microbial geneticist in the Texas Children’s Microbiome Center and a faculty member in the department of pathology and immunology at Baylor College of Medicine. Spinler’s Twitter handle is @DrJKSpinler. Disclosure: Spinler reports receiving unrestricted funds from BioGaia AB and BioGaia Pharma.

COUNTER

It is highly unlikely that multistrain or single-strain probiotics can repair microbiota damage before CDI.

The question rests on a premise that probiotics promote intestinal health by restoring balance in the intestinal microbial composition. A common version of this idea is that the probiotic strains of microbes are the “good” microbes we want in our intestines because they are especially beneficial. Given that CDI generally follows an antibiotic-induced perturbation of the intestinal microbiota, the idea that probiotics can help prevent it has been studied for decades. The results have been largely disappointing, but the idea refuses to die. Why?

Alexander Khoruts

I believe part of the answer lies in the cartoonish view of the intestinal microbes held by most health care providers, which categorizes microbes as either “good” or “bad.” Whereas there are clearly intestinal pathogens, most intestinal microbes cannot be thus classified. Instead, microbiota must be viewed as a whole entity that cannot be divided into individual components. It is often the case that the intestinal microbiota is severely damaged before CDIs. Therefore, it is highly unlikely that any one or even a few strains of bacteria can repair such damage.

It is possible that defined microbial preparations will be developed that will be able to prevent CDIs. However, use of these preparations must be based on a mechanistic understanding of the C. difficile life cycle. For example, we and others have shown that loss of secondary bile acid metabolism after antibiotics creates a vulnerability to C. difficile infection because it encourages C. difficile spore germination and vegetative growth. Conversely, fecal microbiota transplantation results in restoration of secondary bile acid metabolism and inhibition of C. difficile spore germination and vegetative growth. Certain strains of bacteria have been identified that can carry out these chemical transformations, and they might be developed into therapeutics. Clinical trials will need to be done to test their efficacy relative to current therapies.

However, it is important to realize that if such preparations will emerge, they will and should be categorized as biologic drugs. Regulation of drugs is obviously very different from probiotics, which currently fall into the same regulatory bin as dietary supplements. These products are supposed to present little risk, and the regulators are weary of telling consumers how they may wish to spend their money. Notably, recent investigations suggest that probiotics may actually delay post-antibiotic recovery of the intestinal microbiota, and may not be as harmless as we have assumed. Furthermore, virtually no systematic data are available on any adverse events that may be associated with their use.

Many manufacturers take full advantage of the regulatory neglect and focus their efforts on creative marketing. I counsel my patients in all these facts and tell them that probiotics are not going to alter their risk for CDI. However, in the absence of more data to tell otherwise, I do not stand in their way if they feel the products make them feel better.

Alexander Khoruts, MD, is a professor of medicine at the University of Minnesota, and a scientific advisory board member for the American Gastroenterological Association Center for Gut Microbiome Research and Education. Khoruts can be reached at media@gastro.org. Disclosure: Infectious Disease News was unable to confirm relevant financial disclosures at time of publication.

Click here to read the Cover Story, Probiotics: An unproven answer to prevent C. difficile infection

POINT

Research has shown that multistrain and single-strain probiotics may have an effect on CDI.

CDI — a battle we must fight in the war on antibiotic resistance — is uniquely complex and multifactorial. Several tactics are required to keep this deadly disease in check, and the use of probiotics is but one offensive strategy aimed at CDI prevention. Regardless of continued opposition related to insufficient data required for clinical recommendation, the use of probiotics as a preventive strategy persists.

Jennifer K. Spinler

Inherent in the nature of C. difficile susceptibility is the breakdown of a healthy gut microbiome. Antibiotic treatment for an unrelated illness diminishes the natural microbial barrier required to keep C. difficile at bay, and adjunct probiotic therapy could replenish the microbiota and fend off C. difficile. Multistrain probiotics are favored to maintain a diverse microbiota capable of inhibiting C. difficile growth, whereas single-strain probiotics with specific activity against C. difficile are also promising.

Bio-K+, a multistrain lactobacilli probiotic currently implemented as standard adjunct therapy in Canada, has been credited with decreased incidence and severity of CDI in participating hospitals. Additionally, the use of this formulation has been tracked for over a decade and has not been associated with downstream negative effects in adult patients regardless of comorbidities in these settings. Recent findings in a United States hospital counter this claim with data showing Bio-K+ had no impact on CDI in their hospital, highlighting our need to strive for rigor and reproducibility in probiotic clinical trials.

Alternatively, a single-strain probiotic potent enough to inhibit C. difficile growth without broadly impacting the gut microbiota has potential as a preventive strategy. Under the right conditions, the well-studied probiotic Lactobacillus reuteri produces a natural antimicrobial compound that directly impedes C. difficile growth with minimal effects on the residual bacterial community. Formulations critical for translating this finding to human trials have yet to be defined, but it lends promise to the potential that a single-strain probiotic may have in fighting CDI.

The plethora of available probiotics combined with an increasing public awareness and demand for functional applications toward disease treatment and prevention puts added pressure on clinicians to reliably recommend specific probiotics as options to their patients. Based on current literature, we can only suggest probiotic formulations that may be useful in the fight against C. difficile. However, as the field of microbiome science continues to sharpen its cutting edge and regulatory agencies revisit regulations surrounding the use of live microbes as drugs, it is only a matter of time before next-generation probiotics become standard therapy in treating C. difficile among other important diseases.

Jennifer K. Spinler, PhD, is a microbial geneticist in the Texas Children’s Microbiome Center and a faculty member in the department of pathology and immunology at Baylor College of Medicine. Spinler’s Twitter handle is @DrJKSpinler. Disclosure: Spinler reports receiving unrestricted funds from BioGaia AB and BioGaia Pharma.

PAGE BREAK

COUNTER

It is highly unlikely that multistrain or single-strain probiotics can repair microbiota damage before CDI.

The question rests on a premise that probiotics promote intestinal health by restoring balance in the intestinal microbial composition. A common version of this idea is that the probiotic strains of microbes are the “good” microbes we want in our intestines because they are especially beneficial. Given that CDI generally follows an antibiotic-induced perturbation of the intestinal microbiota, the idea that probiotics can help prevent it has been studied for decades. The results have been largely disappointing, but the idea refuses to die. Why?

Alexander Khoruts

I believe part of the answer lies in the cartoonish view of the intestinal microbes held by most health care providers, which categorizes microbes as either “good” or “bad.” Whereas there are clearly intestinal pathogens, most intestinal microbes cannot be thus classified. Instead, microbiota must be viewed as a whole entity that cannot be divided into individual components. It is often the case that the intestinal microbiota is severely damaged before CDIs. Therefore, it is highly unlikely that any one or even a few strains of bacteria can repair such damage.

It is possible that defined microbial preparations will be developed that will be able to prevent CDIs. However, use of these preparations must be based on a mechanistic understanding of the C. difficile life cycle. For example, we and others have shown that loss of secondary bile acid metabolism after antibiotics creates a vulnerability to C. difficile infection because it encourages C. difficile spore germination and vegetative growth. Conversely, fecal microbiota transplantation results in restoration of secondary bile acid metabolism and inhibition of C. difficile spore germination and vegetative growth. Certain strains of bacteria have been identified that can carry out these chemical transformations, and they might be developed into therapeutics. Clinical trials will need to be done to test their efficacy relative to current therapies.

However, it is important to realize that if such preparations will emerge, they will and should be categorized as biologic drugs. Regulation of drugs is obviously very different from probiotics, which currently fall into the same regulatory bin as dietary supplements. These products are supposed to present little risk, and the regulators are weary of telling consumers how they may wish to spend their money. Notably, recent investigations suggest that probiotics may actually delay post-antibiotic recovery of the intestinal microbiota, and may not be as harmless as we have assumed. Furthermore, virtually no systematic data are available on any adverse events that may be associated with their use.

Many manufacturers take full advantage of the regulatory neglect and focus their efforts on creative marketing. I counsel my patients in all these facts and tell them that probiotics are not going to alter their risk for CDI. However, in the absence of more data to tell otherwise, I do not stand in their way if they feel the products make them feel better.

Alexander Khoruts, MD, is a professor of medicine at the University of Minnesota, and a scientific advisory board member for the American Gastroenterological Association Center for Gut Microbiome Research and Education. Khoruts can be reached at media@gastro.org. Disclosure: Infectious Disease News was unable to confirm relevant financial disclosures at time of publication.