Safety and Tolerability of Probiotics

by Melissa Blake, ND

Introduction

As clinicians, we all want to make effective, safe recommendations, and the evidence of safety is an essential consideration prior to prescribing an intervention. Safety of probiotics is no exception.  With evidence mounting on the many benefits and overall safety profile, it’s not surprising that probiotic supplementation quadrupled between 2007 and 2012.¹

With a few considerations, probiotic therapy is generally accepted as safe and well-tolerated, particularly in healthy people. However, few studies have specifically addressed the safety of probiotics in detail and further safety studies are required.

Supplementation, however, does not come without some risk, particularly in certain populations such as immunocompromised and critically ill patients. In these patient populations, safety of probiotic therapy is an especially important consideration.  Theoretical safety concerns of probiotic therapy include systemic infections, deleterious metabolic effects, excessive immune stimulation, and transfer of antibiotic resistance genes.

This article reviews the evidence available related to these four specific safety concerns, as well as contraindications and tolerability of probiotic supplementation.

Identification and safety

Standards and guidelines on the definition and use of probiotics were the first steps in ensuring safety in humans. Identification at the strain level (alphanumeric designation) is an important safety consideration for probiotic use in humans, as different strains of the same species confer different benefits and/or risks.²

A good example is contained in the Escherichia coli species. Escherichia coli O157:H7 is a resistant, food-borne pathogen that contributes to human disease worldwide.³ While patients infected with E. coli O157:H7 may experience watery diarrhea,⁴ probiotic supplementation with Escherichia coli Nissle 1917 has been shown to be safe, to help reduce diarrhea, and may be helpful in the management of ulcerative colitis.⁵

Within the genus Bacillus, different bacteria elicit different effects. Bacillus anthracis, for example, is a species responsible for anthrax, an acute, airborne infection that poses a risk to all mammals, including humans.⁶ Conversely, strains of Bacillus coagulans have been identified as generally recognized as safe (GRAS), with the official notice on file with the FDA.⁷

Tolerability vs. safety

Probiotics rarely cause serious complications;⁸ however, mild side effects can occur. Typically transient, these side effects may include gas, bloating, nausea, and changes in bowel health and are more common in certain patient subsets.

An observational study of 30 patients concluded that patients with dysmotility or low acid conditions or those taking medications (such as opioids or proton pump inhibitors) that impair gastrointestinal function were more likely to experience side effects related to prolonged or excessive probiotic use.⁹

Although unwanted side effects can occur, the issue here is more one of tolerability versus probiotic safety. Symptoms are generally mild and self-limiting but may require discontinuation of probiotic therapy temporarily to assess and treat the underlying imbalance or impairment.

Theoretical safety concerns

Although complications are rare for most populations,¹⁰ probiotic safety outcomes are inconsistently reported in clinical studies¹¹s, and evidence suggests avoidance in certain at-risk populations. In a 2002 report by WHO and FOA of the United Nations,¹² four specific concerns were identified as theoretical side effects related to probiotics. They include:

1. Systemic infections

A logical safety concern with the use of any bacterial species is that of possible infection. There have been several case reports validating this concern, including events of fungemia associated with S. boulardii and bacteremia associated with Lactobacilli spp.¹³ An important consideration is that these events are rare compared to the incredibly common use of probiotics and were most often reported in critically ill^13-15and severely immunocompromised patients.^16-18

2. Deleterious metabolic activities

The PROPATRIA study was a double-blind placebo-controlled randomized controlled trial that generated concerns around probiotics.¹⁹ The study examined the use of a multistrain probiotic in 296 patients with severe pancreatitis to determine benefits in preventing infectious complications. Sadly, patients in the probiotic group experienced higher mortality attributed to bowel ischemia, and as a result, researchers discouraged the use of probiotics in patients with pancreatitis.

Encouragement for this study came from a few previous small studies showing benefit with a single-strain probiotic in reducing infectious complications in patients with pancreatitis,²⁰ liver transplant recipients,²¹ and patients undergoing elective abdominal operations.²² A more recent systematic review and meta-analysis, while highlighting the lack of consistency in the existing studies in type, dose, and duration of probiotics given, concluded that probiotics neither harmed or benefited patients with pancreatitis.²³

A metabolic effect associated with certain bacterial strains is an increase in D-lactic acid production. Several reports of probiotics contributing to D-lactic acidosis can be found in the literature; however, these reports were in patients with underlying conditions including short bowel syndrome^24-26and small intestinal bacterial overgrowth (SIBO).^9,11 In one reported case, the treatment for D-lactic acidosis was the addition of a cocktail containing non-D-lactate-producing probiotics.²⁷

It is important that clinicians and researchers alike avoid applying broad statements to all probiotics and instead use the evidence to support a strain-condition-specific approach.

3. Excessive immune stimulation in susceptible individuals

The literature supports the positive impact of probiotics on immune health. Their use in susceptible patients or those with existing autoimmune disease, allergies, or other hyperimmune responses has therefore been questioned. However, the evidence suggests probiotics have a modulating influence on the immune system, and trials have demonstrated positive results in a spectrum of immune-related conditions such as the common cold (meta-analyses),^28,29 with emerging evidence suggesting benefits for food hypersensitivities³⁰ and rheumatoid arthritis.³¹

4. Gene transfer

Probiotics require specific traits in order to exist and flourish within the dynamic and otherwise hostile environment of the human gastrointestinal tract. Gene transfer allows for certain traits to be transferred from one bacteria to another, and the phenomenon has led to multi-drug-resistant bacteria.³² The potential for probiotics as the culprit has not been demonstrated, and it remains a theoretical concern, as no clinical evidence of transfer of antimicrobial resistance between probiotics and microbes within the gastrointestinal system has ever been demonstrated.¹¹

Contraindications

Although most of the concerns identified by the WHO/FOA are theoretical, they are more commonly reported in certain populations including patients who are immune-compromised or critically ill.¹¹

Although data that support the use of probiotics in higher risk patients exists, evidence of safety is very specific to the strain and cannot be generalized across all probiotics. For example, studies on Lactobacillus rhamnosis GG demonstrate safety in human populations including “pregnant women, premature neonates, elderly individuals, and hospitalized children and adults with diarrhea.”⁸ It has also been studied in patients with HIV, without significant adverse events. ³³

Both safety and efficacy of probiotics at the strain level need be priorities of future research.

Quality matters

Species and strain specifics aside, probiotics are also graded by factors that measure quality, potency, and durability. Standards are in place to ensure probiotics hit their targets. Currently, based on a report of the joint FAO/WHO working group on probiotics, guidelines suggest probiotics contained in food undergo minimum testing and meet a specific set of requirements to determine safety and efficacy.³⁴  Best practices based on guidelines by The Council for Responsible Nutrition (CRN)/International Probiotic Association (IPA) specify labeling, stability testing and storage recommendations.³⁵

In brief, probiotics, as living microorganisms, should be identified as colony-forming units (CFU), and the storage recommendations should match stability studies. Quantities at expiration also need to be guaranteed and should match the clinically effective dose in order to ensure that the probiotics are delivered at the expected and therapeutic quantity. It is important to note that in several of the studies previously mentioned, a thorough description or evaluation of the probiotics was lacking, so it is unknown whether the probiotics were identified by strain and whether or not there were any undesirable bacteria or other unwanted compounds in the consumed product.

For example, one case report did not identify the strain or characterize the quality and purity of the probiotic-containing “dietary products” consumed,¹⁸ and in another case, the report recognized the difficulty in distinguishing between two strains.¹⁶ One case did, however, show that in a patient with severe ulcerative colitis, there was a 99.78% match of the strain in the blood with what was consumed, highlighting the need to reconsider live probiotics for patients who have compromised intestinal barriers.¹⁵

Summary

Probiotics have a long history of use in humans, both in food and supplement forms, with a relative high level of safety;⁸ however, it is essential to weigh the evidence against the potential risk.  To ensure safe use, it is important for the physician to evaluate the identity and quality of the probiotic to assess whether the specific strain(s) are recognized as safe and effective and without contamination.  Until we have more human data to ensure safety, clinicians should evaluate risk prior to recommending probiotics, particularly in critically ill and immunocompromised patients.

Citations

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Melissa Blake, ND is the Manager of Curriculum Development at Metagenics. Dr. Blake completed her pre-medical studies at Dalhousie University in Halifax, Nova Scotia and obtained her naturopathic medical training from the Canadian College of Naturopathic Medicine. Dr. Blake has over 10 years of clinical experience, specializing in the integrative and functional management of chronic diseases.