The human body is home to trillions of bacteria, and the identification of “good microorganisms” in our body – that is, bacteria that boost the immune system and have beneficial implications for conditions like diarrhea and irritable bowel syndrome – has led to the birth of the probiotics industry. Millions of people use probiotics in North America alone, and this industry is ever-growing with the market expected to exceed $73 billion USD by 2024. But the question remains: are probiotics really as safe and effective as we think they are?

Several widescale attempts have been made to assess the safety of probiotics. The Southern California Evidence-based Practice Centre reviewed over 600 studies sponsored by the National Institutes of Health (NIH) and US Food and Drug Administration (FDA) that used at least one of the six most popular bacterial genera in probiotics: Lactobacillus, Bifidobacterium, Saccharomyces, Streptococcus, Enterococcus and Bacillus. The authors concluded that while there is no compelling evidence of risk associated with probiotics in these studies, researchers should aim to provide comprehensive evaluations of the safety of probiotics including in vitro, animal and human clinical trial studies in healthy populations at the very least. In fact, researchers have recently raised the serious issue of the lack of transparency in studies involving the use of probiotics. In 2018, the team of Bafeta and colleagues from Colombia University conducted a methodological, systematic review of 384 randomized controlled clinical trials to assess the ability of probiotics, prebiotics (essential food for “good microorganisms”) or a combination of both in altering the microbiome for improved health outcomes. They found that 70% of these trials did not report the number of patients who withdrew from the trial due to adverse events; this is in stark contrast to clinical trials involving a new drug where detailed safety and pharmacokinetics reports are required prior to FDA approval. An alarming finding from this study was the lack of a standardized evaluation method for trials assessing the effects of probiotics. Only 2% of the trials clearly defined adverse events and the method used to collect such data, and just 18% of the studies identified the population that was included in the safety analysis. Reporting all safety data in a systematic way is integral and necessary to improve the transparency and quality of research moving forward.

Importantly, research on the safety of probiotics in vulnerable populations such as infants, immuno-compromised people, the elderly or specific patients is even scarcer. This lack of safety information may have serious consequences as evidenced by the PROPATRIA study from Besselink and colleagues that assessed the effect of probiotics on preventing infectious complications in 296 patients with severe acute pancreatitis. Their 2008 publication in Lancet showed that taking probiotics significantly increased the risk of death compared to the placebo group. The authors suspected that the probiotics may have increased oxygen demand in the gut where blood flow was already low in these patients, which in turn led to bowel ischemia as detected during operation or autopsy. This example demonstrates how probiotics may not be completely harmless in some cases, especially in the context of patients with severe diseases.

As it stands, the FDA has applied the Generally Recognized as Safe (GRAS) designation to certain probiotics added to food. So, assuming that probiotics are generally safe, another important aspect to consider is whether probiotics are as effective as they claim to be. This is arguably a more difficult question to answer as many studies lack proper control groups and may be subjected to the placebo effect. Moreover, deciphering the exact bacterial strains and their link to health or disease is tricky business. For instance, while most studies do find a difference between the gut microbiome of patients with Parkinson’s disease and healthy controls, there is a lack of consensus on the exact culprit; some suggest that Parkinson’s disease is linked to an increase in Bifidobacterium and a decrease in Prevotella while others found no difference with respect to these two genera. Of course, not being able to pin down the exact bacterial strains of interest can yield ineffective products. In the case of using probiotics to confer resistance to Listeria monocytogenes infection, studies in mouse models have shown that only the Lactobacillus salivarius UCC118 strain is effective in providing this resistance, but not others. This suggests that a high level of precision is required in developing and producing probiotics. Finally, even the products that are already on the market may not provide consumers with a reliable range of effectiveness because probiotics are not as heavily regulated as drugs. This is evident as two different batches of a commercially available probiotic were shown to have significantly different efficacy in the treatment of a mouse model of colitis. As such, the same issue prevails – there is very little regulation and standardization when it comes to effective probiotic usage.

Specimens that are used to test for probiotics efficacy are not standardized either; while the majority of literature is based on stool microbiome analysis, this may not be the most ideal choice. A recent study published in Cell showed that in fact, the microbiome load is vastly different throughout the human gastrointestinal tract; this bacterial gradient load starts from the upper gastrointestinal tract and continues all the way to stool samples where bacterial load is highest. Therefore, another limitation in these systems is the use of not-so-ideal stool samples to assess the effect of probiotics on microbiome changes in the gut. Furthermore, the research team showed that whether probiotics led to colonization in the gut depended on the individual person, the bacterial strains for colonization and the specific region within the gut. Some people were identified as being “permissive” to colonization of the probiotic strains while others were more “resistant”, but there was no identifiable factor to pre-determine the outcome. Yet again, this study highlighted the complex nature of probiotics and their conferred microbiome changes in different individuals.

Probiotics have been frequently recommended as a way to replenish the “good microorganisms” after their eradication during antibiotics treatment. Interestingly, Suez and colleagues from the Weizmann Institute of Science challenged this idea of using probiotics to restore microbiomes disrupted by antibiotic use in their recent publication in Cell. The team compared the efficacy of probiotic use to 1) spontaneous reconstitution, meaning observing patients without any intervention, and 2) autologous fecal microbiota transplant, the procedure of transplanting bacteria from a patient’s own stool to recolonize those strains ablated by antibiotic use. It took around three weeks for patients to spontaneously return to their pre-antibiotic state, while the use of autologous fecal microbiota transplant led to a near-complete recolonization of the gut microbiome within days. Surprisingly, the use of probiotics significantly delayed this reconstitution to more than five months. In this case, the use of probiotics was not only ineffective but arguably harmful since it performed worse than the control group undergoing natural recovery. Given that several studies have linked antibiotic-induced microbiome disruption with increased susceptibility to infectious and chronic diseases, delayed reconstitution conferred by probiotics can have important implications for health outcomes in these patients.

With advances in biotechnology, scientists can now identify bacterial strains that were traditionally impossible to isolate, culture and study. This in turn will undoubtedly lead to more therapeutic options to explore, and subsequently increase the number of probiotic consumers. With more healthcare providers prescribing probiotics to their patients for various reasons, efforts should focus on creating safe probiotics tailored to different contexts. There is no one-size-fits-all when it comes to probiotics.

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Yoojin Choi

Yoojin is a graduate student in the Department of Immunology at the University of Toronto.

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