The Pros, Cons, and Many Unknowns of Probiotics
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PERSPECTIVE https://doi.org/10.1038/s41591-019-0439-x The pros, cons, and many unknowns of probiotics Jotham Suez1,7, Niv Zmora1,2,3,7, Eran Segal 4,5* and Eran Elinav 1,6* Consumption of over-the-counter probiotics for promotion of health and well-being has increased worldwide in recent years. However, although probiotic use has been greatly popularized among the general public, there are conflicting clinical results for many probiotic strains and formulations. Emerging insights from microbiome research enable an assessment of gut colo- nization by probiotics, strain-level activity, interactions with the indigenous microbiome, safety and impacts on the host, and allow the association of probiotics with physiological effects and potentially useful medical indications. In this Perspective, we highlight key advances, challenges and limitations in striving toward an unbiased interpretation of the large amount of data regarding over-the-counter probiotics, and propose avenues to improve the quality of evidence, transparency, public awareness and regulation of their use. he concept of oral consumption of microorganisms as a indications. These are discussed elsewhere11. We will highlight nota- means of inducing health benefits has intrigued humans ble examples to discuss the following: the ‘knowns’ and challenges Tfor centuries. The term ‘probiotics’ first appeared in this with respect to the strength of evidence and clinical interpretation context in 1974 and has conceptually evolved to its current com- of studies assessing the health benefits of probiotics; the suggested mon definition as live microorganisms that confer a health ben- probiotic mechanisms of action, relating to the debate of whether efit when consumed in adequate amounts, suggested by the Food these will require gut colonization; interactions of probiotic strains and Agriculture Organization/World Health Organization in 2002 with the gut microbiome; safety; and future directions. (ref. 1). Nowadays, probiotics constitute a constantly growing multi-billion-dollar industry2 and are one of the most commonly Clinical efficacy consumed food supplements worldwide3. Foods such as yogurt, The effects of probiotics on humans have been extensively studied cheese, ice cream, snacks and nutrition bars, breakfast cereals and both by scientists and the food and drug industry for decades. This infant formulas are supplemented with probiotics, as are cosmetic has led to multiple suggested prophylactic and therapeutic health products. Probiotics are also commercialized as lyophilized pills4. indications and claims, such as prevention or treatment of acute, Probiotic consumption is widely supported by physicians5, specifi- antibiotic-associated and Clostridium difficile–associated diarrhea; cally gastroenterologists6. amelioration of inflammatory bowel disease and irritable bowel The popularity of probiotics notwithstanding, data from decades syndrome (IBS); and reduction of risk for neonatal late-onset sepsis of research on the efficacy of probiotics in the treatment and preven- and necrotizing enterocolitis. Other claims include, among many tion of disease often point toward opposing conclusions and remain others, eradication of Helicobacter pylori, reduction in incidence conflicting, debated and confusing in many cases. Moreover, the and severity of respiratory infections, alleviation of depression, major medical regulatory authorities, such as the European Food prevention or treatment of atopic dermatitis and reduction of car- Safety Authority7 and the US Food and Drug Administration8, have diovascular risk factors associated with the cardiometabolic syn- yet to approve any probiotic formulation as a therapeutic modality. drome10. Regretfully, despite the fact that some clinical trials related As a result, marketing of probiotics as dietary supplements is often to the above health claims are of high methodological quality driven by properties such as safety, viability in the gastrointestinal and validity12–16, for most of the above indications, there are also (GI) tract and lack of impact on the taste of food, rather than by studies of similarly high methodological quality featuring negative unequivocal health-promoting effects9. This confusing state merits or opposing results, collectively leading to conflicting, ambiguous better evidence-based proof of the impacts that probiotics have on and debatable overall conclusions. humans and their adverse effects10. The current confusing situation may stem from a number of In this Perspective, we will highlight and discuss some of the issues, including the fact that many readouts from probiotic trials are major prospects and limitations of the current approach to probiotic based on empirical clinical data that vary in collection methodology, research, present challenges in the interpretation of available data clinical endpoints and analytical rigor. Many reports use qualitative, and suggest possible strategies to clarify these issues and transform self-reported parameters of ‘well-being’, such as emotional or social investigation of probiotics into a more reproducible and universally function17,18. Others provide quantification of markers that do not accepted measurement-based approach. In our work, the reviewed necessarily have clinical significance, for example clinically insig- over-the-counter microbial interventions will be termed probiotics nificant reduction of the inflammatory marker C-reactive protein regardless of their benefit and efficacy or lack thereof. Of note, the (CRP) in healthy individuals19, or elevation of glucose-stimulated aim of this Perspective is not to review investigational, non-com- glucagon-like peptide 1 (GLP-1) in glucose-tolerant individuals20. mercially-available ‘next-generation’ microbial therapy approaches Likewise, there is great variability in the systems analyzed in these that are being proposed as interventions for various medical trials, including extrapolations from cell cultures, in vitro studies, 1Immunology Department, Weizmann Institute of Science, Rehovot, Israel. 2Digestive Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 3Internal Medicine Department, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 4Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel. 5Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot, Israel. 6Cancer-Microbiome Research Division, DKFZ, Heidelberg, Germany. 7These authors contributed equally: Jotham Suez, Niv Zmora. *e-mail: [email protected]; [email protected] NATURE MEDICINE | www.nature.com/naturemedicine PERSPECTIVE NATURE MEDICINE animal models and human studies that may be observational or randomized placebo-controlled trials assessing treatment with randomized, placebo-controlled trials. At times, even among high- L. rhamnosus (LGG or R0011), with or without Lactobacillus hel- quality, placebo-controlled studies, different trials uncover conflict- veticus R0052, in over 1,800 children who presented with acute ing putative benefits of probiotics21,22. gastroenteritis to the emergency department demonstrated no Another contributor to the variability in probiotics research is the clinical benefits41,42. An earlier meta-analysis in over 4,000 children disparity of studied strains. The dominant microorganisms used in showed that the quality of evidence with regard to this indication the probiotics industry even nowadays belong to the Lactobacillus and was low to very low43, leading to the omission of probiotics from Bifidobacterium genera, as well as Lactococcus spp., Streptococcus ther- one set of clinical management guidelines44, whereas another study mophilus, E. coli Nissle 1917 and the yeast Saccharomyces boulardii23. still advocates for the use of LGG and S. boulardii while stating that While some health-associated mechanisms of action are common the evidence upon which these recommendations are based is of in multiple probiotic genera and species (for example, the produc- low quality45. Notwithstanding this dispute, many parents ‘self-treat’ tion of bile salt hydrolases)24, other traits may be species- or even their children when they contract gastroenteritis with ‘functional strain-specific, or may require interaction between different strains foods’ containing probiotics46. to produce an effect. To counteract the above methodological and analytical limita- Clostridium difficile–associated diarrhea. C. difficile thrives in the tions and to overcome underpowered findings, researchers and gut when microbiome-conferred colonization resistance is compro- clinicians frequently integrate results from multiple studies in the mised, such as upon antibiotic treatment in hospitalized patients. form of systematic reviews and meta-analyses. The use of such tools The result is a disease that can range in severity from mild diarrhea may be highly useful in revealing general trends; however, it may to a life-threatening condition termed pseudomembranous colitis. also be susceptible to biases that can be introduced in each analyti- Several meta-analyses have shown a cumulative beneficial outcome cal step25, such as the inclusion of outlier studies that dominate the of orally administered probiotics: prevention of C. difficile infection collective results and obscure actual effects, or the lack thereof. In or its associated morbidity47, especially when administered close to particular, meta-analyses concerning probiotics tend, at times, to antibiotic exposure48.