Probiotic – friend or foe?

Journal Pre-proof Probiotic – friend or foe? Jurica Zucko, Antonio Starcevic, Janko Diminic, Damir Oros, Amir M Mortazavian, Predrag Putnik

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https://doi.org/10.1016/j.cofs.2020.01.007

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Current Opinion in Food Science

Please cite this article as: Zucko J, Starcevic A, Diminic J, Oros D, Mortazavian AM, Putnik P, Probiotic – friend or foe?, Current Opinion in Food Science (2020), doi: https://doi.org/10.1016/j.cofs.2020.01.007

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Probiotic – friend or foe? Jurica Zucko1, Antonio Starcevic1, Janko Diminic1, Damir Oros1, Amir M. Mortazavian2 Predrag Putnik1 1University 2Food

of Zagreb, Faculty of Food Technology and Biotechnology, Zagreb, Croatia

Safety Research Center, Faculty of Nutrition Sciences and Food Technology, Shahid

Beheshti University of Medical Sciences, Tehran, Iran Corresponding authors:

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Predrag Putnik, PhD; [email protected]; University of Zagreb, Faculty of Food Technology and Biotechnology

Jurica Zucko, PhD; [email protected]; University of Zagreb, Faculty of Food Technology and

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Biotechnology

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Probiotics are very popular addition to human nutrition with proven health benefits. They represent lucrative segment of food markets. Their manufacturing is not sufficiently regulated on worldwide markets. The safety is insufficiently tested while their intake might have adverse effects. More work is necessary fully to confirm health benefits and safety of probiotics.

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    

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Highlights

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Abstract

Probiotics are modern-day panacea with claims to alleviate or cure everything from diarrhea

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to obesity and Alzheimer’s disease. They seem effective for numerous conditions (e.g. antibiotic-associated diarrhea), although these views have been challenged recently. Greater issue is the lack of confirmed efficacy for majority of claims provided by producers. While offering products without adequate clinical research, industry has more simplistic approach for probiotic treatments, i.e. ‘one-formula-fits-all.’ In contrast, recent studies showed different efficacies of probiotic mixtures with multiple strains without fully understanding factors behind it. Furthermore, important parameter for prescribing probiotic treatment is the 1

individual native microbiota. Interactions among probiotic strains and microbiota needs more research, so there is a long way paved with ‘big data’ and chemometric analysis before it is possible to make full use of probiotics.

Keywords: probiotics, safety, efficacy, microbiota, regulation

Introduction

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Probiotics are now defined by the International Scientific Association for Probiotics and Prebiotics (ISAPP) as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host", a definition that has been slightly revised from the original definition set by the WHO in 2001 [1]. With the consensus statement on probiotics, the ISAPP

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has clarified its stance on traditionally fermented foods containing live microbes, where it does not recommend calling them ‘probiotics’ because of inability to distinguish clearly the

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contribution of the live microbes from that of the food matrix. This is additional to inability to well define strain composition and stability of microbial communities used in traditional

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fermented foods [1].

Probiotic microorganisms originated mainly from fermented milk products and vegetables that have been traditionally consumed for centuries. They have been consumed

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for their positive effects on health, especially on gastrointestinal disturbances. Ever since officially recognized by Metchnikoff, more than a century ago, their popularity rose and the

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usage in general public [2]. Interestingly enough, with their increased usage the way we use them has also changed over time. Although fermented dairy drinks are still their popular

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sources, probiotics are increasingly becoming consumed as dietary supplements in a form of capsules or pills [3]. With this shift from traditional fermented foods to dietary supplements in capsules, the number of live bacteria from food intake has also increased by thousand times on average, or from 105-8 of live bacteria per gram of fermented food [4] to a 1010-12 per single dose, taken as a food supplement [5]. There is no consensus what is an adequate daily amount, but a minimum of 109 colony forming units was recommended by some countries as minimal amount of live microorganisms per dose [1]. Testing involving even higher daily doses of live 2

microorganisms have shown not to be harmful [6]. Regardless of the amount, it is important that probiotics are manufactured and formulated in a way to assure microbial survival in a sufficient number during the entire shelf-life [7,8]. Probiotics are popular in food industry as an ingredient for production of functional foods or they are sold as supplements [9]. Nowadays the usage of probiotics has also been extended even to animals as promoters of growth, survival, and health [10–12]. This increase in usage has also been reflected in the value of the probiotics market, which is rapidly growing worldwide. In 2013, the value was $32.06 billions [13], while estimates for worldwide

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probiotic market in 2024 should expand to $73.8 billion [14].

Good and bad influences on health

Probiotics are increasingly used for their health benefits in number of diseases and ailments, e.g. for allergies, obesity, depression, bacterial vaginosis, and even cancers [15–19]. However,

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it seems that the safety of probiotics is rarely focus of a research (Figure 1). Publications about the safety of probiotic administration lags after the published research on probiotics’ benefits.

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This might be partially due to reluctance of the researchers to publish negative studies or due to firm perception that probiotics as our allies in fighting various ailments. Additionally,

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current literature makes it very difficult to clearly separate benefits from contraindications of probiotics. Hence, what is the current consensus on evidence-based efficacy and safety of probiotics?

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Firstly, it is important to note that historically the most common applications of probiotics include gastrointestinal disorders; therefore, we will only focus on such research

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and applications as a paradigm to highlight deficiencies and problems in the field [20]. A metaanalysis by Ritchie and Romanuk [21] has found significant positive effects of probiotics on

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pouchitis, infectious diarrhea, irritable bowel syndrome, Helicobacter pylori, Clostridium difficile disease, necrotizing enterocolitis, and antibiotic associated diarrhea, while probiotics showed no significant effects on Traveler's Diarrhea [21]. From the strains and mixtures tested, all but Lactobacillus acidophilus, Lactobacillus plantarum and Bifidobacterium infantis had positive effect. Meta-analysis of probiotics in remission of inflammatory bowel disease by Ganji-Arjenaki and Rafieian-Kopaei [22] has found significant effect in patients with ulcerative

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colitis and children with inflammatory bowel disease, while effect was not significant for Chron's disease. Here, the most effective were mixtures of multiple probiotic strains [22]. Meta-analysis investigating efficacy of probiotics on irritable bowel syndrome (IBS) by Ford and colleagues [23] has shown that particular combinations of probiotics may have beneficial effects on global IBS symptoms and abdominal pain. However, specific combination(s) of probiotics, species or strains that are effective remained undefined. The comprehensive review of meta-analyses evaluating the efficacy of probiotics consumption in clinical practice has reported that from all of evaluated usages, evidence-based beneficial effects of probiotics can only be claimed for antibiotic- and Clostridium difficile-associated

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diarrhea and respiratory tract infections [24] . For other applications, probiotic consumption has shown some beneficial results, but with conflicting evidence.

The majority of previously reported studies that are focused on efficacy of probiotic

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consumption and gastrointestinal disorders, regardless of the probiotics taken, are still insufficient. The situation is similar when efficacy of two best-documented probiotic strains is

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examined, i.e. Lactobacillus rhamnosus GG (LGG) and Bifidobacterium animalis subsp. lactis BB-12 (BB-12). Flach and colleagues [25] concluded that "the current evidence indicates that

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LGG and BB-12 supplementation may promote human health and support the daily wellness of consumers, although most (earlier) trials do not meet the stringent standards required for scientific substantiation of a health claim in Europe" [25].

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To add insult to injury, problem of lacking the hard evidence for medicinal benefits of probiotics is exacerbated by worrisome reports that claim probiotics can even have negative

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effects on the health. This notion has been present for some time now, especially for at-risk populations, as immunocompromised patients, those with abnormal gastrointestinal mucosal barrier, or patients recovering from surgical procedures [26]. The most common reported

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problems of probiotics were fungemia and bacteremia [27], but the list has probably just started to expand [28]. Another recently arisen issue in published reports of randomized controlled trials (RCT) is lack or inadequate reporting of harms involving probiotics. Almost a third of RCTs does not even mention harms-related data and only about 2% adequately reported the methods of harm-assessment, clearly reflecting strong beliefs about the safety of probiotics [29]. Hence, before starting probiotic supplementation, it is important to question common views of probiotics as ‘good bacteria’ and general claims put forward by the 4

industry. This is especially true for vulnerable populations where needs to be considered all possible side effects before embarking on probiotic odyssey. Among the factors influencing efficacy of probiotics are interactions of probiotic bacteria with the host and its gut microbiota [30]. Gut microbiota is the largest reservoir of microorganisms in the human body and putative list of its functions is constantly expanding [31,32]. In order to exert beneficial effects, probiotics must chemically or physically inhibit the growth of pathogenic microorganisms and stimulate the growth of beneficial microorganisms [33].

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As for the efficacy of probiotics, their effect on the GI-microbiota is controversial or unclear. Systematic review of the RCTS on the effects of probiotic supplementation on fecal microbiota composition in healthy adults demonstrated "…a lack of evidence for an impact of probiotics on fecal microbiota composition in healthy adults" [34]. A different outcome is

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reported for patients in intensive care unit (ICU), where clinical data demonstrated that probiotics can reduce ICU-infections, although strength of observations is limited by

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significant clinical variability [35]. Two recent publications shed some new light on interactions between probiotics and microbiota. Zmora and colleagues [36] showed probiotics transiently

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colonize the human gut mucosa in highly individualized patterns that is dictated by the indigenous gut microbiome [36]. Hopefully, future investigations on this topic will generate large datasets (i.e. ‘big data’) that can be successfully analyzed with chemometric tools [37]

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to draw solid conclusions about the influence of probiotics on the GI-microbiota. Suez and colleagues [38] investigated the effects of probiotic supplementation after

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antibiotic treatment and found that probiotics perturbed rather than aided microbiota recovery back to baseline. Antibiotic therapy significantly enhanced gut mucosal colonization by probiotics, which then delayed indigenous gut mucosal reconstitution for up to 5 months

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[38]. Recent reports from Zmora and colleagues and Suez and colleagues, combined with growing number of meta-analyses and systematic reviews reported lack of efficiency or even worrisome adverse effects in this instance. This is especially true given the well-established and popular recommendation ‘always take probiotics when taking antibiotics.’

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Legal framework Judging by of the market size and future predictions, probiotics are quite lucrative business, but not without the regulatory issues. That is the lack of worldwide legal framework for consumers’ protection and safe probiotics usage. Meaning, that even at the basic level of classification, probiotics are not globally harmonized, so they can be sold as drugs, dietary supplements, or foods [39]. Dependent of the particular classifications for a probiotic product, differs the legal procedure that it must pass through to reach the market [39]. For instance, if manufacturer is not making some specific disease-related health claim(s), probiotics are regulated as foods or dietary supplements. It is unfortunate that here regulation is focused on

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the legitimacy of any claims and not with efficacy, safety, and quality of the product [40].

Recently, European Union adopted new, stricter, regulatory policy due to the lack of convincing evidence that probiotics improve human health and wellbeing [41]. The European

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Food Safety Authority (EFSA) had rejected all health claims for probiotics, except for improvement in lactose digestion in individuals with lactose maldigestion [42]. The US has

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taken the opposite approach with minimal regulation, and is relying on the market ‘forces’ and producers to deliver the products with required characteristics and quality [43]. This might

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not be in the best interest of consumers, as even though Food and Drug Administration (FDA) is responsible for quality control of probiotics on the market, and even though FDA-tests showed adherence to the ingredients claims, still truthfulness and accuracy of the claims was

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questionable and with faults [44]. Although this approach is highly welcomed by the manufacturers for allowing quicker and easier translation of scientific research to the market,

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it has already shown its downsides [45]. Worldwide harmonization and consensus of all stakeholders in the probiotic market is

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crucial, as in this age of internet commerce, social networks and aggressive media advertising, physical boundaries between differently regulated markets became minimal [46]. Additionally, harmonized and standardized, regulatory guidelines that guarantee ‘do no harm’ principle should be globally enforced, with clear labeling stating reliable and truthful information for consumers. This debate about efficacy of probiotics will most likely continue into the next decade, but consumers have right to know immediately that probiotics they purchase are safe, have been evaluated for genes coding for antibiotic resistance, genomic risk factors and acute toxicity for mammalian hosts [6]. 6

Conclusions Although a long history of probiotic consumption from traditional fermented products with great number of studies implied friendliness with human health and wellbeing, it seems there is still a long way until scientific community and regulators sufficiently dismantle the doubts surrounding safety and efficacy of probiotic supplements. Addressing these questions is at the early stages of a research, while complex patterns of microbiota’s influence on human health and wellbeing are just beginning to emerge. Scientific community must fully clarify how native microbiota affects human health and wellbeing while reliably modeling predictions of

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interactions of probiotic strains and native gut microbiota. This will allow successful personalization of probiotic supplementations, determine the length of a therapy and define the optimal dosages for individuals to maintain their health or to ameliorate some disease. This is especially relevant for the next generation of probiotics that will soon enter the

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markets, which are isolated from human gut microbiota without being found in traditional fermented foods [47]. It is very likely that future probiotic supplementations and probiotic

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food incorporations will follow the ‘bugs-as-drugs’ concept(s) that will be based on personalized medicine and well-studied probiotic strains optimized for individual’s microbiota

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content that targets specific ailments. With all those issues resolved and with evidence-based

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positive influences of health it would be truly possible to call probiotics human friends.

Declaration of interests

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The authors declare that they have no known competing financial interests or personal

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relationships that could have appeared to influence the work reported in this paper.

Acknowledgments This work was supported by Croatian Science Foundation research grant IP-2016-06-3509.

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Figure 1. Number of scientific papers over the last 30 years that are indexed with Pubmed, and that matched search terms: “probiotic”; “probiotic AND safety”; and “probiotic AND (“adverse effect” OR “adverse effects”).“ Figure shows steep growth of publications focused on probiotics, but not those that deal with their safety.

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