Equine Probiotics-What Are They, Where Are We and Where Do We Need To Go?

Probiotics are live microorganisms that when consumed in adequate amounts confer a health benefit to the host. The objective of this review is to critically evaluate the definition of probiotics with reference to their use as supplements in horses, research regarding quality control, and propose areas for future focus. Several studies, performed over a 19-year period, have consistently identified deficiencies when comparing actual contents to label claims. Furthermore, basic information such as expiration dates and storage instructions are often missing from the labels. Finally, the authors will propose several criteria that consumers should consider when choosing probiotics marketed for use in horses.

Probiotics and the Microbiome-How Can We Help Patients Make Sense of Probiotics?

The notion of probiotics as microbes that confer health benefits has its origins in the speculative ideas that are more than a century old, yet remain largely unsubstantiated by scientific evidence. The recent advances in microbiome science have highlighted the importance of intestinal microbes in human physiology and disease pathogenesis. These developments have provided a boost to the probiotics industry, which continues to experience exponential growth driven mainly by creative marketing. Consumers, patients, and most health care providers are not able to discern the underlying science or differentiate the permitted claims that promise vague health benefits from disease-specific claims reserved for drugs. No probiotic product has been able to satisfy the regulatory requirements to be categorized as a drug, a substance intended to cure, mitigate, or prevent disease. However, patients take probiotic products in the belief that they will help to treat their intestinal or systemic diseases. Thus far, the regulators have failed to create policies that would assist to inform the public in this area. In fact, the existing regulatory regime actually creates formidable barriers to research that could provide evidence for clinical efficacy of probiotic products. We propose a potential solution to this vexing problem, where a committee created through a partnership of academia, professional organizations, and industry, but free of potential conflicts of interest, would be charged with rigorous evaluation of specific probiotic products and the evidence in support of their different claims. Companies that would submit to this process would earn the trust of consumers and healthcare providers, as well as a distinction in the marketplace.

Live biotherapeutic products: the importance of a defined regulatory framework.

Probiotics have been defined as "Live microorganisms that when administered in adequate amounts confer a health benefit on the host". This definition covers a wide range of applications, target populations and (combinations of) microorganisms. Improved knowledge on the importance of the microbiota in terms of health and disease has further diversified the potential scope of a probiotic intervention, whether intended to reach the market as a food, a food supplement or a drug, depending on the intended use. However, the increased interest in the clinical application of probiotics may require specific attention given their administration in a diseased population. In addition to safety, the impact of the type of product, in terms of quality, production method and, e.g., the acceptance of side effects, is now part of the current regulatory constraints for developers. In the European Union, foods are regulated by the European Food Safety Authority and drugs by the European Medicines Agency; in the United States, the Food and Drug Administration (FDA) deals with both categories. More recently, the FDA has defined a new "live biotherapeutic products" (LBP) category, clarifying pharmaceutical expectations. Since 2019, the quality requirements for this category of drug products have also been clarified by the European Pharmacopoeia (Ph. Eur.). Similar to all products intended to prevent or treat diseases, LBPs will have to be registered as medicinal products to reach the market in the US and in Europe. In this area, regulatory authorities and the pharmaceutical industry will routinely use guidelines of the "International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use" (ICH). Although ICH guidelines are not legally binding, they provide very important recommendations, recognized by almost all drug authorities in the world. In this review, we discuss some aspects of this regulatory framework, especially focusing on products with an intended use in a diseased or vulnerable target population.

Probiotics: Versatile Bioactive Components in Promoting Human Health.

The positive impact of probiotic strains on human health has become more evident than ever before. Often delivered through food, dietary products, supplements, and drugs, different legislations for safety and efficacy issues have been prepared. Furthermore, regulatory agencies have addressed various approaches toward these products, whether they authorize claims mentioning a disease's diagnosis, prevention, or treatment. Due to the diversity of bacteria and yeast strains, strict approaches have been designed to assess for side effects and post-market surveillance. One of the most essential delivery systems of probiotics is within food, due to the great beneficial health effects of this system compared to pharmaceutical products and also due to the increasing importance of food and nutrition. Modern lifestyle or various diseases lead to an imbalance of the intestinal flora. Nonetheless, as the amount of probiotic use needs accurate calculations, different factors should also be taken into consideration. One of the novelties of this review is the presentation of the beneficial effects of the administration of probiotics as a potential adjuvant therapy in COVID-19. Thus, this paper provides an integrative overview of different aspects of probiotics, from human health care applications to safety, quality, and control.

The Development of High-Quality Multispecies Probiotic Formulations: From Bench to Market.

Probiotics are live microorganisms that, when administered in adequate amounts, confer a health benefit on the host. To date, there is an increasing number of commercially available products containing probiotics on the market. Probiotics have been recommended by health care professionals for reasons ranging from their long-term immunomodulatory effects to proven benefits in the management of different health conditions. For probiotic products, there are several important aspects that determine the success rate of the development from bench to market. The aim of this review is to explore how the current knowledge on microbe-microbe and host-microbe interactions can be used to develop high-quality, evidence-based probiotic formulations, specifically probiotic dietary supplements, with a focus on the selection of safe strains with relevant functional properties. In addition, we will highlight aspects of the probiotic manufacturing process that need to be considered during the product development and the subsequent manufacturing process to guarantee consistent efficacy of a probiotic product. For each high-quality probiotic formulation, it is important to screen multiple strains, and select only those strains that show relevant functional properties and that can be considered safe for human consumption. In addition, it is imperative that attention is paid to the product development and manufacturing process, and that safety and quality properties are monitored. Importantly, the beneficial effects of probiotics should be evaluated in product efficacy studies and post-marketing surveys in order to demonstrate their clinical efficacy. All these aspects need to be evaluated and validated during the development of a successful high-quality and ready-to-market probiotic.

Effects of Probiotics, Prebiotics, and Synbiotics on Calcium Homeostasis and Bone Health With Aging: A Systematic Review.

BACKGROUND: Calcium homeostasis and bone health are an increasing concern for middle-aged and older adults. Many studies have explored the positive effects of probiotics, prebiotics, or synbiotics on serum calcium and bone mineral density (BMD) or other parameters related to bone health. However, the participants, the species, doses and duration of interventions, outcomes, and measurements varied among these studies. AIMS: To systematically evaluate the effect of probiotics, prebiotics, or synbiotics on maintaining calcium homeostasis and improving bone health in middle-aged and older adults. METHODS: We identified studies in Cochrane Library, Embase, PubMed, Web of Science, CINAHL, China National Knowledge Infrastructure, and Wanfang and articles in English and Chinese published from inception up to January 10, 2019. Randomized controlled trials (RCTs) involving probiotics, prebiotics, or synbiotics for middle-aged or older adults were employed for meta-analysis by using RevMan 5.3, and heterogeneity and risk of bias assessment were performed. RESULTS: A total of eight studies, involving 564 participants, were included. Probiotics, prebiotics, or synbiotics supplementation was able to significantly elevate serum calcium levels (0.52 mg/dl, 95% CI [0.38, 0.66]), heterogeneity: p = .13, I2  = 44%), while the results of meta-analysis failed to support the effects of this supplementation on the parameters related to bone health in middle-aged and older adults, including BMD, parathyroid hormone, osteocalcin, and alkaline phosphatase. LINKING EVIDENCE TO ACTION: Probiotics, prebiotics, or synbiotics supplementation exerts a facilitating influence on the level of serum calcium, while the present study has not yet supported the beneficial effects of such interventions on bone health. Therefore, further studies with high-quality RCTs are required to determine the effects of probiotics, prebiotics, or synbiotics supplementation on middle-aged and older adults.

The pros, cons, and many unknowns of probiotics.

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 colonization 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.

The Unregulated Probiotic Market.

BACKGROUND & AIMS: This narrative review provides an overview of the current regulation of probiotics, with a focus on those used for the dietary management of medical conditions (Medical Foods). FINDINGS: The probiotic market has grown rapidly, both for foods and supplements intended to enhance wellness in healthy individuals, and for preparations for the dietary management of disease. Regulation of probiotics varies between regions. Unless they make specific disease-related health claims, probiotics are regulated as food supplements and regulation is focused on the legitimacy of any claims, rather than efficacy, safety and quality. Many properties of probiotics are strain-specific, and safety and efficacy findings associated to specific formulations should not be generalized to other probiotic products. Manufacturing processes, conditions and ingredients are important determinants of product characteristics and changes to manufacturing are likely to give rise to a product not identical to the "original" in efficacy and safety if proper measures and controls are not taken. Current trademark law and the lack of stringent regulation of probiotic manufacturing mean that the trademark owner can commercialize any formulation under the same brand, even if significantly different from the original. These regulatory deficits may have serious consequences for patients where probiotics are used as part of clinical guideline-recommended management of serious conditions such as inflammatory bowel diseases, and may make doctors liable for prescribing a formulation not previously tested for safety and efficacy. CONCLUSIONS: Current regulation of probiotics is inadequate to protect consumers and doctors, especially when probiotics are aimed at the dietary management of serious conditions.

The ascent of the blessed: regulatory issues on health effects and health claims for probiotics in Europe and the rest of the world.

The outcome of the first series of health claim applications for probiotics in Europe as evaluated by the European Food Safety Authority (EFSA) has, up to 2013 almost completely yielded negative results. All recent applications also have been rejected, including the latest on prevention of mastitis in breastfeeding mothers. In other developed countries, such as Switzerland, Japan and Canada, the health effects of probiotics, for which scientific evidence has been provided, can be communicated to potential consumers. The number of clinical trials with probiotics over recent years shows a trend to level off or even decline. At the same time, clinical research into the role of (gut) microbiota in a wide variety of diseases and conditions is booming. Ultimately, this may offer new indications for gut microbiota management by probiotics, prebiotics or other food supplements.

Probiotic use in at-risk populations.

OBJECTIVE: To inform health care providers about quality standards for manufacture of probiotic products being recommended for at-risk patient populations. SUMMARY: Probiotics are used in a variety of clinical settings, sometimes in at-risk populations for therapeutic endpoints. Although probiotics might not be approved as drugs, they are sometimes used for the prevention or treatment of disease. In the United States, and many regions of the world, probiotic products are marketed as dietary supplements (not drugs) and are therefore subject to different manufacturing and quality control standards than approved drugs are. Health care providers need to be assured that probiotic products used in at-risk populations are safe for this use. Pharmacists should require certificates of analysis, which document quality standards, from manufacturers of products stocked in hospital formularies or other pharmacies dispensing to at-risk people. Although responsible manufacturers use stringent quality standards on their processes and finished products, using a third party to verify compliance with manufacturing and accuracy of product labeling adds assurance to end users that the product is of high quality. CONCLUSION: It is in patients' best interest to use probiotics in the prevention and treatment of conditions when the evidence is convincing. To protect high-risk patients, probiotic products should meet stringent microbiological standards. Product testing results should be available for review before recommending probiotic products to at-risk individuals. For products used in at-risk populations, manufacturers should provide this information or participate in a third-party verification program that certifies compliance.

Advancing probiotic research in humans in the United States: Challenges and strategies.

This is a summary from a workshop convened as part of the 13(th) annual meeting of the International Scientific Association for Probiotics and Prebiotics. A group of 24 stakeholders, including clinical experts, researchers, federal government officials, funding agencies, lawyers and industry experts met to review the challenges of the current regulatory approach to human research on probiotics in the USA and to discuss ways to move research forward. There was agreement that some of the current regulatory requirements imposed on probiotic research in the United States hindered research progress and increased cost without improving study subject safety. Many situations were outlined by clinical investigators demonstrating the impact of regulatory delays on research progress. Additionally, research is compromised when study designs and outcomes require manipulation so as to invoke less burdensome regulatory requirements. These responses by investigators to regulatory requirements have placed United States' researchers at a disadvantage. The public ultimately suffer when research to clarify the role of these products on health is stalled. Workshop participants concurred that regulatory oversight should balance study subject vulnerability with documented safety for the intended use for the probiotic strain, and that human research on foods and supplements should not be be regulated as drug research. Challenges and potential improvement strategies are discussed.

Health claims substantiation for probiotic and prebiotic products.

The topic of "Health Claims Substantiation for Probiotic and Prebiotic Products" was discussed at the 8 (th) annual International Scientific Association for Probiotics and Prebiotics (ISAPP) meeting. The topic is especially timely considering that the regulatory review process for health benefit claims on probiotic and prebiotic products in Europe has not resulted in a single claim being approved (120 negative opinions on probiotic claims and 19 negative opinions on prebiotic claims through February 2011). This situation in Europe and elsewhere has driven companies to seek clarity on a research path that would stand up to scientific scrutiny as well as satisfy regulatory demands for health claim substantiation. It can be challenging to negotiate rigid regulatory distinctions, such as between health and disease, when these states are more realistically represented by continua. One research approach focused on improved homeostasis is explored as a statistically robust approach to measuring physiological parameters in healthy populations, which are the required target for food and supplement claims. Diverse global regulatory frameworks complicate this issue, and harmonization of different approaches globally would simplify requirements for industry, decrease consumer confusion and improve the scientific framework for the research community to set up appropriate research pathways. This report highlights key points from this discussion. 

The science and regulations of probiotic food and supplement product labeling.

Presented by the New York Academy of Sciences, the U.S. Food and Drug Administration (FDA), and the U.S. Office of Dietary Supplements of the National Institutes of Health, the symposium "Probiotic Foods and Supplements: The Science and Regulations of Labeling," was held on June 12, 2010 at the New York Academy of Sciences, New York, NY, the goals of which were to facilitate the exchange of ideas regarding labeling and substantiation of claims for probiotics among academic, industry, and regulatory professionals, and to discuss ways to translate and communicate research results in a truthful way to the consumer and to such health professionals as physicians, pharmacists, and dieticians. The target audience for this symposium included academicians interested in conducting research on the health benefits of probiotics; scientists; communications personnel, and regulatory specialists from companies involved in, or interested in, the marketing of probiotics; U.S. government regulatory experts tasked with oversight of probiotic foods and dietary supplement products; and other experts in the field interested in the development of probiotics for the U.S. market.

[Effect of phytocompositions on biological activity of probiotic strains of Bacillus subtilis].

Influence of phytocompositions containing silica and medical herbs on growth and biological activity of probiotic strains of Bacillus subtilis and some representatives of obligate microflorae of intestine has been studied. Biocompatibility of studied strains with both pure aerosil bacteria, and its phytocompositions has been shown in the article. It is supposed that phytocompositions can be considered as components for creation of complex probiotic preparations from bacilli for the purpose to increase their therapeutic efficiency.

Probiotic foods and drugs: impact of US regulatory status on design of clinical trials.

Probiotics have been in widespread use since ancient times and are increasingly being consumed to maintain health and to prevent and treat a wide range of conditions. In the United States, probiotics are considered to be foods or biologics, depending on their intended use. This article addresses the similarities and differences between approaches to conducting clinical trials of probiotics as foods (which leads to health claims) or as biologics (which leads to therapeutic claims). Most probiotics are manufactured as foods, which makes it challenging for academic investigators in the United States to meet the requirements of an Investigational New Drug application that enables them to study the therapeutic effects of these novel agents. Although it is important to ensure the safety and quality of probiotic products, there also may be value in adapting the US Food and Drug Administration's Guidance for Industry for Botanical Products to probiotic products, in part to allow the research agenda to move forward with products for which there are no safety concerns.

Probiotics in the United States.

Probiotics are live microbial products that have a defined health benefit. Scientific research has established that there are validated indications for the use of some probiotics available in the United States; however, in many cases, they are often used for conditions for which no benefit has been established. This article will review the uses of probiotics in the United States, as well as the current state of regulatory issues surrounding probiotics. Although the use and scientific understanding of probiotics are rapidly increasing, it is evident that there is a need to clarify the regulatory issues, which, at present, are unclear and subject to misinterpretation. In addition to efficacy, safety issues must be considered in determining when and how probiotics are to be used.

Preclinical testing in the development of probiotics: a regulatory perspective with Bacillus strains as an example.

Preclinical testing of the microbial strains is the first important step in the development of probiotics. Requirements for the set of tests can vary depending on the bacterial species and the expected mechanism of action in the organism. Common approaches to preclinical testing of probiotic strains include strain identification (i.e., determination of phenotypic and genotypic properties), safety evaluation (i.e., characterization of history of use [safety contact], assessment of resistance to antibiotics, and evaluation of pathogenic properties in vitro and in animal models), and efficacy testing (i.e., functional characterization). Future progress in probiotics requires more studies to determine the mechanisms of their action, as well as an understanding of the basis and mechanisms of pathogenicity for different probiotic strains. Special attention should be given to recombinant probiotics, particularly in the formulation of criteria for selection of the host strain, for assessment of environmental safety, and for tracing the fate of recombinant DNA in vitro and in vivo.

[Assessment of probiotics according to the international organizations (FAO/WHO)].

The guidelines of international organizations (FAO/WHO) are presented in the paper for the purpose of estimation of probiotic properties of the strains of microorganisms as well as functional food products in respect of their influence on health. Modern scientific researches served as the basis for minimum requirements necessary for the competence of probiotic status. The chart of the experiment sequence is presented that has to be used for probiotics estimation: bacteria systemizing with the use of phenotype and genetic techniques, description of functional properties of the probiotic and estimation of its safety. The in vitro tests for determination of safety of probiotics are described.