Why do clinical guidelines for probiotics differ?

Clinical guidelines are recommendations for healthcare providers regarding patients with specific conditions. These guidelines should be based on practice experience and the best available research evidence. However, guidelines developed by various health organisations worldwide often do not agree with each other. This is also true for the current guidelines for the clinical use of probiotics. This article aims to provide examples of conflicting clinical guidelines for probiotics, define reasons for this phenomenon, describe standard tools for improving their quality, and suggest ways to enhance the development and assessment of suitable clinical guidelines for the appropriate clinical use of probiotics in specific conditions.

Quality Management of Probiotics: Ensuring Safety and Maximizing Health Benefits.

Consumption of probiotics, which are beneficial live microorganisms, has received a lot of attention because of their potential to improve health and wellness. Robust quality control measures are necessary to ensure the safety of probiotics and maximize their health effects. This review delves into the topic of quality management in probiotics, highlighting the significance of sticking to strict guidelines from manufacture to storage to distribution. Probiotic quality standards, Good Manufacturing Practices (GMP) implementation, quality control and testing techniques, and documentation and traceability systems are all discussed in detail. The importance of taking precautions to avoid microbial contamination, meeting all applicable regulations, and clearly marking and packaging probiotic products is also emphasized. In addition, it reviews the clinical evidence supporting the possible health advantages of probiotics and investigates the processes through which probiotics enhance health. The review continues by stressing the significance of educating and informing consumers about probiotics and their proper use in order to maximize health benefits. Probiotics' potential health benefits can be maximized and consumer faith in these helpful microbes can be bolstered by adopting thorough quality management measures to ensure their safety, efficacy, and consistency.

Recent progress in the use of purple non-sulfur bacteria as probiotics in aquaculture.

The use of probiotics in aquaculture is widely recognized as an ecological and cost-effective approach to raising healthy, pathogen-tolerant aquatic animals, including fish and shrimp. In particular for shrimp, probiotics are viewed as a promising countermeasure to the recent severe damage to the shrimp industry by bacterial and viral pathogens. Purple non-sulfur bacteria (PNSB) are Gram-negative, non-pathogenic bacteria with wide application potential in agriculture, wastewater treatment, and bioenergy/biomaterials production. In aquaculture, lactic bacteria and Bacillus are the major probiotic bacteria used, but PNSB, like Rhodopseudomonas and Rhodobacter, are also used. In this review, we summarize the previous work on the use of PNSB in aquaculture, overview the previous studies on the stimulation of innate immunity of shrimp by various probiotic microorganisms, and also share our results in the probiotic performance of Rhodovulum sulfidophilum KKMI01, a marine PNSB, which showed a superior effect in promotion of growth and stimulation of immunity in shrimp at a quite low concentration of 1 × 103 cfu (colony forming unit)/ml in rearing water.

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.

Protective Effects of the Probiotic Bacterium Streptococcus thermophilus on Candida albicans Morphogenesis and a Murine Model of Oral Candidiasis.

Background: Oral candidiasis is a frequent form of candidiasis, caused by Candida species, in particular, Candida albicans (C. albicans). The transition of C. albicans from yeast to hyphae allows its attachment to epithelial cells, followed by biofilm formation, invasion, and tissue damage. Hence, we investigated the effect of Streptococcus salivarius subspecies thermophilus (S thermophilus) on the growth as well as biofilm and germ-tube formation of C. albicans both in vitro and in vivo in a murine model. Methods: This experimental study was performed in the Department of Medical Mycology and Parasitology, School of Medicine, in collaboration with the Central Research Laboratory and the Comparative Biomedical Center, Shiraz University of Medical Sciences, Shiraz, Iran (2017 to 2018). The inhibitory activity of S. thermophilus against Candida species growth was evaluated using the broth microdilution method, and the inhibition of C. albicans biofilm formation was measured using the XTT assay. The inhibition of C. albicans germ-tube formation by S. thermophilus was evaluated using the plate assay and fluorescence microscopy. The experimental activity of the probiotic bacterium was assessed by culture and histopathological methods in six groups of five mice, comprising those treated with four concentrations of probiotics, fluconazole, and distilled water. The one-way analysis of variance, followed by a Tukey post hoc test, was used and a P value of less than 0.05 was considered significant. Results: S. thermophilus inhibited Candida species growth at concentrations of 16 to 512 µg/mL. This probiotic inhibited the formation of C. albicans biofilms and germ tubes in a dose-dependent manner. S. thermophilus significantly reduced the colony-forming units in the mice receiving 30 mg/mL of this probiotic treatment compared with the control group (P=0.024). The histopathological analysis showed that Candida colonization was diminished in the mice following the administration of the probiotic. Conclusion: Given the inhibitory activity of S. thermophilus against the growth, transition, and biofilm formation of C. albicans, it could be used in the management of oral candidiasis.

Invited review: Probiotic yogurt quality criteria, regulatory framework, clinical evidence, and analytical aspects.

Yogurt is a milk-based product manufactured by lactic acid fermentation enabled by symbiotic yogurt cultures. Yogurt is largely considered to be a health product, and it is employed to deliver probiotics and prebiotics to the consumer. However, not all yogurts are probiotic, neither are they all functional products. There is increasing demand for health-promoting beverages, which is prompting the dairy industry to develop functional probiotic yogurts to meet the demand. However, there seems to be a scarcity of reviews providing critical information on regulatory frameworks in regions of the world, clinical trial outcomes, and methodological approaches for enumerating multiprobiotic strains in yogurt. This review, relating to functional probiotic yogurt, covers the newest information on the topic for the period mostly between 2014 and 2019. Conformance to regulations is paramount and hence, global regulatory frameworks for probiotic yogurt and prebiotic and nonprebiotic ingredients included in yogurt are reviewed. The paper emphasizes the need for convincing clinical trial outcomes that provide the dairy industry with an opportunity to market products with substantiated beneficial claims. The paper also discusses probiotic strains in functional yogurt, which is required to have population levels above the recommended therapeutic minimum during shelf life. The multiprobiotic species added to yogurt may present challenges relating to methodological and analytical approaches needed to determine viability of each strain contained in such yogurt. Hence, the review also presents the pros and cons of the culture-dependent and culture-independent approaches for the enumeration of probiotic cells in yogurt. The review is arguably valuable to the dairy industry, functional food developers, related scientists, and researchers, as well as policy makers.

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.

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.

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.

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.

The effect of probiotics used as a single therapy on functional constipation: Study protocol for a systematic review and meta-analysis.

BACKGROUND: Constipation is a frequent gastrointestinal symptom. It is intimately related to many diseases. 1st-line therapy can not alleviate constipation for some patients. Alternative treatments are therefore commonly used, such as probiotics. Nevertheless, the efficacy and safety of probiotics used as a single treatment are still uncertain. A systematic review and meta-analysis will be carried out to answer the issue. METHODS: The protocol accompanied Preferred Reporting Items for Systematic Reviews and Protocol Meta-Analysis. PubMed, Cochrane, Embase, and Web of Science databases were practiced for randomized controlled trials without language constraint. In addition, We have also conducted backward (manually) and forward (with Google Scholar) citation checks to identify any additional relevant papers.Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is treatment success (spontaneous bowel movements (sBMs) >3 times per week), defecation frequency. The second result will be consistency, fecal incontinence, other symptoms (e.g. flatulence, abdominal pain), and adverse event rates and types. RESULTS: This study provides helpful information about whether probiotics can be used as a single therapy on functional constipation CONCLUSION:: The findings of the review will be disseminated through peer-review publications.

Probiotics as a Tx resource in primary care.

While probiotics have not been marketed as drugs, clinicians can still recommend them in an evidence-based manner.

Retail refrigerated probiotic foods and their association with evidence of health benefits.

Probiotic usage in food is widespread and growing. The objective of this study was to determine the percentage of probiotic food products sold in the refrigerated section of retail grocery stores in the Washington DC area that we could link to evidence of any health benefit. We surveyed refrigerated sections of eight large grocery stores representing five national chains for probiotic products. Based on declared probiotic composition (strain and count) for each product, we searched PubMed for controlled trials that provided evidence of any health benefit. Our assessment showed that 49% (22 out of 45 distinct probiotic foods) could be linked to evidence supporting a health benefit. All products indicating strain composition could be linked to evidence. Our study suggests that consumers have a reasonable likelihood of purchasing a refrigerated probiotic food with evidence, but room for improvement exists.

How probiotics face food stress: They get by with a little help.

The dietary consumption of probiotics in the form of pharmaceuticals or functional food can improve human health and contribute to disease prevention. However, the biological activity and health potential of food-delivered probiotics can be severely compromised by the stress conditions encountered by the microorganisms throughout the manufacture process, from probiotic preparation to their inclusion into food, subsequent storage and ingestion. Here, we give an account of the stress factors that can have major negative impacts on probiotic viability and functionality, with a focus on food-related environmental adverse conditions. We also describe some of the mechanisms elicited by the microbial cells to counteract these stresses and summarize a few relevant approaches proposed in literature to develop more robust and competitive probiotics by enhancing their stress tolerance, with the aim to improve the efficacy and health value of probiotic functional food.

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.

Establishing What Constitutes a Healthy Human Gut Microbiome: State of the Science, Regulatory Considerations, and Future Directions.

On December 17, 2018, the North American branch of the International Life Sciences Institute (ILSI North America) convened a workshop "Can We Begin to Define a Healthy Gut Microbiome Through Quantifiable Characteristics?" with >40 invited academic, government, and industry experts in Washington, DC. The workshop objectives were to 1) develop a collective expert assessment of the state of the evidence on the human gut microbiome and associated human health benefits, 2) see if there was sufficient evidence to establish measurable gut microbiome characteristics that could serve as indicators of "health," 3) identify short- and long-term research needs to fully characterize healthy gut microbiome-host relationships, and 4) publish the findings. Conclusions were as follows: 1) mechanistic links of specific changes in gut microbiome structure with function or markers of human health are not yet established; 2) it is not established if dysbiosis is a cause, consequence, or both of changes in human gut epithelial function and disease; 3) microbiome communities are highly individualized, show a high degree of interindividual variation to perturbation, and tend to be stable over years; 4) the complexity of microbiome-host interactions requires a comprehensive, multidisciplinary research agenda to elucidate relationships between gut microbiome and host health; 5) biomarkers and/or surrogate indicators of host function and pathogenic processes based on the microbiome need to be determined and validated, along with normal ranges, using approaches similar to those used to establish biomarkers and/or surrogate indicators based on host metabolic phenotypes; 6) future studies measuring responses to an exposure or intervention need to combine validated microbiome-related biomarkers and/or surrogate indicators with multiomics characterization of the microbiome; and 7) because static genetic sampling misses important short- and long-term microbiome-related dynamic changes to host health, future studies must be powered to account for inter- and intraindividual variation and should use repeated measures within individuals.

Thermophysical Fingerprinting of Probiotic-Based Products.

Variability in efficacy and safety is a worldwide concern with commercial probiotics for their growing and inevitable use in food and health sectors. Here, we introduce a probiotic thermophysical fingerprinting methodology using a coupling thermogravimetry and differential scanning calorimetry. Qualitative and quantitative information on the material decomposition and transition phases is provided under heating conditions. By monitoring the changes in both mass and internal energy over temperature and time, a couple of thermal data at the maximum decomposition steps allow the creation of a unique and global product identity, depending on both strain and excipient components. We demonstrate that each powder formulation of monostrain and multistrain from different lots and origins have a unique thermophysical profile. Our approach also provides information on the formulation thermostability and additive/excipient composition. An original fingerprint form is proposed by converting the generated thermal data sequence into a star-like pattern for a perspective library construction.

Probiotics in Food Systems: Significance and Emerging Strategies Towards Improved Viability and Delivery of Enhanced Beneficial Value.

Preserving the efficacy of probiotic bacteria exhibits paramount challenges that need to be addressed during the development of functional food products. Several factors have been claimed to be responsible for reducing the viability of probiotics including matrix acidity, level of oxygen in products, presence of other lactic acid bacteria, and sensitivity to metabolites produced by other competing bacteria. Several approaches are undertaken to improve and sustain microbial cell viability, like strain selection, immobilization technologies, synbiotics development etc. Among them, cell immobilization in various carriers, including composite carrier matrix systems has recently attracted interest targeting to protect probiotics from different types of environmental stress (e.g., pH and heat treatments). Likewise, to successfully deliver the probiotics in the large intestine, cells must survive food processing and storage, and withstand the stress conditions encountered in the upper gastrointestinal tract. Hence, the appropriate selection of probiotics and their effective delivery remains a technological challenge with special focus on sustaining the viability of the probiotic culture in the formulated product. Development of synbiotic combinations exhibits another approach of functional food to stimulate the growth of probiotics. The aim of the current review is to summarize the strategies and the novel techniques adopted to enhance the viability of probiotics.

Addressing safety concerns of probiotic use in preterm babies.

More than 10,000 preterm babies worldwide have been enrolled in trials evaluating probiotics administration for the prevention of necrotising enterocolitis, with very few adverse events reported. Despite this, probiotic safety is frequently cited as a concern when using this intervention. This review addresses why a preterm baby may be at risk when administered a live microbial product, short- and longer-term safety data in relation to probiotic use and regulatory aspects around probiotic manufacture and preparations.