{"id":7221,"date":"2021-04-21T06:55:00","date_gmt":"2021-04-21T11:55:00","guid":{"rendered":"https:\/\/internationalprobiotics.org\/?p=7221"},"modified":"2021-04-21T08:51:59","modified_gmt":"2021-04-21T13:51:59","slug":"asked-and-answered-again-probiotics-are-safe","status":"publish","type":"post","link":"https:\/\/internationalprobiotics.org\/home\/asked-and-answered-again-probiotics-are-safe\/","title":{"rendered":"Asked and Answered, AGAIN! Probiotics are safe!"},"content":{"rendered":"\n
written by Margaret Haldeman, Ph.D., Education & Communication Co-chair<\/strong><\/em><\/p>\n\n\n\n Probiotics are defined as \u201clive microorganisms that, when administered in adequate amounts, confer a health benefit on the host\u201d 1<\/sup>. To be considered a true probiotic, a microorganism must confer a health benefit when consumed in appropriate amounts. In order to provide a health benefit, this consumption must be safe. In addition to the definition, there are important criteria that illustrate the research that must be done before a microbial strain can be categorized as \u201cprobiotic\u201d. These criteria further define probiotics in the context of efficacy and safety 2<\/sup>. <\/p>\n\n\n\n Sufficiently characterized <\/p>\n\n\n\n There is a menu of assessments that can be done for microorganisms to help understand their function, including carbohydrate utilization, enzymatic activities, antibiotic susceptibility, and environmental preferences. <\/p>\n\n\n\n The strain designation is often overlooked but we know that some species have strains that are beneficial for health while others may cause health problems. One example of this is the E. coli <\/em>story. E. coli<\/em> K12 delivers many health benefits such as vitamin production in the gut while E. coli<\/em> O157:H7 is notorious for causing food poisoning with symptoms of diarrhea and vomiting. <\/p>\n\n\n\n This helps to ensure that the isolated strain is preserved and available to the scientific community for further development and understanding.<\/p>\n\n\n\n Safe for the intended use <\/p>\n\n\n\n Lack of transmissible antibiotic resistance genes; antibiotic resistance happens when microorganisms develop abilities to defeat the drugs designed to kill them. The microorganisms then become resistant to the drug. This is one of the biggest challenges for modern medicine and also for animal agriculture. Microorganisms can harbor \u201cresistance genes\u201d. Probiotics are screened to ensure they do not have transmissible resistance genes.<\/p>\n\n\n\n The stomach and small intestine encompass harsh environments; acidic pH and bile salts function to control the microorganisms in the gastrointestinal tract by suppressing the growth of pathogens. It is commonly assumed that a probiotic must be robust enough to survive through the upper gastrointestinal tract. <\/p>\n\n\n\n Supported by at least one well-designed, human clinical trial<\/p>\n\n\n\n Once a probiotic is characterized both in vitro<\/em> and in vivo<\/em>, the results can be crafted into a hypothesis for how the strain might benefit health. It is then critical to prove this hypothesis in humans. A well-designed clinical trial will specify the strain and the dose, typically expressed in colony-forming units<\/em> (CFUs), needed to deliver the benefit. <\/p>\n\n\n\n The product should meet this dose, or label declaration, throughout the product\u2019s shelf life and that this label declaration should be greater than or equal to the studied dose.<\/p>\n\n\n\n Viable probiotic activity guaranteed throughout processing, handling, and storage.<\/p>\n\n\n\n Guarantees through expiration date are dependent on the manufacturing of the bulk probiotic and of the product formula but also by the packaging, shipping and storage of the product. <\/p>\n\n\n\n A comprehensive approach of in vitro<\/em>, in silico<\/em>, and in vivo<\/em> safety testing to thoroughly characterize probiotic strains can identify features of the strain such as antibiotic resistance or virulence genes, toxin genes, histamine synthesis and oral toxicity that could preclude use as a probiotic due to safety concerns. Strains that meet these criteria and are provided in a product that ensures the maintenance of these criteria, should be considered safe. D-lactate production is sometimes included in the safety evaluation even though it is uncertain that D-lactate production actually is a risk for the consumer; including infants.<\/p>\n\n\n\n In the United States, most probiotics are regulated by the Food and Drug Administration (FDA), https:\/\/www.fda.gov\/food\/dietary-supplements<\/a>. Probiotics can be approved by \u201cGenerally Recognized as Safe\u201d (GRAS), self-GRAS and New \u200bDietary \u200bIngredient \u200bNotification (NDIN). Select probiotic strains have undergone rigorous safety assessment for status as GRAS, which is followed by notification of the FDA for comment. This assessment includes many of the aforementioned criteria for a probiotic. In Europe, the European Food Safety Authority\u2019s Qualified Presumption of Safety (QPS) list of microbes includes those that have been assessed as safe for food use. This list is based on a history of safe use and additional relevant data on the absence of acquired resistance or virulence. <\/p>\n\n\n\n Primary critics of probiotics typically evaluate through the lens of pharmaceuticals. This classification is incorrect and out of scope: probiotics may be foods or supplements according to the FDA, unless they come with a drug registration. Just as drugs are not solving all the medical problems in the world, probiotics should not be seen as the magic solution to all clinical issues; both have their place within the healthcare system. For the most part, probiotics have not gone through pharmaceutical evaluation processes. As such, probiotics do not make medical claims to treat, cure or prevent disease, unlike drugs. Probiotics are generally not prescribed as an exclusive therapy in disease management, but most often suggested as part of the normal healthy diet or as an adjunct to standard treatment. There is no noted toxicity level and it has been very rare to have an Adverse Event Reporting due to the nature of probiotics. Side effects of probiotics are very rare and mild for healthy individuals, in stark contrast to drugs. <\/p>\n\n\n\n The governmental group American Health Care Research and Quality (AHRQ) <\/a> has described extensive safety data for probiotic strains in health and illness. The results of this extensive report, showing safety of probiotic therapy in over 600 published clinical trials and case reports, should be reassuring to clinicians and consumers with regard to the safety of probiotic administration in health and disease states <\/sup>3<\/sup>, although isolated adverse effects of probiotic administration have been reported <\/sup>4<\/sup>. This extensive AHRQ report indicates that probiotic intervention in both adults and pediatric populations was not found to be associated with any increased risk of infectious morbidity or other adverse events in either health or illness. Notably, this report revealed a trend towards fewer adverse events in ICU patients receiving select probiotic strains. <\/p>\n\n\n\n According to the National Institute of Health (NIH), Office of Dietary Supplements (ODS)<\/a>, \u201cMany probiotic strains are derived from species with a long history of safe use in foods or from microorganisms that colonize healthy gastrointestinal tracts\u201d. Probiotics are consumed in increasing quantities, yet there is no evidence of increased levels of infections. The ODS goes on to say that \u201cgiven the large quantities of probiotics consumed around the world, the numbers of opportunistic infections that result from currently marketed probiotics are negligible\u201d. Probiotics are safe for the general population. <\/p>\n\n\n\n Numerous clinical trials of probiotics have been in a range of vulnerable patient groups5-8<\/sup>, including pre-term infants9,10<\/sup>, organ transplant patients11<\/sup>, immunocompromised patients such as HIV-positive volunteers12,13<\/sup>, critically ill patients14-16<\/sup>, people treated for cancer17-19<\/sup>, and elderly populations20-23<\/sup> at doses ranging as high as 1012<\/sup> CFU per day. While relatively rare, the most serious adverse effects of probiotics have been bacteremia and fungemia. Due to these rare instances of infection, we know that there are certain populations that should proceed with caution and these are the same populations that are simply at higher risk for all supplements and drugs. Predisposing factors to increased risk for probiotic-induced bacteremia or fungemia, include patients with critical illness and severe underlying disease, compromised immune function, a damaged gastrointestinal barrier, prosthetic heart valves, indwelling central venous catheter, administration of multiple antibiotics, and prolonged treatment with probiotics or use of excessive dosages. Probiotics should be used with caution, or possibly be avoided after risk-benefit evaluation in patients who have such predisposing factors. In summary, the World Gastroenterology Organization<\/a> (WGO) advises restricting probiotic use to the strains with proven efficacy for those with compromised immune function or other serious underlying diseases. <\/p>\n\n\n\n As with other approaches, risk assessment and risk management are critical. Risk assessment includes understanding the characteristics and confirming efficacy of the probiotic strain for the intended benefit as demonstrated by at least one well-designed human clinical trial. The complete genome sequence and in vitro <\/em>assessment should support mechanisms of action. The strain\u2019s antibiotic susceptibility profile should be known so that, in the rare case of infection, effective antibiotics are identified. <\/p>\n\n\n\n Product selection plays a role in risk management. Good Manufacturing Practices should be the minimum requirement for a probiotic product. The selected strain should be commercialized in a product known to be validated and delivered at an efficacious dose through shelf life. The presence of excipients that could behave as allergens should be ascertained. Like all foods and dietary supplements, common allergens must be clearly identified and declared on label.<\/p>\n\n\n\n The product should participate in adverse event tracking. In the US, reported adverse events are monitored by the FDA (https:\/\/www.fda.gov\/safety\/medwatch-fda-safety-information-and-adverse-event-reporting-program<\/a>).This type of surveillance provides a feedback loop to inform best practices. <\/p>\n\n\n\n