written by Margaret Haldeman, Ph.D., Education & Communication Co-chair
Probiotics are defined as “live microorganisms that, when administered in adequate amounts, confer a health benefit on the host” 1. 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 “probiotic”. These criteria further define probiotics in the context of efficacy and safety 2.
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.
- Genus, species and strain identified by molecular techniques.
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 story. E. coli K12 delivers many health benefits such as vitamin production in the gut while E. coli O157:H7 is notorious for causing food poisoning with symptoms of diarrhea and vomiting.
- Strains are generally deposited in an internationally recognized culture collection.
This helps to ensure that the isolated strain is preserved and available to the scientific community for further development and understanding.
- Probiotic benefits are generally strain specific but some health benefits may be common among many strains. Each strain should be supported by clinical study(ies).
Safe for the intended use
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 “resistance genes”. Probiotics are screened to ensure they do not have transmissible resistance genes.
- Identification of genes which can cause other types of virulence.
- Persist in a viable state in gastrointestinal tract.
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.
- Most are used in foods; including conventional foods, dietary supplements and infant formula, where their intended use is to provide health benefits as part of the daily diet.
Supported by at least one well-designed, human clinical trial
Once a probiotic is characterized both in vitro and in vivo, 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 (CFUs), needed to deliver the benefit.
- The probiotic strain must be alive in sufficient numbers in the product at time of consumption and maintain an efficacious dose throughout shelf life.
- A probiotic product must deliver the dose demonstrated to be clinically effective in order to claim the health benefit. The consumer needs that minimum dose to be guaranteed to the expiration date.
The product should meet this dose, or label declaration, throughout the product’s shelf life and that this label declaration should be greater than or equal to the studied dose.
- Evaluation of probiotic safety and efficacy should be based on individual interventions and not by grouping interventions using different probiotic strains and combinations of strains into one analysis.
Viable probiotic activity guaranteed throughout processing, handling, and storage.
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.
- The probiotic should remain viable throughout the shelf life
A comprehensive approach of in vitro, in silico, and in vivo 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.
In the United States, most probiotics are regulated by the Food and Drug Administration (FDA), https://www.fda.gov/food/dietary-supplements. Probiotics can be approved by “Generally Recognized as Safe” (GRAS), self-GRAS and New Dietary Ingredient Notification (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’s 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.
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.
The governmental group American Health Care Research and Quality (AHRQ) 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 3, although isolated adverse effects of probiotic administration have been reported 4. 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.
According to the National Institute of Health (NIH), Office of Dietary Supplements (ODS), “Many probiotic strains are derived from species with a long history of safe use in foods or from microorganisms that colonize healthy gastrointestinal tracts”. Probiotics are consumed in increasing quantities, yet there is no evidence of increased levels of infections. The ODS goes on to say that “given the large quantities of probiotics consumed around the world, the numbers of opportunistic infections that result from currently marketed probiotics are negligible”. Probiotics are safe for the general population.
Numerous clinical trials of probiotics have been in a range of vulnerable patient groups5-8, including pre-term infants9,10, organ transplant patients11, immunocompromised patients such as HIV-positive volunteers12,13, critically ill patients14-16, people treated for cancer17-19, and elderly populations20-23 at doses ranging as high as 1012 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 (WGO) advises restricting probiotic use to the strains with proven efficacy for those with compromised immune function or other serious underlying diseases.
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 assessment should support mechanisms of action. The strain’s antibiotic susceptibility profile should be known so that, in the rare case of infection, effective antibiotics are identified.
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.
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).This type of surveillance provides a feedback loop to inform best practices.
By following these guidelines we can assure that the products available to the consumer do not misuse the term “probiotic” and more importantly that these product are efficacious and safe. For additional information about best practices with respect to probiotic products, please visit the IPA website, https://internationalprobiotics.org/resources-2/
1 Hill, C. et al. Expert consensus document. The International Scientific Association for Probiotics and Prebiotics consensus statement on the scope and appropriate use of the term probiotic. Nature reviews. Gastroenterology & hepatology 11, 506-514, doi:10.1038/nrgastro.2014.66 (2014).
2 Binda, S. et al. Criteria to Qualify Microorganisms as “Probiotic” in Foods and Dietary Supplements. Frontiers in Microbiology 11, 1662 (2020).
3 Hempel, S. et al. Safety of probiotics used to reduce risk and prevent or treat disease. Evidence report/technology assessment, 1 (2011).
4 Costa, R. L., Moreira, J., Lorenzo, A. & Lamas, C. C. Infectious complications following probiotic ingestion: a potentially underestimated problem? A systematic review of reports and case series. BMC Complement Altern Med 18, 329, doi:10.1186/s12906-018-2394-3 (2018).
5 Baldassarre, M. E. et al. Lactobacillus GG improves recovery in infants with blood in the stools and presumptive allergic colitis compared with extensively hydrolyzed formula alone. The Journal of pediatrics 156, 397-401, doi:10.1016/j.jpeds.2009.09.012 [doi] (2010).
6 Grenov, B. et al. Effect of probiotics on diarrhea in children with severe acute malnutrition: a randomized controlled study in Uganda. Journal of pediatric gastroenterology and nutrition 64, 396-403 (2017).
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13 Ishizaki, A. et al. Effects of Short-Term Probiotic Ingestion on Immune Profiles and Microbial Translocation among HIV-1-Infected Vietnamese Children. International journal of molecular sciences 18, doi:10.3390/ijms18102185 (2017).
14 Mahmoodpoor, A. et al. Effect of a Probiotic Preparation on Ventilator-Associated Pneumonia in Critically Ill Patients Admitted to the Intensive Care Unit: A Prospective Double-Blind Randomized Controlled Trial. Nutr Clin Pract 34, 156-162, doi:10.1002/ncp.10191 (2019).
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16 Angurana, S. K. et al. Evaluation of Effect of Probiotics on Cytokine Levels in Critically Ill Children With Severe Sepsis: A Double-Blind, Placebo-Controlled Trial. Crit Care Med 46, 1656-1664, doi:10.1097/ccm.0000000000003279 (2018).
17 Zaharuddin, L., Mokhtar, N. M., Muhammad Nawawi, K. N. & Raja Ali, R. A. A randomized double-blind placebo-controlled trial of probiotics in post-surgical colorectal cancer. BMC Gastroenterol 19, 131, doi:10.1186/s12876-019-1047-4 (2019).
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19 Österlund, P. et al. Lactobacillus supplementation for diarrhoea related to chemotherapy of colorectal cancer: A randomised study. British journal of cancer 97, 1028-1034 (2007).
20 Wang, B. et al. Probiotics to prevent respiratory infections in nursing homes: a pilot randomized controlled trial. Journal of the American Geriatrics Society 66, 1346-1352 (2018).
21 Kobayashi, Y., Kuhara, T., Oki, M. & Xiao, J. Z. Effects of Bifidobacterium breve A1 on the cognitive function of older adults with memory complaints: a randomised, double-blind, placebo-controlled trial. Benef Microbes 10, 511-520, doi:10.3920/bm2018.0170 (2019).
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23 Lei, M., Hua, L. M. & Wang, D. W. The effect of probiotic treatment on elderly patients with distal radius fracture: a prospective double-blind, placebo-controlled randomised clinical trial. Benef Microbes 7, 631-637, doi:10.3920/bm2016.0067 (2016).