US Pharm. 2021;46(12):18-20.
ABSTRACT: Probiotics are live microorganisms that are available without a prescription for use as dietary supplements. In the United States, millions of adults have taken some form of probiotic to treat or prevent a variety of conditions, most commonly gastrointestinal (GI) disorders. Based on the widespread use of these products specifically for improvement of GI health, in 2020 the American Gastroenterological Association published clinical practice guidelines with evidence-based recommendations for probiotics in the treatment and/or prevention of prioritized disorders. Pharmacists should incorporate these recommendations into patient care and educational activities as appropriate, and they should understand the variations in available probiotic formulations and combinations as well as the need for more research to determine the safety and potential health benefits of different probiotic strains.
The human gut is thought to contain trillions of microbial cells of different species that are responsible for various metabolic functions, protect against disease-causing bacteria, and maintain overall intestinal health. Disruptions to the gut environment, often caused by bacterial infections, dietary changes, or antibiotic use, can contribute to the development of various chronic diseases. Reintroducing beneficial bacteria, which are present in probiotic products, has been found instrumental in restoring gut microbial homeostasis.1
Probiotics
The Food and Agriculture Organization and the World Health Organization define probiotics as “live microorganisms which when administered in adequate amounts confer a health benefit on the host.”2 Probiotics, which are available without a prescription, are added to a variety of food sources, such as cultured milk products, breakfast cereals, and infant formula, and are in some cosmetic products. For nutritional purposes, probiotics are available in both tablet and powder formulations. Over the past two decades, interest in the role of probiotics in improving various conditions has greatly increased, particularly among persons with gastrointestinal (GI) disorders.3,4 In 2012, a National Health Interview Survey found that approximately 4 million U.S. adults (1.6%) had used a probiotic product in the previous 30 days, making probiotics one of the most-used dietary supplements other than vitamins and minerals.5
Mechanisms of Action
The mechanisms of action for the benefits of probiotics are multifactorial, complex, and not entirely understood. In addition, it is difficult to find commonality with probiotics, as they are all not alike. Benefits seen with one species of probiotic cannot be generalized and assumed to occur with another. Some general mechanisms include 1) immunomodulation through induction of protective cytokines and suppression of proinflammatory cytokines in the GI mucosa; 2) displacement of pathogenic bacteria, thereby inhibiting invasion, adherence, and proliferation in the epithelium; 3) improvement of intestinal-barrier function; 4) protection from physiological stress through increased gamma-aminobutyric acid receptor expression in the brain; and 5) analgesic effects through mu-opioid and cannabinoid receptor induction in intestinal epithelial cells.3,6
Probiotic Qualifications
The most common microorganisms used in probiotics belong to the Lactobacillus, Bifidobacterium, and Saccharomyces genera; other genera include Streptococcus, Enterococcus, Escherichia, and Bacillus.5 For a microorganism to be considered a probiotic, several criteria must be met. First, the organism must be properly categorized through accurate strain identification and genus and species naming. The probiotic must also be deemed safe for human consumption in foods and supplements, and it must be free of pathogenic bacteria and not contain any transferable antibiotic-resistant genes. The probiotic must be able to survive transit through the intestinal tract and must endure the acid and bile contents in the upper-GI tract before reaching the small intestine and colon; it also must adhere to the intestinal mucosa and colonize for a brief time in the intestines. Additionally, the probiotics must demonstrate positive effects on a person’s health, with this benefit documented in at least one phase II study. Finally, the probiotic must maintain stability during processing and while stored. Throughout its shelf life, the product should contain sufficient levels of the probiotic strain to deliver its claimed health benefit.6
Regulation
In the U.S., probiotics are sold primarily as dietary supplements (capsules, powders, liquids, etc.) and do not require FDA approval before they become available on the market. These products are regulated as vitamins and food, and they often contain various strains at different quantities. Probiotics are referred to by their genus, species, and strain and are measured in colony-forming units (CFU). CFU indicate an estimate of the number of live and active microbial cells in one serving of a probiotic supplement. Probiotic CFU counts may be included on product labels (e.g., 1 × 109 for 1 billion CFU, 1 × 1010 for 10 billion CFU). Many probiotic supplements contain 1 billion to 10 billion CFU per dose, but some products contain up to 50 billion or more CFU. However, a higher CFU count does not necessarily increase a product’s claimed health benefit.7
Current labeling regulations require manufacturers to list only the total weight of the microorganisms on a probiotic product’s Supplement Facts label. This weight includes both live and dead microorganisms and does not correlate to the actual number of viable microorganisms in the product. Manufacturers may voluntarily list a product’s CFU—ideally, for each strain—along with total microorganism weight on the Supplement Facts label, provided that it is not misleading. Because probiotics must be consumed live to have health benefits and can die during their shelf life, consumers should seek products that are labeled with the number of CFU at the end of the product’s shelf life, not at the time of manufacture.8 Consumers should also be aware of the storage instructions for products; some require refrigeration, whereas others may be stored at room temperature.7,8
Probiotics and GI Health
Some of the more commonly recommended probiotics available commercially are Align (Bifidobacterium longum subsp. infantis 35624), Bacid (Lactobacillus acidophilus), Culturelle (Lactobacillus rhamnosus GG), Florastor (Saccharomyces boulardii), and VSL#3 (L acidophilus, Lactobacillus plantarum, Lactobacillus casei, Lactobacillus delbrueckii subsp. bulgaricus, Bifidobacterium breve, B longum, Bifidobacterium infantis, Streptococcus thermophilus). Probiotic interventions have shown promise in various areas of medicine, most notably with regard to GI disorders.9 In 2020, the American Gastroenterological Association (AGA) published evidence-based clinical practice guidelines on the role of probiotics in managing 1) Clostridioides difficile–associated diseases; 2) inflammatory bowel disease; 3) irritable bowel syndrome; 4) infectious gastroenteritis; and 5) necrotizing enterocolitis. The aforementioned were prioritized for review by the AGA based on data suggesting that probiotics are most commonly considered for these particular GI disorders and on the lack of sufficient evidence for other GI conditions.4
AGA 2020 Clinical Practice Recommendations
C difficile–Associated Diseases: The AGA recommends the use of probiotics in patients with C difficile infection only in the context of a clinical trial.4 For adults and children on antibiotic treatment, S boulardii or the combinations of L acidophilus CL1285 plus L casei LBC80R or L acidophilus plus L delbrueckii subsp. bulgaricus plus Bifidobacterium bifidum with or without Streptococcus salivarius subsp. thermophilus are recommended over no or other probiotics in order to prevent C difficile. It is important to note that the benefit effect for prevention of C difficile was driven by patients at high risk (>15%) for developing the infection.4
Inflammatory Bowel Disease: In adults and children with Crohn’s disease or ulcerative colitis, the AGA recommends probiotic use only in the context of a clinical trial.4 Studies evaluating probiotics’ role in the induction or maintenance of remission of inflammatory bowel disease were determined to be of low quality, consisted of small sample sizes, were heterogeneous, and included variable strains of probiotics. However, the AGA does suggest the use of an eight-strain combination (Lacticaseibacillus paracasei subsp. paracasei DSM 24733, L plantarum DSM 24730, L acidophilus DSM 24735, L delbrueckii subsp. bulgaricus DSM 24734, B longum subsp. longum DSM 24736, B breve DSM 24732, B longum subsp. infantis DSM 24737, and S salivarius subsp. thermophilus DSM 24731) over no or other probiotics for the treatment of pouchitis in adults and children with inflammatory bowel disease.4
Irritable Bowel Syndrome: In adults and children with symptomatic irritable bowel syndrome, the AGA recommends probiotic use only in the context of a clinical trial.4 Although 76 randomized, controlled trials were identified and reviewed for probiotic use in irritable bowel syndrome, these trials used 44 different probiotic strains or combinations of strains for various durations. These trials were also found to have significant heterogeneity in study design and outcomes.4
Infectious Gastroenteritis: The use of probiotics in children with acute infectious gastroenteritis is not recommended by the AGA.4 The majority of studies have been conducted outside of the U.S. and Canada and used various probiotics and combination products. Two high-quality studies from the U.S. and Canada failed to demonstrate any benefit in this patient population.4
Necrotizing Enterocolitis: In preterm (gestational age <37 weeks) and low-birthweight infants, the AGA recommends the use of the following to prevent necrotizing enterocolitis over no or other probiotics: combination Lactobacillus and Bifidobacterium spp. (L rhamnosus ATCC 53103 and B longum subsp. infantis; or L casei and B breve; or L rhamnosus, L acidophilus, L casei, B longum subsp. infantis, B bifidum, and B longum subsp. longum; or L acidophilus and B longum subsp. infantis; or L acidophilus and B bifidum; or L rhamnosus ATCC 53103 and B longum Reuter ATCC BAA-999; or L acidophilus, B bifidum, Bifidobacterium animalis subsp. lactis, and B longum subsp. longum), or B animalis subsp. lactis (including DSM 15954), or Limosilactobacillus reuteri (DSM 17938 or ATCC 55730), or L rhamnosus (ATCC 53103 or ATC A07FA or LCR 35).4 Findings from 63 studies that compared probiotics (single and combination products) against placebo in infants with necrotizing enterocolitis revealed overall reductions in severe necrotizing enterocolitis, number of days to reach full enteral feeds, duration of hospitalizations, and all-cause mortality.4
Gastroesophageal Reflux Disease
Gastroesophageal reflux disease is a chronic condition in which contents from the stomach flow back into the esophagus and may cause patients to experience esophageal irritation, difficulty swallowing, chest pain, and other symptoms. Although the 2020 AGA clinical practice guidelines on probiotics’ role in managing of GI disorders did not include this particular GI condition, a systematic review of the 13 available prospective studies was conducted to examine the efficacy of probiotics in adults with gastroesophageal reflux disease.10 Eleven (79%) of these studies reported positive benefits of probiotics for symptoms of gastroesophageal reflux disease, including reduced regurgitation and improvements in reflux or heartburn, dyspepsia, and other upper-GI symptoms (e.g., nausea, abdominal pain, belching, gurgling, burping). It was concluded that probiotics may have a place in the treatment of symptoms of gastroesophageal reflux disease; however, additional placebo-controlled, randomized, double-blind clinical trials with a greater number of participants and longer durations are necessary to confirm the overall role and safety of these products in gastroesophageal reflux disease.10
The Pharmacist’s Role
Pharmacists remain the most accessible and frequently visited healthcare professionals in the U.S., as nearly 90% of Americans live within 5 miles of a community pharmacy.11,12 With an estimated 4 million adults having used probiotics as a dietary supplement, it is imperative that pharmacists are aware of evidence-based recommendations for their proper use. Additionally, all healthcare professionals should understand the variations in available probiotic formulations and combinations, as well as the need for more research to determine the safety and potential health benefits of the different probiotic strains in various patient populations.
Conclusion
Probiotics are one of the most-used dietary supplements in the U.S. Millions of adults have taken some form of probiotic to treat or prevent various conditions. In 2020, the AGA published clinical practice guidelines with evidence-based recommendations for probiotic use in selected GI disorders. Healthcare professionals should be aware of these recommendations in order to properly care for and educate patients with these disorders.
REFERENCES
1. Kim SK, Guevarra RB, Kim YT, et al. Role of probiotics in human gut microbiome-associated diseases. J Microbiol Biotechnol. 2019;29(9):1335-1340.
2. Food and Agriculture Organization of the United Nations and World Health Organization. Probiotics in food: health and nutritional properties and guidelines for evaluation. www.fao.org/3/a0512e/a0512e.pdf. Accessed November 9, 2021.
3. Suez J, Zmora N, Segal E, Elinav E. The pros, cons, and many unknowns of probiotics. Nat Med. 2019;25(5):716-729.
4. Su GL, Ko CW, Bercik P, et al. AGA clinical practice guidelines on the role of probiotics in the management of gastrointestinal disorders. Gastroenterology. 2020;159(2):697-705.
5. National Center for Complementary and Integrative Health. Probiotics: what you need to know. www.nccih.nih.gov/health/probiotics-what-you-need-to-know. Accessed August 26, 2021.
6. Verna EC, Lucak S. Use of probiotics in gastrointestinal disorders: what to recommend? Therap Adv Gastroenterol. 2010;3(5):307-319.
7. National Institutes of Health Office of Dietary Supplements. Probiotics. https://ods.od.nih.gov/factsheets/Probiotics-HealthProfessional/. Accessed August 26, 2021.
8. FDA. Draft guidance for industry: policy regarding quantitative labeling of dietary supplements containing live microbials. www.fda.gov/regulatory-information/search-fda-guidance-documents/draft-guidance-industry-policy-regarding-quantitative-labeling-dietary-supplements-containing-live. Accessed November 9, 2021.
9. Wilkins T, Sequoia J. Probiotics for gastrointestinal conditions: a summary of the evidence. Am Fam Physician. 2017;96(3):170-178.
10. Cheng J, Ouwehand AC. Gastroesophageal reflux disease and probiotics: a systematic review. Nutrients. 2020;12(1):132.
11. National Association of Chain Drug Stores. Re: health care workshop, project no. P131207 [letter]. www.nacds.org/ceo/2014/0508/supplemental_comments.pdf. Accessed September 30, 2021.
12. Gasdek Manolakis P, Skelton JB. Pharmacists’ contributions to primary care in the United States collaborating to address unmet patient care needs: the emerging role for pharmacists to address the shortage of primary care providers. Am J Pharm Educ. 2010;74(10):S7.
The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.
To comment on this article, contact rdavidson@uspharmacist.com.
