A recent cover of the journal The Scientist proclaimed "Probiotics: A Gut Issue." Although this illustrates the lofty heights to which probiotics are now being regarded, it misses an important point. Probiotics are not only good bacteria for the gut. Rather, they are "live microorganisms which, when administered in adequate amounts, confer a health benefit on the host."1 The benefits of probiotics go beyond the gut.
Probiotics are often misrepresented. In India and Eastern European countries, the tradition of eating yogurt and kefir (fermented milk with live bacteria) has been passed down through generations. I hesitate to say yogurt and kefir are not true probiotics, but most have never been proven (versus placebo, in reproducible dosage forms) to benefit the host. They may be beneficial, but for clarity they should be called fermented milks, not probiotics.
Further, probiotics are not yogurt; at best, if a yogurt contains living Lactobacillus delbreukii sub-species bulgaricus and Streptococcus thermophilus when eaten, it may reduce symptoms of lactose intolerance, and in that sense the organisms are conferring a probiotic effect. But the primary role of these organisms is to ferment milk. On the other hand, an actual probiotic yogurt or drink contains a bacterial strain(s), usually added just prior to sealing the container, and these organisms confer a health benefit. There are only a handful of bacterial strains proven to be probiotic. Some researchers estimate five to 15. Such organisms include L. acidophilus NCFM, L. rhamnosus GG, Bifidobacterium lactis BB12, B. longum BB536 (although peer-reviewed publications are sparse) or L. casei Shirota. Either way, the majority of products on the market do not contain strains that have undergone rigorous clinical tests with results published in peer-reviewed journals.
Test The Labeling
Probiotic organisms are specific and must be named, characterized and proven to benefit the host in the form in which they are used. Examine the product's labeling or information on a brochure or Web site. Organisms must be properly named (L. sporogenes, for example, does not exist, and organisms such as E. coli are not regarded as being probiotic); have an identification "number" (such as L. acidophilus NCFM, L. rhamnosus GG); and have a viable count at the time of use (not at time of manufacture). The latter aspect is of pivotal significance to shelf life. Bacteria such as lactobacilli and bifidobacteria are fickle and lose viability, especially if they are exposed to tiny amounts of water. The best processing practices can reduce viability loss, and manufacturers can take steps to improve survival rate at room temperature. Not all products are made with these technologies, however, and without refrigeration or care to lock out moisture, the organisms die. Live organisms at the time of manufacture do not guarantee live organisms when the product is purchased.
Claims on product labels, literature or on a Web site should include credible references. A scan of many sites shows inaccurate and misleading claims about products that have never undergone proper clinical testing. And a detailed read of the references cited often reveals the organism tested in the research is not the same one offered in the product. Examples of claims made for probiotics include "gently tone, exfoliate and moisturize your skin, restoring its natural luster;" "act as 'watchdogs' by keeping an eye on, and effectively controlling, the spread of undesirable microorganisms;" and "can be used as a preventative or as part of a program of treatment for irritable bowel syndrome, osteoporosis, skin problems, diarrhea, bloating, flatulence, candidiasis, bowel cancer and constipation."2 Patient testimonials are nice, but they prove nothing. Ask company representatives to provide data for their product or strain.
Challenge The Information
Retailers generally have little time for in-depth study of various product lines and often rely instead on producers and marketers. Too many producers and marketers of so-called probiotics, however, have reaped sales benefits without proving their products are actually probiotics, meaning they cause a positive change in gut or systemic function. Unless a particular strain has been tested, there is no way to know if it works better or worse than other strains.
Strangely, one marketplace practice involves using the term L. acidophilus or simply acidophilus in association with intestinal well-being. In fact, Lactobacillus has four sub-species—L. acidophilus, L. crispatus, L. jensenii and L. gallinarum—and they are not considered the dominant intestinal lactobacilli. Thus, let's not mislead the public into believing they need this species in probiotic products, and let's be sure which of the four species is actually being used.
The market for probiotics is projected to grow exponentially in the next five to 10 years. For this to happen, physicians, pharmacists and other health care professionals must act as gatekeepers and educate their patients about probiotics, and what the specific products and strains can do. Products themselves must be based on sound scientific, strain- or product-specific evidence. They must also be reliable, high quality, clinically proven safe and effective (even if this is simply health retention), and shelf stable.
Natural products retailers can lead the way by:
- knowing the definition of a probiotic1;
- regularly reading Medline or other journal browsers to identify key studies on probiotics;
- demanding proven products and supportive clinical documentation to pass to consumers3;
- acting as an intermediary between physicians and patients.
A relatively small number of bacterial strains are noteworthy, and only those available or due for release in North America within the next year are discussed here. The five major conditions probiotics have been tested for are diarrhea prevention and intestinal well-being (gut health), stomach ulcers, immunity, women's urogenital health and surgical care.
Gut health: There is good clinical data on reducing the duration of rotavirus diarrhea using L. rhamnosus GG (ConAgra, USA, marketed as Culturelle)4,5 and B. lactis BB12.6 For example, children aged 1 month to 3 years with acute-onset diarrhea were enrolled in a double-blind, placebo-controlled study. The group receiving oral rehydration plus a live preparation of L. rhamnosus GG (at least 1010 cfu/250 ml) had shorter duration of diarrhea (56.2 versus 76.6 hours).5 Although there is some concern about adverse effects of using yeast as probiotics, there are reports of successful remediation of Clostridium difficile infections using Saccharomyces boulardii (Codex, Seattle; also offered by Jarrow Formulas, Los Angeles).7 Assuming the L. reuteri strain proven successful in human studies8,9 is the same one licensed to McNeil Consumers USA (the label doesn't indicate), then the company's Probiotica product may also have merit in this regard.
Combination products, such as those containing L. acidophilus LA-5, L. bulgaricus LBY-27, B. lactis BB-12 and S. thermophilus STY-31 (ProFlora, Pangeo Pharma, Canada), were shown to reduce episodes of traveler's diarrhea compared with placebo (47 percent of those taking the probiotic got diarrhea versus 73 percent taking placebo).10 This combination also reduced, to some extent, symptoms of lactose intolerance in 50 adults, according to internal Chr Hansen reports. But the failure to publish these findings in a peer-reviewed journal reduces the data's credibility.
Reducing pathogen translocation across the intestine to distant sites has been demonstrated with probiotic strains such as L. rhamnosus GR-1 and L. fermentum RC-14 in mice11 and L. johnsonii La-1 in rats.12 The concept of tightening the gut's permeable barrier also is an active area of investigation. Studies in New Zealand using L. rhamnosus DR20 in milk showed increases in lactobacilli and enterococci in the feces, but no health benefits were documented.13 This strain is being introduced in various formulations by Danisco in Europe and North America, but more clinical evidence of its benefits is needed. Likewise, L. salivarius strain UCC118 appears helpful for patients with bowel disorders, but no studies have been published yet.
A new pharmaceutical combination product, VSL#3, given in high doses (6 g/day), contains three species of Bifidobacterium, four strains of Lactobacillus and one strain of Streptococcus. This blend was shown to maintain remission of ulcerative colitis and pouchitis, and to prevent postoperative Crohn's disease recurrence.14 In one randomized, placebo-controlled study of 40 patients in clinical and endoscopic remission from pouchitis (a small infected and inflamed pouch near the rectum), those who received 6 g/day of VSL#3 for nine months relapsed 20 percent of the time compared with a 100 percent relapse rate among the control patients. The mechanisms of action are not yet understood, and the need for such high dosing is unusual, yet the clinical effect appears good.
In contrast to the positive outcomes from other studies, researchers from a recent study stated, "Probiotics are ... likely to be of limited benefit in treating diarrheal illnesses of short duration, such as viral enteritis."15 According to the researchers, colonization must occur before benefits of probiotics can be realized. They suggest beneficial effects of probiotics may be limited to prophylactic usage in high-risk populations. Although there are numerous problems and unanswered questions, it is important a product be recommended only when there is good evidence for its use, and when the consumer understands its benefits and limitations.
Stomach ulcers: L. rhamnosus GG, S. boulardii, a combination of Lactobacillus spp and Bifidobacterium, may significantly lower the incidence of therapy-induced diarrhea and flavor-perception disturbance in asymptomatic H. pylori-positive patients, according to one trial.16 However, this result was counteracted by a study showing that yogurt containing three Lactobacillus spp and one commercial starter culture, all showing strong in vitro inhibitory effects on the growth of H. pylori, did not alter the breath-test findings (a marker of H. pylori stomach infections).17 Thus, the yogurt did not eradicate the infection.
Additional studies are being conducted; for example, researchers in South Korea are trying to determine whether lactobacilli have a role in either eradicating infection, reducing symptoms or improving well-being in H. pylori patients.
Immunity: The first documented probiotic strain, L. casei Shirota (Yakult, Japan), and its primary European dairy drink competitor, L. casei DN 114 001, have long been promoted on the basis of boosting host immunity against disease. The basis for these claims is perhaps less than optimal; with the science of innate and acquired immunity advancing rapidly, it is too simplistic to say probiotics boost immunity. For one, the stimulation of peripheral immunity may not be beneficial. Also, the host reacts differently to bacterial strains and immune pathway activation. In some cases, enhancing intestinal or vaginal immunity may help prevent disease or deliver vaccines. In this regard, data is available mostly from animal studies on strains L. rhamnosus DR20, L. rhamnosus GR-1, L. fermentum RC14, B. lactis HN019 and L. plantarum NCIMB8826.11,18,19,20,21,22,23
Modulation of immunity may also affect cancer and allergies. The L. acidophilus NCFM strain was found to inhibit aberrant crypt formation (enlarged pits in the connective tissue surrounding the small intestine that show proliferative, biochemical and biomolecular abnormalities) in mutagenized rats, indicative of activity that could decrease colon cancer risk.24 In a randomized, double-blind, placebo-controlled trial, feeding L. rhamnosus GG to 132 pregnant women and their newborns postnatally for six months resulted in significant reduction in the occurrence of atopic dermatitis.25
In other studies, probiotic use, especially with oxalobacteria, was associated with reduced risk of kidney stone disease caused by oxalate crystals that degrade in the gut and lodge in the kidney.26 Other potential attributes of probiotic use, such as lowering serum cholesterol, were shown in animals.27,28 For example, administering 10,000 viable L. reuteri CRL 1098 cells per day for seven days prior to inducing hypercholesterolemia (by feeding mice a fat-enriched diet for the subsequent seven days) led to a 17 percent increase in the ratio of high-density to low-density lipoproteins. Strains used in these studies are not yet commercially available.
Urogenital health: Since 1974, Andrew Bruce, M.D., (aided since 1982 by this author) has been developing scientifically proven probiotics for women's urogenital tracts. With about 150 peer-reviewed papers on this topic, there is clear evidence that strains such as L. rhamnosus GR-1 and L. fermentum RC-14 can colonize the vagina and confer health benefits to the host, including reduced risk of colonization and infection by bladder and vaginal bacterial and yeast.29,30,31,32 In the most recent randomized, placebo-controlled trial of 64 healthy women, daily oral doses of strains GR-1 and RC-14 for two months resulted in a reduced bacterial and yeast count in the vagina, and increased levels of lactobacilli.32 This illustrated an improvement even in women who otherwise felt healthy at the beginning of the study.
These strains should become available commercially this year. Their mechanisms of action are likely multi-functional, due to pathogen inhibition, immune- and host-cell modulation, cell-cell signaling and production of pathogen growth inhibitors.
Surgical care: In 2002, four papers indicated the probiotic lactobacilli may have a major impact on surgical patient care. Three studies using L. plantarum 299 showed significant reduction in infection rates in abdominal, pancreatic and transplant surgery patients at high risk of morbidity and mortality.33,34,35 The liver transplant study was particularly interesting. Complications of this procedure can result in organ rejection and death. In a prospective, randomized, placebo-controlled trial involving 95 liver transplant patients, the incidence of postoperative infections was reduced from 48 percent to 13 percent using a fiber-containing formula plus living L. plantarum 299 taken orally after surgery.
In summary, mounting evidence indicates probiotic strains can benefit health. The challenge is to continue obtaining clinical evidence from well-designed trials and to unmask the mechanisms by which these organisms operate. Perhaps just as significant a challenge is to educate health care professionals and consumers about exactly what probiotics are and what they can and can't do. Furthermore, it is critical that companies selling probiotics use the highest manufacturing standards and strains that are clinically proven. Claims associated with these products must be based on what the contents actually do in humans.
The future for probiotics appears quite promising. Look for a wide range of new probiotic products. It won't be long before you see them as cheeses, fruit and milk drinks, fermented meats and vegetables, and maybe even candies and toothpastes.
Gregor Reid, Ph.D., MBA, is a professor of microbiology, immunology and surgery at the University of Western Ontario, and director of the Canadian Research and Development Centre for Probiotics in London, Canada. He has worked on probiotics for 21 years and holds patents to strains GR-1 and RC-14 under a university spin-off company Urex Biotech Inc. He is secretary of the International Scientific Association for Probiotics and Prebiotics.
1. FAO/WHO. Evaluation of health and nutritional properties of powder milk and live lactic acid bacteria. Food and Agriculture Organization of the United Nations and World Health Organization Expert Consultation Report 2001. www.fao.org/es/ESN/Probio/probio.htm.
2. Reid G, et al. Urogenital lactobacilli probiotics, reliability and regulatory issues. J Dairy Sci 2001;84(E Suppl):E164-9.
3. FAO/WHO. Guidelines for the evaluation of probiotics in food. Food and Agriculture Organization of the United Nations and World Health Organization Working Group Report 2002.
4. Szajewska H, et al. Efficacy of Lactobacillus GG in prevention of nosocomial diarrhea in infants. J Pediatr 2001;138(3):361-5.
5. Guandalini S, et al. Lactobacillus GG administered in oral rehydration solution to children with acute diarrhea: a multicenter European trial. J Pediatr Gastroenterol Nutr 2000;30:54-60.
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7. Elmer GW, et al. Biotherapeutic agents and infectious diseases. Humana Press (Totowa, NJ);1999. p1-316.
8. Shornikova A-V, et al. Lactobacillus reuteri as a therapeutic agent in acute diarrhea in young children. J Pediatr Gastroenterol Nutr 1997;24:399-404.
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10. Black FT. Placebo-controlled double-blind trial of 4 lactobacilli strains (HIP) used as prophylactic agent against traveler's diarrhea (2 trials). Report by G. Nirnberger, Bioconsult GmbH, Austria; 1996.
11. Reid G, et al. Ability of Lactobacillus GR-1 and RC-14 to stimulate host defenses and reduce gut translocation and infectivity of Salmonella typhimurium. Nutraceut Food 2002;7:168-73.
12. Chiva M, et al. Effect of Lactobacillus johnsonii La1 and antioxidants on intestinal flora and bacterial translocation in rats with experimental cirrhosis. J Hepatol 2002 Oct;37(4):456.
13. Tannock GW, et al. Analysis of the fecal microflora of human subjects consuming a probiotic product containing Lactobacillus rhamnosus DR20. Appl Environ Microbiol 2000 Jun;66(6):2578-88.
14. Madsen KL. The use of probiotics in gastrointestinal disease. Can J Gastroenterol 2001 Dec;15(12):817-22.
15. Costa-Ribeiro H, et al. Limitations of probiotic therapy in acute, severe dehydrating diarrhea. J Pediatr Gastroenterol Nutr 2003 Jan;36(1):112-5.
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17. Wendakoon CN, et al. Lack of therapeutic effect of a specially designed yogurt for the eradication of Helicobacter pylori infection. Digestion 2002;65(1):16-20.
18. Gill HS, Rutherfurd KJ. Immune enhancement conferred by oral delivery of Lactobacillus rhamnosus HN001 in different milk-based substrates. J Dairy Res 2001 Nov;68(4):611-6.
19. de Waard R, et al. Antagonistic activity of Lactobacillus casei strain shirota against gastrointestinal Listeria monocytogenes infection in rats. Int J Food Microbiol 2002 Feb 25;73(1):93-100.
20. Gill HS, et al. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr 2001 Dec;74(6):833-9.
21. Gill HS, Rutherfurd KJ. Viability and dose-response studies on the effects of the immunoenhancing lactic acid bacterium Lactobacillus rhamnosus in mice. Br J Nutr 2001 Aug;86(2):285-9.
22. Sanders ME, Klaenhammer TR. Invited review: the scientific basis of Lactobacillus acidophilus NCFM functionality as a probiotic. J Dairy Sci 2001 Feb;84(2):319-31.
23. Grangette C, et al. Mucosal immune responses and protection against tetanus toxin after intranasal immunization with recombinant Lactobacillus plantarum. Infect Immun 2001 Mar;69(3):1547-53.
24. De Roos NM, Katan MB. Effects of probiotic bacteria on diarrhea, lipid metabolism, and carcinogenesis: a review of papers published between 1988 and 1998. Am J Clin Nutr 2000;71:405-11.
25. Kalliomaki M, et al. Probiotics in primary prevention of atopic disease: a randomised placebo-controlled trial. Lancet 2001;357(9262):1076-9.
26. Kumar R, et al. Role of Oxalobacter formigenes in calcium oxalate stone disease: a study from North India. Eur Urol 2002 Mar;41(3):318-22.
27. Usman HA. Hypocholesterolemic effect of Lactobacillus gasseri SBT0270 in rats fed a cholesterol-enriched diet. J Dairy Res 2001;68(4):617-24.
28. Taranto MP, et al. Effect of Lactobacillus reuteri on the prevention of hypercholesterolemia in mice. J Dairy Sci 2000;83(3):401-3.
29. Reid G, et al. Instillation of Lactobacillus and stimulation of indigenous organisms to prevent recurrence of urinary tract infections. Microecology Therapy 1995;23:32-45.
30. Reid G, et al. Oral probiotics can resolve urogenital infections. FEMS Microbiol Immunol 2001;30:49-52.
31. Cadieux P, et al. Lactobacillus strains and vaginal ecology. JAMA 2002;287:1940-1.
32. Reid G, et al. Oral use of Lactobacillus rhamnosus GR-1 and L. fermentum RC-14 significantly alters vaginal flora: randomized, placebo-controlled trial. FEMS Immunol Med Microbiol 2003;in press.
33. Rayes N, et al. Early enteral supply of lactobacillus and fiber versus selective bowel decontamination: a controlled trial in liver transplant recipients. Transplantation 2002 Jul 15;74(1):123-7.
34. Rayes N, et al. Early enteral supply of fiber and Lactobacilli versus conventional nutrition: a controlled trial in patients with major abdominal surgery. Nutrition 2002 Jul-Aug;18(7-8):609-15.
35. Olah A, et al. Randomized clinical trial of specific lactobacillus and fibre supplement to early enteral nutrition in patients with acute pancreatitis. Br J Surg 2002 Sep;89(9):1103-7.