Prophylactic and therapeutic uses of probiotics: A review Lori Kopp-Hoolihan, PhD, RD ISTRACT Probiotics, live microbial food supplements that beneficially affect the host by improving its intestinal microbial balance, are quickly gaining interest as functional foods in the current era of self-care and complementary medicine. Microbes have been used for years in food and alcoholic fermentations and relatively recently have undergone sclentific scratiny to examine their purported health benefits, Some of the claims for which research supports a beneficial effect of probiotic consumption include: improv- ing intestinal tract health, enhancing the immune system, synthesizing and enhancing the bioavailability of nutrients, reducing symptoms of lactose intolerance, decreasing the prevalence of allergy in susceptible individuals, and reduc- Ing risk of certain cancers, The mechanistas by which probiotics exert their effects are largely unknown, but may involve modifying gut pH, antagonizing pathogens through production of antimicrobial and antibacterial compounds, competing for pathogen binding and receptor sites as well as for available nutrients and growth factors, stimalating, immunomodulatory cells, and producing lactase, Selection criteria, efficacy, food and supplement sources and safety issues around probiatics are reviewed. Nutrition profession als can provide a tremendous service by helping clients overcome negative perceptions of all bacteria and, when appropriate, by developing individualized dietary plans to take advantage of the benefits probiotics may confer. J Am Diot Assoc, 2001;101:229-238, 241. /which health care is changing. The evolution of health /maintenance organizations and the increased availabil- ity of health information tothe consumer viathe Internet are two driving forces behind this transformation. Other fac- tors include a growing interest in self-care and increased acceptance of and demand for integrative medicine therapies. Efforts to optimize health and quality of life, stemming largely ‘from our aging baby boomer population, provide further impe~ tus to this evolution in health care ‘Asaresult, the development and consumption of functional foods, or foods that promote health beyond providing basic nutrition, are on the rise. Sport bars, soy-based ice cream, cholesterol-reducing margarines and calcium fortified orange Julee are examples of functional food products that have thrived in this era, Probiotics—live microbial food supple- ‘ments that beneficially affect the host by improvingits intesti- nalmicrobial balance (1)—and prebiotics—nondigestible food ingredients that encourage the growth and activity of favorable intestinal bacteria - are quickly gaining attention as functional foods. This review will summarize the history of probioties, review the literature on the most widely recognized health effects and provide the practicing clinician some basies on interpreting these findings in order to answer clients’ ques- tions and make appropriate recommendations. H ealth professionals are well aware of the rapid pace at HISTORY Microbes have been essential to food and alcoholic fermenta- tons for thousands of years. Over the last century, diferent microorganisms have been used for their supposed ability to Lori Kopp-Hoolihan, PhD, RD, is Project Manager for the Dairy Council of California, 2222 Martin Ave #155, Irvine, CA 92612. Joural af THE AMERICAN DIETBTIC ASSOCIATION /229Tablet Cornmercally used probiotic species" Lacobat specie tS {eran { gaze sons {praca ‘fino tian Utmonue Lssrane sicitecorim sscios "These species aw avaiable caraln yogurts fermented rik roa ‘Cosing pourable yomuts) fred hid mex, andor supperent fn 290 /February 2001 Volume 101 Number 2 prevent and cure diseases, leading to the coining of the term pprobioties, or ‘pro-life” (2).’The concept of probiotics evolved around 1900, when Nobel Prize-winning Elie Metchnikotf hy- pothesized that the long, healthy lives of Bulgarian peasants ‘were the result of thelr consumption of fermented milk prod- uucts, The first elinical trials were done in the 1990s on the effect of probiotics on constipation, Research on probiotieshas steadily increased since then, much ofit taking place in Europe and Asia, Worldwide, probiotics are currently available in a variety of food products and supplements. Inthe U.S., the food products containing probioties are almost exclusively dairy products fluid milk and yogurt —due to the historical associa~ tion of lactic acid bacteria with fermented milk. The most frequently used bacteria in these products belong to the Lactobacillus and Bifidobacterium species. PHYSIOLOGY OF THE INTESTINES. Itisestimated thatthe hurman intestine contains more than 400 different bacterial species and approximately 10" bacterial cells, which ismore than ten times the numberof cells compris ing the human body. The most prevalent resident bacterial species inhabiting the adult intestinal tract in Western societ- Jes include bacteroides, eubacteria, peptostreptococei, bifidabacteria, enterobacteria, streptococci, lactobacilli, clostridia and staphylococci (3). Because some of these bacte- ria are beneficial to health while others are dangerous, the ‘microbial colonization of the intestine has important. health implications for humans, ranging from effects on susceptibility to infection to toxic or carcinogenic effects. “Many factors affect the composition ofthe bacteria present in the intestines. The age of the individual, their nutritional requirements and immunological status, antibiotic use, stress, alcohol consumption, and the pH, transit time and presence of ‘material in the gut are just a few factors thought to affect the bacterial composition. The amount and type of fermentable material (Le. growth substrate) in the gut also plays a role in Getermining the bacterial species present (1). Diet not only regulates the species and concentration of microorganismas in the gut, but also has been reported to influence the metabolic activities of those microorganisms. Thus, it may be possible, at Teast transiently, to manipulate the gut microbiotia through dietary supplementation, "Themechanism(s) by which probiotics exerttheireffects.on the host are sill speculative, Probiotics may antagonize patho ‘gens directly through production of antimicrobial and antibac- terial compounds such as eytokines and butyric acid (4-6), reduce gut pH by stimulating the lactic acid ~ producing microflora (7), compete for binding and receptor sites that pathogens occupy (6,8), improve immune function and stimu- late immunomodulatory cells (9,10,11), compete with patho- {gens for available nutrients and other growth factors (11), or produce lactase which aids in lactose digestion. Future re- Search will be needed to determine under what physiological circumstances these mechanisms might play a role in mediat- ing the health effects of probiotics. ‘tis uncertain whether the ability of probiotics to adhere to {intestinal mucosal cells is required for optimal health effects, ‘Some experts believe that adhesion is necessary, with adhe~ sion properties depending upon bacterial concentration, resi-dent pl, transit time, and dietary factors. Prebioties such as nondigestible oligosaccharides, lactulose and whey-specific factors are also thought to increase adherence time for certain microbe species. Others believe that probiotics exert their effect through only a loose affiliation with the mucosal layer that does not require site-specific attachment. Microbes may. exert their effects without adhering if consumed on a regular basis, as in the case of yogurt bacteria aiding lactose digestion, ‘Selection Criteria and Common Probiotics Currently Used ‘The selection of probiotic strains has been in ange part histori- cal, based on years of use with no harmful side effects. Other criteria for use of appropriate strains include the ability to 1) exert a beneficial effect on the host, 2) survive transit through the intestinal tract, 3) adhere to the intestinal epithelial cell lining, 4) produce antimicrobial substances towards patho- ‘ens and 5) stabilize the intestinal microflora. On a practical hote, probiotics must also have good shelf-life in food or preparations, contain large number of viable cells at the time ‘of consumptionandbenon-pathogenicand nontoxic. Probiotics added to food products generally meet at least some of these criteria, However, those usedinover-the-counterhealthsupple- ‘ments often have not met these criteria and may not even survive in the gastrointestinal tract. Table 1 lists some corm- ‘mercially available probiotics that are added to foods or con- centrated in supplements intended for human consumption, ‘The most extensively studied and widely used probiotics are the lactic acid bacteria, particularly the Lactobacillus and Bifidobacterium species. NUTRITIONAL AND THERAPEUTIC EFFECTS OF PROBIOTICS Ofthe variety of proposed beneficial health effects of probiotics, only a few have significant research to back up the claims, ‘These will be more thoroughly discussed here. ‘Stomach and Intestinal Tract Health ‘There are a number of studies in humans that suggest that lactic acid bacteria ata level of 10? 10" per day can decrease the incidence, duration and severity of some gastric arid intes- tinal illnesses. L, acidophilus may reduce the symptoms of small bowel bacterial overgrowth brought. on by end-stage Kidney disease (12) and may reduce the severity of alcoholic liver disease (13). Probiotic bacteria. have been shown to preserve intestinal integrity and mediate the effects of a ‘number of other intestinal diseases such as antibiotic-associ- ated diarrhea, inflammatory bowel diseases, pediatric diar- ‘hea, travellers’ diarzhea, iitable bowel syndrome and colitis (814-25). Although many of these were pilot studies with only small number of subjects, the majority of the evidence suggests that probiotic bacteria may be beneficial in treating some intestinal diseases. ‘There is some preliminary evidence that probiotic bacteria ‘may inhibitthe gastric colonization andactivity of Helicobacter pylori, which is associated with gastritis, peptic ulcers and gastric cancer. L. salivarius was found to inhibit H. pylori ‘colonization in in vitro studies as well asin mice (26,27). An inhibition of H. pylori infection was also shown in humans Lactobacilus species acioophius case! Termentom gasseri johnson facts paracasei plantarum router! ‘Rarmnosus Bilidobacterium species 8. bifcur 8 breve B lactis longum Streptococcus species ‘S thermophilus Yeasts and molds ‘Saccharomyces bovlardii FIG 1: Commercially used probiotic spevies* “These species are available in certain yogurts, formented smile products C*peurable yoours", fortified fluid milk, ‘and/or in supplement form. ‘Journal of THE ANBRICAN DIETETIC ASSOCIATION /231consuming L: johnsonit (28). Studies have shown an improvement in symptoms of inflam matory bowel disease (IBS), pouchitis and ulcerative colitis with consuraption of eertain strains of lactobacilli (17,24,25), A recent clinical trial in 60 patients with IBS indicated that daily administration of a 400 ml drink containing 5 x 10" cfu/ml L. plantarum reduced pain and flatulence over the 4 week study period (25) As research in the field of probiotics progresses and we have more concrete information from which to draw, educating clients on the beneficial effects of probiotics and helping them develop a dietary plan to take full advantage of these effects will be a tremendous service Evidence also suggests that lactic acid bacteria may improve Intestinal mobility and relieve constipation (29,30), possibly through a reduction in gut pH (31). One study showed that consumption of bifidus silk improved intestinal motility and bowel Dehavior ina group of 18 constipated seniors (29). ‘Another study showed a marked improvement of the intestinal ‘motility in60 elderly patients whowereadministeredL. acido- philus supplements (30). ‘A variety of studies have found probiotic consumption to be useful in the treatment of many types of diarrhea, including antibiotic-induced diarrivea in adults (18-20), travellers’ diar- 1282 / February 2001 Volume 101 Number thea (16,21) and diarrheal disease in young children caused by rotaviruses (9,22,32). The problotie species that show the ‘most promise in treating diarrheal diseases in children include Lactobacillus GG (GG), L. reuteri, L. casei, Saccharomy ces boulardi, B. bifidum and Streptococcus thermophilus. Preliminary results ofa placebo-controlled trial show that L6G js effective in reducing the recurrence rate of Clostridium aipficile diarrhea and in alleviating symptoms (20). A recent. study in children 1-3 months of age with acute-onset diarrhea also showed that administering an oral rehydration solution containing LGG resulted in ashorter duration of diarrhea, less chance of @ protracted course, and faster discharge from the hospital (22). Because diarthea isamajor cause of infant death worldwide and canbe incapacitating in adults, the widespread use of probiotics could be an important, non-invasive means to prevent, and treat these diseases, particularly in developing countries Immune Function ‘The effect of probioties on the immune response has been comprehensively reviewed (33-36). The majority of evidence fromin vitro systems, animal modelsand humans suggests that probiotics can enhance both specific and nonspecific immune responses (37). These effects are believed to be mediated ‘through activating macrophages increasinglevels of cytokines, increasing natural killer cell activity and/or increasing levels of {msmunoglobulins (88). Most importantly, probiotics can exert ‘these positive effects on the immune system without eliciting a harmful inflammatory response. The immune response may bbe further enhanced when one or mote probiotics are con- sumed together and work synergisticaly, as seems to be the cease when Lactobacillus is administered in conjunetion with bifidobacteria (39). It is important to remember, however, that there has been very limited testing on immune function effects in humans, Clinical testing has focused mostly on immune cell levels and not on actual incidence of disease. Thus, itis difficult to extrapolate results from immune function studies to the ex- pected effects on human health. In addition, due to the rela- tively short duration of most studies, its unelear whether any benefit to the imunune system isa temporary response or could be expected to continue with long-term consumption of probiotics, ‘As the U.S. population continues to age, this intriguing research on the beneficial effects of probiotics on the immune response comes at a particularly appropriate time, Mucosal immunity decreases withage, making the elderly more suscep- tuble toinfectiousdisease, andthe prophylacticuse ofprobictics may prove important in enhancing their immune response Future research will clarity the levels of probiotics needed to exert positive effects on the immune response and identify other agents that may work in conjunction with probiotics to fenhance the response further. ‘Nutrient synthesis and bioavailability ‘The action of microorganisms during the preparation of cul- ‘ured foods orin the digestive tract has been shown to improve the quantity, availability and digestibility of some dietary nutrients, Fermentation of food with lactic acid bacteria inQ: 18 it better to get probictics trom foods or from ‘supplement sources? ‘Although consuming the levels needed may be more Convenient trough supplements, foods are a better choice {due fo the synergistic effect betwosn components of foods {and probiotic cultures. Dairy products containing probiotice provide a number of high quality nutrients including calcium, protein, bioactive peptides, sphingaipids, and conjugated linoleic acids, The natural burfering of stomach acid by food also anhancos the stability of consumed probiatis. Finally, long-term compliance has always been an obstacle with supplements, whereas incorporating foods containing probiotics becomes a ifasiyle abt based on one's Inherent eed to ea {: What level of probiotic consumption is needed to realize the desired benefits? Many studiae of probiotic bacteria on physiological effects such as diarrhea, lactose intolerance, and colon cancer biomarkers chow an effective dose a! 10"~ 10° organisms: ‘ber day. This corresponds to an intake of about a iter of ‘2cidophilus mik par day, formulated at the typical ievel of 2 40° cfu (76), Elects of consuming tower levels has not ‘been documented in research studies but may benefit select inaWviduals. Its possi that consumption of more than one probiotic bacterial species acts synergistically so that a lesser ‘bsoluta volume is required. Sirutaneous consumption of prebiotics may also enhance the lifespan and activity of he probiatics, mediating offocts a a lower love : How long does one need to take probiotics for the ttfects to last? itis believed that most probictics do not permanently adhere Inthe Inestine, but exon thelr effects as they metabolize and ‘grow during their passage through the intestine (colonization), ‘Thus, dally consumption o these bactela is probably he Dest way to maintain their effectiveness FIG 2: Commonly asked questions and answers on probiotics. Q: What are some good food souroes of probiotics? Yogurt and mik to which probiate bacteria have been added and fermontod mik products such as kofis are the primary {ood sources of probiotics in the U.S. Some researchers bolieve that a synergistic effect exists between components in dairy foods ana probiotic cultures, and thet there are ‘Comporents in mik that turn on the Beneficial ganes in probiotic bacteria, making dairy foods an oxcallent vahico for Introducing these bacteria ino the gut. As the feld progress: ‘5 wo will undoubtedty see probiotics added to otter foods as wel {: What kind of information on probiotics can be found on food labels? ‘The shelhife and species of probiotic bacteria included in dairy products are goneraly isted onthe label of products The Specic stain and levels of viable cells, however, are not typically shown. As the industry matures and the consumer requests more detailed information, labeling wil likely become more routine and even mandatory. The major brand amos ‘Generaly can be Counted on for higher reliability in fem tion and labeling ofthe product. On yogurt labels look for the “Live Active Culture” seal which assures the consumer that viable lactic acid bacteria are in the product. Yogurt probably has the most reiabie reported lovele of probiotics due to Is. shor sheibite and because itis refrigerated : What is the shelf-life for most problotic products? The shett.ife for refigerated products containing probiotics range from about 3-8 weeks. The probiotic content of these product is usualy more stable an in non-efrigerated products. The shite for dried eupplements is about 12 onthe, however the levels of probiotics may drop off Significantly during this ime, Selecting and consuming products af close to the beginning of their shet-ife wll ‘ensure the highest loveis of probictics. Journal of THE AMERICAN DIETETIC ASSOCIATION / 288.