Promoting gut health with probiotics: living medicines for treating digestive disorders

Promoting Gut Health with ProbioticsLiving Medicines for Treating Digestive Disorders Sala Horowitz, Ph.D.
first brought the health benefits of beneficial bacteria to publicattention. Believing that this process could enhance health andlongevity, Dr. Metchnikoff named one of the primary bacteria in Probiotics are foods or dietary supplements that contain live yogurt cultures, Lactobacillus bulgaricus, for the famously long-
microorganisms that can restore needed balance to the lived, yogurt-loving Bulgarians.10 intestinal microflora. Probiotic products, such as yogurt Lactobacillus acidophilus and Bifidobacteria are other strains of with live bacterial cultures, have a long history of use in tradi- bacteria that have long been utilized in traditional diets and tional diets and medicine. Probiotics are increasingly being stud- medicine to balance the beneficial and pathogenic bacteria in the ied scientifically regarding their role in treating inflammatory gastrointestinal (GI) tract for general immune-system enhance- bowel disease and other digestive disorders. This paper explores ment. These lactic acid–producing bacteria are major constituents the research-based evidence for such applications of probiotics.
of the resident intestinal microflora in humans. Streptococcus ther-mophilus is another "friendly" bacterium used to culture true yogurt, (i.e., a fermented dairy product that has culturing bacteriathat have not been destroyed in the pasteurization process).
Probiotics are commonly called "good" bacteria and include Natasha Trenev, a Southern California-based producer of, and live cultures found in some brands of yogurt and acidophilus recognized authority on, probiotics cautions that some yogurt is milk. Most probiotics are bacterial strains but the yeast Saccha- produced with minimally beneficial strains of bacteria.10 romyces boulardii is also used as a probiotic.1 Probiotics have beendefined as "living microorganisms which upon ingestion in cer- Standards and Formulations
tain numbers, produce health benefits beyond supporting inher-ent general nutrition."2 For the aforementioned reason, the National Nutritional Foods Other terms that are associated with probiotics are prebiotics Association (NNFA) adopted the NNFA Probiotic Labeling Stan- and synbiotics. Prebiotics, such as nondigestible sugars in foods, dard in 1989. This standard recommends that probiotic supple- known as fructo-oligosaccharides (FOS), stimulate the growth of m ent supp liers specify on their product labels the type and beneficial bacteria. Because sufficient FOS to treat health condi- quantity of the living bacteria present, a viable cell count, expira- tions is difficult to obtain from foods, supplements are generally tion date, certification of the absence of pathogens, storage recommended.3 Other prebiotics include inulin, bran, psyllium, requirements, and a list of any additional ingredients. (See box and germinated barley food stuff.4 The term "synbiotics" was entitled Resources.) coined to describe the synergistic actions of pre- and probiotics.5 Ms. Trenev wrote that "unfortunately. .virtually none of the To describe this innovative approach to calibrating the com- probiotic suppliers adheres to these standards."10 (See box enti- plex ecology of the gut microflora with probiotics, the terms tled Recommended Reading.) Of the probiotic supplements test- "ecoimmunonutrition,"5 "ecotherapeutics,"6 and "biotherapeu- ed more recently by Con sumerLabs.com, approximately one tics"7 have been used.
third contained far fewer than the labeled number of organisms.9 Probiotic supplements are available as capsules, freeze-dried powders, wafers, and liquids. Dairy-free acidophilus productsare available for vegans and patients who are allergic to milk In Europe, Japan, and Australia, probiotics and related prod- products. Ms. Trenev advises against using liquid probiotics, ucts to improve intestinal health currently represent the largest stating that they lose their po tency rapidly and may conta in segment of the functional foods market. The European Commis- buffering additives. For optimum benefit for general health pur- sion has sponsored research projects on these products' safety poses, she recommends taking powdered probiotics in conjunc- and efficacy.8 Probiotics are also now among the most popular tion with combined L. acidophilus, Bifidobacterium bifidum, and L. selling supplements in the United States.9 bulgaricus in a sunflower oil–matrix capsule with unchilled fil- Physiologist Elie Metchnikoff (a cowinner of the Nobel Prize in tered water; the total dose is 1 capsule, 2 times per day, with one- physiology and medicine in 1908 for identifying phagocytosis) half of a teaspoon of each of these powdered super strains.10 ALTERNATIVE & COMPLEMENTARY THERAPIES—OCTOBER 2003 bacterial bowel infection, even after treatment with the potentantibiotics metronidazole and/or vancomycin. Lactobacillus GG Research on Probiotic Therapy
was found to be effective in reducing patients' symptoms of diar- rhea and abdominal cramps and the infection recurrence rate at 3 weeks compared to placebo. The researcher who conducted this Malabsorption of Assisted absorption study concluded that probiotics hold promise for treatment of of calcium, other primary as well as recurring Clostridium difficile.12 minerals, and vitamins Shortened courses of Providing Natural Antibiotics and Antivirals pediatric bouts of acute Researchers in the 1970s discovered that strains of friendly bac- diarrheal infections teria produced microbial-inhibiting substances in addition to Antibiotic-induced Decreased symptoms acids. Acidolin and acidophilin were isolated from L. acidophilus, and bulgarican was extracted from super strain DDS-14 of L. bul- Clostridium difficile Prevented recurrent bouts garicus. These natural alternatives to standard antibiotics are unique in that they appear to be active against both bacteria and reduced levels of viruses.10 This is a particularly important development with procarcinogenic enzymes pathogens becoming increasingly drug-resistant. Some strains of Inhibited tumor growth L. bactobacilla also secrete viridical compoun ds (e.g., hydrogen peroxide) that kill viruses.10 Prebiotic lactulose alleviated constipation safely Boosting the Immune System Inhibited ulcer-causing Being that approximately 70 percent of the body's immune sys- tem is GI tract–based, it is hardly surprising that the GI microflo- Inflammatory bowel A multibacterial product prevented postsurgical ra have a major influence on overall health and disease. It has been noted that the collective metabolic activity of the estimated Achieved remission in 400–500 species of anaerobic and other bacteria that populate the ulcerative colitis g ut justify this m icroflora being considere d "the negle cted Reduced IBS symptoms S. Bengmark, M.D., of Lund University, Lund, Sweden, and colleagues opined that not only is the gut vulnerable to inflam- lactose digestion mation and cancer because of the organ's sheer size but alsobecause of Western hygiene practices, antibiotics, and diets that The product tested was VSL#3TM (VSL Pharmaceuticals, Inc., Ft. Lauderdale, Florida).
frequently expose the gut to enzyme additives used to extend theshelf-life of processed foods.14 Main Clinical Uses of Probiotics
Serving as Anticancer Agents Counteracting Antibiotic GI Side-Effects Probiotics have demonstrated anticancer properties. Early lab- A common modern medical application of probiotics, taken as oratory studies with mice identified glycopeptides from the cell fermented dairy products or as supplements, is to counteract the walls of L. bulgaricus bacteria that exhibited antitumor activity.15 effects of antibiotic therapy, which destroys protective bacteria as L actobacillus GG was later found to reduce the incidence of well as targeted pathogens. Diarrhea and stomach upset are com- mon side-effects of the elimination of beneficial GI bacteria when h um an s, L. acido philu s, supplie d v ia milk or sup ple me nts , broad-spectrum antibiotics are used for an extended period of reduced the levels of enzymes considered to be procarcino- time. A meta-analysis of 22 studies supported probiotic efficacy genic.10 Unlike standard chemotherapy agents, probiotic-derived in treating antibiotic-associated diarrhea.11 agents target tumor cells without harming normal cells or caus- To counter such adverse effects, Ms. Trenev recommends tak- ing immune suppression and other adverse side-effects.15 These ing, after each prescribed dose of antibiotic, 2 capsules each of L. bacteria compete with or inhibit the pathogenic bacteria.
acidophilus and B. bifidum along with 1 teaspoon of L. bulgaricus Proposed mechanisms by which lactobacilli play an anticancer- powder mixed in 6–8 ounces of unchilled filtered water. Another role include: (1) neutralizing procarcinogenic substances (e.g, dose of the powders may be taken at bedtime. Ms. Trenev also nitrates) produced by harmful bacteria before they are converted advises doubling or tripling this regimen for up to 2 weeks to into active carcinogens (e.g., nitrosamines) in the intestinal tract; ensure recolonization of the beneficial enteric bacteria.10 (2) suppressing the metabolic action of such bacteria as Clostridi- Probiotics are being studied as a novel modality for treating um and certain Bacteroides, which produce higher amounts of Clostridium difficile colitis, the leading cause of nosocom ially enzymes (e.g., beta glucuronidase and b-glucosidase) that act by acquired intestinal infection in the United States. It has been esti- cleaving glucuronic acid conjugates of environmental toxins or mated that 20 percent of patients will have recurrent bouts of this steroidal hormones and allowing the unconjugated forms to go ALTERNATIVE & COMPLEMENTARY THERAPIES—OCTOBER 2003 back into the enterohepatic circulation and by outcom petinghealthy bacteria for nutrients; and (3) suppressing the induction and growth of some tumors directly.10 Crohn's & Colitis Foundation of America, Inc. (CCFA)
386 Park Avenue South, 17th Floor Assisting Vitamin and Mineral Uptake New York, NY 10016 Probiotics increase the bioavailability of vitamins and protein Phone: (800) 932-2423 or (212) 685-3440 in the GI tract as a result of increased acidification of the gut pH Web site: www.ccfa.org The CCFA sponsors support group chapters nationwide for by the lactic acid produced by bacterial strains. Compared to patients with inflammatory bowel disease (IBD) and their families, milk, yogurt results in better absorption of such vitamins and educational materials, workshops, advocacy, and funding for minerals as calcium, copper, iron, manganese, phosphorous, and research toward a cure for IBD. Probiotics is a recent area of the zinc.10 Prebiotics also improve calcium bioavailability.17,18 Mal- CCFA's research focus. absorption of nutrients can be a serious problem in inflammatory National Nutritional Foods Association (NNFA)
bowel disease (IBD) and other digestive ailments.
3931 MacArthur Boulevard, Suite 101 Newport Beach, CA 92660-3013 Reducing the Immune Overresponse in Inflammatory Bowel Disease Phone (800) 966-6632 or (949) 622-6272 Accruing experimental and clinical evidence suggests that an Fax: (949) 622-6266 overgrowth of bacterial organisms that may also exist in healthy Web site: www.nnfa.org As the nation's largest and oldest nonprofit organization people (e.g., Helicobacter pylori, Mycobacterium paratuberculosis, devoted to the natural foods industry, the NNFA created and Bacterioides vulgatus)—in conjunction with genetic and environ- adopted the NNFA Probiotic Labeling Standard in 1989. mental facto rs that impair the intestinal lining and immuneresponse—plays an etiologic role in IBD (the collective term forCrohn's disease and ulcerative colitis). Serving as more than justa barrier for pathogens, the enteric lining of the GI tract contains levels of harmful bacteria. This Herxheimer reaction, named after resident bacteria that engage in crucial intercellular communica- one of the German physicians who identified this "healing crisis" phenomenon, is the consequence of a sudden, massive die-off of harmful bacteria. While this reaction is considered to be a posi- It is has been hypothesized that probiotics can help to turn off tive sign of the healing process, it and the discomfort it causes the inappropriate, overreactive immune response in IBD by con- patients, can be averted by gradually increasing the amount and trolling regulatory signaling between the bacteria and these cells, frequency of probiotic intake.10 and influencing mucosal integrity favorably.19 Animals who areraised in germ-free environments as experimental models of IBD Research on Major Additional Uses of Probiotics
have deficits in protective gut functions, such as decreased toler-ance of ingested antigens.13 This focus on the com plex ecology of the GI tract reflects a "Knockou t" experimental mod els of IBD, in which genetic major shift from an emphasis on regulating immune mediators engineering methods breed selectively for the lack of a protective and the inflammatory response via systemic drugs to more bio- element in the immune system, have shown that animals bred in logic targeted therapies and recognition of defective regulation of this way experience an increase in aerobic luminal bacteria that the patient's macro- and microenvironments in initiating or per- invade their intestinal linings aggressively. Mice born without IL- petuating IBD. According to Joseph B. Kirsner, M.D., Ph.D., Uni- 10 have decreased GI levels of beneficial Lactobacillus bacteria.
ve rsity of Chicag o M edical Ce nte r, Illinois, the se differing When normal Lactobacillus levels were restored in one study, the emphases are what distinguish twenty-first century from twenti- levels of problematic bacteria were reduced and the development eth century treatment for IBD.20 of colitis was prevented.23 Until recently, in biomedicine, the role of diet in IBD has been In related work, testing the hypothesis that prebiotics (such as largely limited to alleviating symptoms and compensating for certain nondigestible carbohydrates) can prom ote bacterial nutritional deficiencies. Thus, the use of probiotics for modifying growth, a research group foun d that lactulose could prevent the enteric flora represents a major shift in the dietary manage- inflammation of the gut.24 ment of IBD.21 Such alternative therapies are clearly neededbecause standard pharmaceuticals for IBD are often not effective Developing Specific-Purpose Bacteria for many patients.22 Whereas L. acidophilus and some strains of Lactobacillus reside primarily in, and are protective of, the small intestine and colon, Healing Reactions to Probiotics
Bifidobacteria inhabit the colon. L. bulgaricus is a transient strainthat works with the other two strains as it passes through the Although probiotics are considered to be safe even in amounts digestive tract.10 According to Fergus Shanahan, M.D., of Cork exceeding those recommended by their manufacturers, a newly University Hospital, Wilton, Ireland, the diverse clinical courses introduced regime of probiotics may elicit such temporary symp- of these diseases "implies that strain-specific properties may be toms as bloating, gas, and/or headaches in patients with toxic required for subset-specific categories of patients."25 Thus, ALTERNATIVE & COMPLEMENTARY THERAPIES—OCTOBER 2003 were evaluated clinically, histologically, and endoscopically after1, 3, 6, 9, and 12 months. The subjects also rated their health- related quality of life on a standard IBD questionnaire at baseline For health professionals
and at these other intervals.
Handbook of Probiotics This highly concentrated dose of VSL# 3 w as found to be By Yuan-Kun Lee, Koji Nomoto, Seppo Salminen, and Sherwood L. Gorbach effective in lowering the incidence of relapse in patients with New York: John Wiley & Sons, 1999 chronic pouchitis who had been previously treated with antibi-otics. Only 2 of the 20 patients (10 percent) treated with the For professionals and their patients
probiotic experienced an acute episode of pouchitis—after 9 Priobiotics: Nature's Internal Healers and 11 months compared to 8 of the 20 placebo-treated patients Garden City Park, NY: Avery Publishing Group, 1998 (40 percent). Treatment-group patients who did not developpouchitis also reported a significantly higher quality of life andlower stool frequency. No side-effects or significant deviationfrom any of the baseline laboratory parameters were noted in specifically formulated supplements, rather than foods, would either patient group.1 This study confirmed an earlier review generally be preferred for delivering therapeutic strains and of the research suggesting that probiotics can be an effective doses to patients.
therapy for maintaining rem ission in patients with chronicpouchitis.26 The concept of "reflorastration" in normalizing enteric bacteria Maintenance Treatment of IBD in IBD was described by McCann and colleagues in a 1994 paper.
Jeffrey A. Katz, M.D., associate professor of medicine, division In a 3-year study of patients with IBD, McCann sought to nor- of gastroenterology, Case Western Reserve University School of malize their compromised bowel flora using L. acidophilus (DDS-1 Medicine in Cleveland, Ohio, speculated that: "Given the similar- strain), B. bifidum (Mayloth strain), and benign E. coli bacteria ity between pouchitis and ulcerative colitis, probiotic therapy (Nissel 1917 strain). McCann's protocol involved using antibi- could also prove useful in the maintenance treatment of this con- otics and antifungals to depopulate the patients' bodies of all bacteria. Normal bacteria were reintroduced via oral supplemen- Dr. Katz also noted that probiotics are a promising alterna- tation and retention enemas. All of the patients (N was unspeci- tive to the continuous regimen of antibiotics, corticosteroids, fied in the review paper) went into remission and those who immune modulators, and other drugs that are typically used continued the bacterial supplementation remained in remission.
to treat chronic pou chitis. Because there is some correlation McCann concluded: "Reflorastration is not only a method that between chronic pouchitis and developing dysplasia and car- has the potential to identify putative etiologic antigens, it is also a clinical method to induce long-term remissions without the use tract. Howe ver, prop hylactic treatm ent with probiotics for of toxic drugs."10 Treating IBD Pouchitis with Multibacterial Probiotics Richard Fedorak, M.D., a professor of medicine and director of To date, the efficacy of probiotic therapy in IBD has shown the the division of gastroenterology, at the University of Alberta, most promise in preventing flareups of chronic IBD pouchitis in Edmonton, Canada, reported that 86 percent of patients with clinical trials that have exam ined the effects of the probiotic mild-to-moderate ulcerative colitis who were not responding to preparation VSL# 3TM (VSL Pharmaceuticals, Inc., Ft. Lauderdale, conventional drug therapy had a favorable response to VSL# 3.28 Florida) on patients with recurring pouchi tis. Pouchitis is an In a randomized study of 32 patients with Crohn's disease in inflammatory condition that can occur in patients with ulcerative clinical remission, those who took the nonpathogenic yeast Sac- charomyces boulardii in addition to mesalamine had a significantly lower relapse rate than those who took mesalamine alone (6 per- intestines are formed into ileoanal pouches so that bowel habits cent versus 37.5 percent).29 can be normalized after the diseased colon is removed. This is themost frequent complication following ileostomy closure and is Additional Potential Applications for Probiotics
most likely to occur during the first postsurgical year.
The VSL# 3 product is a combination of eight different lactic Reducing Lactose Intolerance acid bacteria: four strains of Lactobacillus (L. acidophilus, L. casei, L. It is well-known that dairy products and supplement products plantarum, and L. delbrueckii bulgaricus); three strains of Bifidobac- with added lactobacilli bacteria enable many people with some terium (B. longum, L. breve, and B. infantis); and a strain of Strepto- degree of lactose intolerance to digest the milk sugar, lactase.
coccus salivarius thermophilus. However, probiotics will not work for patients who are unable to Forty patients were randomized to receive either a packet of digest casein, a milk protein.10 VSL# 3, containing 900 billion viable bacteria, per day (with a Lactose intolerance can also trigger irritable bowel syndrome maize starch filler) or an identical placebo for 12 months. Patients ALTERNATIVE & COMPLEMENTARY THERAPIES—OCTOBER 2003 Addressing Irritable Bowel Syndrome After noting that preliminary results regarding probiotics for Lactobacilli are also useful for treating patients with IBS, a con- management of IBD are promising, Gary R. Lichtenstein, M.D., in dition that is characterized by abnormal muscle contractions of the department of gastroenterology, University of Pennsylvania the bowels, because they release several amino acids, including School of Medicine, Philadelphia, similarly summarized the tryptophan, which produces the calming neurotransmitter sero- probable mechanisms of action of probiotics as basically involv- tonin. Besides anxiety, lactose intolerance can trigger IBS.10 ing increased immunosuppressive and decreased proinflamma- In a double-blinded clinical trial of 18 patients with IBS, sub- tory mediators.33 jects were treated for 6 weeks with L. acidophilus in capsule form.
After a 2-week washout period, the subjects continued to take the Conclusions and Future Directions
supplement for another 6 weeks. The patients who received theprobiotic experienced a 50-percent improvement compared to Foods, such as yogurt, have a venerable history of being used for health-enhancement purposes. Recent controlled studies of According to nutrition specialist James Scala, Ph.D., anything the health benefits of this traditional food and the use of supple- that chronically upsets the normal balance of intestinal flora can mentary probiotics for relieving the symptoms of IBD have gen- result in IBS. Therefore, replenishing the beneficial bacteria can erated considerable interest in the potential of beneficial bacterial normalize the gut environment and relieve IBS symptoms. Dr.
to remedy the imbalance of intestinal flora that is characteristic of Scala recommends taking active cultures of L. acidophilus and B. these serious chronic bowel disorders. Correcting this imbalance bifidum containing a level of at least 15 billion organisms.30 may help modulate gut mucosal barrier functions and immuneresponses. Relieving Acute Gastroenteritis, Food Poisoning, and Diarrhea Probiotics are an innovative, natural, and app arently safe A meta-analysis of 18 studies of acute-onset diarrhea in chil- adjunct to management options for IBD and other conditions that dren concluded that probiotic therapy shortened the duration of rely heavily on immunosuppressants and immunomodulating acute gastroenteritis by approximately one day.31.32 drugs, all of which have high toxicity profiles. In 1998, the Food and Drug Administration approved the use Probiotics also offer a significant treatment alternative to of PreemptTM (MS BioScience, Madison, Wisconsin), a probiotic antibiotics, to which many pathogens are becoming increasingly culture of 29 bacteria intended to prevent Salmonella contamina- resistant. While "[evidence] for the role of probiotics in the main- tion in chickens. Tests indicated that the product may be useful tenance of health or prevention of disease is mounting," con- against other bacteria that cause food poisoning, (e.g., Campy- sumers should still be wary of unsubstantiated health claims lobacter and Listeria).10 made for specific products.34 There is also some evidence suggesting probiotics' efficacy in Basic research will undoubtedly continue to elucidate the com- treating traveler's diarrhea and diarrhea related to pelvic radio- plex microbial ecology of the human gut and its role in the patho- therapy for uterine or cervical cancer. 30 genesis of such bowel diseases as IBD. Controlled clinical studiesneed to be conducted comparing probiotic strains to ascertain Addressing Chronic Constipation which strains might be optimal for treating specific disorders and Lactulose syrup has been successfully used to alleviate elderly to tailor probiotic therapy and dosages to individual patient patients' symptoms of chronic constipation. Unlike many other needs. Additional comparison of probiotics with more standard laxatives, this prebiotic product is not habit-forming, can be used therapies should also be pursued.
by patients with diabetes as it does not effect blood sugar levels, Probiotics represent a new role for diet in IBD in biomedicine, and produces minimal side-effects.33 akin to nutrition's central place in alternative and complemen-tary medicine. One physician-researcher stated: "Dietary modifi- Treating Helicobacter pylori infections L. Acidophilus has been demonstrated to inhibit the ulcer-caus- probiot ics, may em pow er patients. .a nd pr ov ide a simple ing H. pylori bacteria.3,30 method to achieve a greater sense of control in the managementof their illness."13 That role also raises the issue of whether probi- Inhibiting Colon Cancer otics are to be regulated as functional food s, dietary suppl e- Preliminary evidence from animal models of colitis suggests ments, or pharmaceutical drugs.2 that lactobacillus may inhibit the progression of colonic dysplasiato carcinoma.13 1. Gionchetti P, et al. Prophylaxis of pouchitis onset with probiotic thera-
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Madison Avenue, Larchmont, NY 10538-1961, (914) 834-3100.

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