Probiotics and Prebiotics | Probiotic | Gut Flora

Probiotics and Prebiotics: Effects on Diarrhea1,2

1. 2. Michael de Vrese3,* and Philippe R. Marteau4 +Author Affiliations 1. 3Institute of Physiology and Biochemistry of Nutrition, Federal Research Centre for Nutrition and Food, 24103 Kiel, Germany and 4Digestive Diseases, Hopital Lariboisière, 75010 Paris, France ↵*To whom correspondence should be addressed. E-mail:michael.devrese@bfel.de. Next Section

1.

Abstract
Probiotics have preventive as well as curative effects on several types of diarrhea of different etiologies. Prevention and therapy (or alleviation) of diarrhea have been successfully investigated for numerous dietary probiotics to establish probiotic properties and to justify health claims (the medicinal use of probiotic food and the therapy of gastrointestinal diseases itself may not be advertised under current food laws). Other probiotic microorganisms (e.g., Lactobacillus rhamnosus GG, L. reuteri, certain strains of L. casei, L. acidophilus, Escherichia coli strain Nissle 1917, and certain bifidobacteria and enterococci (Enterococcus faecium SF68) as well as the probiotic yeast Saccharomyces boulardii have been investigated with regard to their medicinal use, either as single strains or in mixed-culture probiotics. However, the effects on humans have been assessed mainly in smaller ( n < 100) randomized, controlled clinical studies or in open label trials, but large intervention studies and epidemiological investigations of long-term probiotic effects are largely missing. Perhaps with the exception of nosocomial diarrhea or antibioticassociated diarrhea, the results of these studies are not yet sufficient to give specific recommendations for the clinical use of probiotics in the treatment of diarrhea. Diarrhea (Greek διαρρoια = flowing through) means the increased liquidity or decreased consistency of stools usually associated with an increased frequency of stools and an increased fecal weight. The WHO defines diarrhea as 3 or more watery stools on 2 or more consecutive days. According to the main mechanisms involved, there are several types of diarrhea, which are summarized in Table 1, together with therapeutic measures.
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TABLE 1 Types of diarrhea and therapeutic measures

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Treatment of diarrhea by administering living or dried bacteria to restore a disturbed intestinal microflora has a long tradition. Interestingly, yogurt had originally been developed in Spain and introduced into the market as an inexpensive, easy to prepare, and easily available remedy against diarrhea in children and was sold in pharmacies. However, earlier reports on the successful use of Enterococcus faecium/faecalis, strains of Escherichia coli, or freshly isolated members of the patients' own intestinal microflora were mostly case reports and open studies rather than well-documented, randomized, double-blind, controlled clinical studies. But in the last 2 decades, investigations in probiotic microorganisms by in vitro studies, animal experiments, and appropriate well-designed clinical studies have put this “bacteriotherapy” on a more rational basis. Previous SectionNext Section Probiotics in prevention and treatment of diarrhea The use of probiotic microorganisms for the prevention or therapy of gastrointestinal disorders is an obvious measure and perhaps the most usual application of probiotics because most health effects attributed to them are related directly or indirectly (i.e., mediated by the immune system) to the gastrointestinal tract. The mechanisms and the efficacy of a probiotic effect often depend on interactions with the specific microflora of the host or immunocompetent cells of the intestinal mucosa. The gut (or its associated lymphoid system, GALT)5 is the largest immunologically competent organ in the body, and maturation and optimal development of the immune system after birth depend on the development and composition of the indigenous microflora and vice versa.

Many strains of probiotic microorganisms have been shown to inhibit growth and metabolic activity as well as the adhesion to intestinal cells of enteropathogenic bacteria (Salmonella, Shigella, enterotoxigenic E. coli, or Vibrio cholerae) (1–3) to modulate (temporarily) the intestinal microflora and to have immunostimulatory or -regulatory properties. Suggested mechanisms for the effects on the intestinal microflora are lowering the intestinal pH, the production of bactericidal substances such as organic acids (lactic, acetic, butyric acid) (4), H2O2 and bacteriocines, agglutination of pathogenic microorganisms, adherence to the cellular surface of the mucosa, and competition for fermentable substrates or receptors, strengthening the barrier effect of the intestinal mucosa (5,6), release of gut-protective metabolites (arginine, glutamine, shortchain fatty acids, conjugated linoleic acids), binding and metabolism of toxic metabolites (7–11), immunologic mechanisms (12,13), or regulation of the intestinal motility (14) and mucus production (15). In human and animal experiments, bacterial counts in stool samples and in samples from the small bowel taken from ileostomized patients, have been altered by probiotics. All these methods, however, have drawbacks and only indirectly reflect the real situation in the gastrointestinal tract and its microflora. The interactions between probiotic microrganisms and the GALT or the respective mucosal receptors and signaling pathways as well as the mechanisms of immunomodulation and antiinflammatory probiotic effects are not yet fully understood, but the use of modern techniques such as molecular biology lead to a rapidly growing knowledge of the relations among probiotics, the immune system, and health. Preventive or curative effects of probiotic microorganisms with evidence of the effects on the gastrointestinal microflora and antibacterial, immunostimulatory, and antiinflammatory properties have been investigated in diarrhea caused by (primary) lactose intolerance; acute diarrhea from viral and/or bacterial infections, e.g., nosocomial rotavirus infections in children, gastrointestinal infections in children in day-care centers, and travelers' diarrhea; antibiotic-associated diarrhea (AAD); Clostridium difficile gastroenteritis; diarrhea in tube-fed patients; chemo- or radiotherapy-induced diarrhea; inflammatory bowel diseases (Crohn's disease, ulcerative colitis, pouchitis); small bowel bacterial overgrowth; and irritable bowel syndrome (IBS) with diarrhea. Reduced diarrhea and other gastrointestinal symptoms in lactose intolerance The most thoroughly investigated health effect of fermented milk products is the enhancement of lactose digestion and the avoidance of intolerance symptoms in lactose malabsorbers, that is, in persons with insufficient activity of the lactose-cleaving enzyme β-galactosidase in the small intestine. This effect is based mainly on the fact that fermented milk products with living bacteria contain microbial β-galactosidase that survives the passage through the stomach to be finally liberated in the small intestine and to support lactose hydrolysis there (16). However, depending on the definition of “probiotic,” this is not a specific probiotic effect because it does not depend on su rvival of the bacteria in the small intestine. Yogurt is usually more effective (17,18), and, last but not least, primary or adult-type hypolactasia (the reason for lactose malabsorption) is not a disease but actually the normal physiological state. Many probiotic bacteria show either a lower β-galactosidase activity or, because of their high resistance against acid and bile salts, do not release their enzymes in the small intestine (16). There is no strong correlation, however, between lactose malabsorption and the occurrence of intolerance symptoms such as flatulence, bloating, abdominal cramping and pain, or diarrhea in any case. Many persons with alleged nonallergenic milk intolerance can digest lactose, and some truely maldigesting persons live without symptoms of intolerance. Thus, it may be imagined that probiotic bacteria do not significantly improve lactose digestion in the small intestine but rather avoid symptoms of intolerance directly in the large intestine (16,19). The latter effect depends on the specific strain, concentration, and preparation of the probiotic as well as on the subject's susceptibility to gas and osmotic pressure or, for unknown reasons, the individual responsiveness to probiotics (20). In conclusion, probiotics promote lactose digestion in lactose malabsorbers no better than conventional yogurt. No independent reduction of diarrhea and other gastrointestinal complaints in lactose intolerance has yet been definitely proven. Prevention or alleviation of acute diarrhea caused by viral or bacterial infection Acute diarrhea from viral (mostly rotaviruses) or bacterial infection is still a major health problem worldwide and a frequent cause of death, especially in hospitalized children and in developing countries. But infectious diarrhea is not only a problem of developing countries. Up to 30% of the population in developed countries are affected by food-borne bacterial diarrheas each year. Protection by probiotic bacteria and yeasts with immunostimulatory properties or the alleviation of symptoms and shortening of acute infections are perhaps the best-documented probiotic effects, and these have been demonstrated many times in the past in clinical studies fulfilling scientific requirements. Beneficial effects such as decreased frequency of infections, shortening of the duration of episodes by 1–1.5 d, decreased shedding of rotaviruses or promotion of systemic or local immune response, and an increase in the production of rotavirus-specific antibodies have been demonstrated for a number of food (Lactobacillus rhamnosus GG, L. casei Shirota, L. reuteri, L. acidophilus spec., Bifidobacterium animalis ssp. lactis BB-12, and others) (21–31) and nonfood probiotics (E. coli,Enterococcus faecium SF68, Saccharomyces boulardii) (32–34). In numerous studies probiotics

1 of the most successful probiotics altogether. of acute diarrhea among adults (−26%). This is in accordance with a recent review (58) that states that therapeutic effects of probiotics in children with acute diarrhea seem to be 1) moderate. casei–containing fermented milk (daily for 2 mo). casei (n = 254) compared with yogurt without probiotics (n = 275) (45). bulgaricus.37/0. Yet. respectively. Investigations of the effect of probiotic bacteria on traveler's diarrhea in the past showed inconsistent results (46) because of differences between probiotic strains. CRL438. others found no such effect (50). rhamnosus GG (LGG) or a placebo to 204 malnourished children in Peru (6–24 mo old) was associated with a significantly lower incidence of diarrhea in the treated compared with the placebo group (5. the traveled countries. In other clinical trials in infants.9 ± 6.. the nature of the causative pathogens was not examined in these studies. 2) strain. controlled multicenter clinical trial in a total of 928 children (6–24 mo).2%) and duration (from 3.0 down to 2. reuteri group (43). acidophilus. Whereas some studies revealed fewer or shorter episodes of diarrhea in subjects consuming the probiotic (47–49). controlled French study. and the probiotic product brought it down to 4. When healthy term infants (4–10 mo) from child-care centers in Israel were fed milk formulas containing no bacteria (controls. diarrhea frequency (from 16. Malnourished children or children attending child-care centers are exposed to a higher risk of gastrointestinal and respiratory tract infections (38). reuteri. For reviews see Fonden et al.1% down to 12.02 and 0.13 vs. or both viral and bacterial infections were diagnosed in the cohort studied.were administered as nonfood preparations. reuteri and BB12 groups compared with controls (mean values 0. All microorganisms tested ( Saccharomyces boulardii. Clearly fewer studies show preventive effects of probiotics on diarrhea and other gastrointestinal complaints in healthy adults. However. caseispec. It was therefore concluded that the therapeutic efficacy of probiotic microorganisms is not sufficient in cases of severe infectious diarrhea or that probiotics display their therapeutic effect too slowly. Finnish children from day-care centers who consumed milk containing a probiotic L.2 vs. rhamnosus strain during the winter had 16% fewer days of absence from day care because of diarrhea and gastrointestinal and respiratory tract infections then controls (42).7 or 1 d (53. abdominal pain. In a prospective. a lower frequency of diarrhea was observed compared with the administration of conventional yogurt (15. The analysis of 9 or 18.15/0. the incidence of diarrhea was not different between groups (40).0 mo) in day-care nurseries were administered daily either unfermented jellied milk. or LA5 plus BB12 plus S. bloating. eating habits of the travelers. or a probiotic yogurt product containing 108 cfu/mL L. (9). The data suggested a significant reduction of the risk of acute diarrhea among children (−57%). However. During administration of L.3 d (P < 0. e. which may be reduced by the consumption of probiotic milk products or milk formulas supplemented with probiotic bacteria. each month being followed by 1 mo without supplementation.9 vs. rhamnosus GG. and other strains) showed similar effects. n = 60) or 107 cfu/g formula powder of B. The conventional yogurt brought the mean duration of diarrhea from 8. respectively.0 d down to 5 d. eligible randomized. Altogether there is evidence that some probiotic strains are efficacious in preventing infectious diarrhea in healthy subjects. it has been been published that strains of L. controlled. reuteri SD2112 (n = 68). A reduction in febrile days or in days with respiratory illness was observed only in the L. lactis Bb12) and 3) dose-dependent. a significant reduction in episodes of diarrhea was observed in the L. lactis BB12 (n = 73) or L. over 2 winter and 2 summer periods.6 d) was nonsignificantly decreased following consumption of probiotic yogurt containing L.0 episodes per child per year) (39). conventional yogurt. de Roos and Katan (36). delbrückii ssp. 22%. randomized. and of acute diarrhea of various causes (−34%). blind studies on acute diarrhea in otherwise healthy infants showed a mean reduction in the duration of episodes by 0. L. in a study in Israeli soldiers. Prevention of infectious diarrhea in healthy children and adults In large part. the local microflora. This was confirmed by a recent meta-analysis of the available data from 34 randomized placebo-controlled trials evaluating the efficacy of selected strains of probiotic bacteria in different types of acute diarrhea (51).05) (41). L. 6. occasional episodes of diarrhea.(LGG. rhamnosus were effective only in the treatment of rotavirus-induced diarrhea in children but not in the treatment of diarrhea of other etiology (55). as clinically utilized probiotica are also called) (52) were performed in young children. as a powder or suspended in oral rehydration solutions (35). L.. (37). studies demonstrating positive effects on the prevention and alleviation of infectious diarrhea in healthy human populations have been performed in infants and children. This study was expanded to a randomized. of travellers' diarrhea (−8%). 287 children (18. Administration of L.31). as a capsule or a fermented milk product) of administering the probiotic.59/0.e. or Marteau et al. Young children may be particularly responsive to probiotics because of the immaturity of their immune system and the greater simplicity of their intestinal microflora compared with that of adults.6 stools on d 2 of treatment (53) in the groups receiving probiotics (mainly lactobacilli). was ineffective in nosocomial rotavirus infections (56) and in severe dehydrating diarrhea (57). Administration of fermented milk products containing between 5 × 10 5 and 107 cfu/g LGG.01). LGG.g. 0. Many of them suffered from nosocomial rotavirus infections.54) and a reduction in stool frequency of 1. L. Treatment of infectious diarrhea using probiotics The majority of successful treatments of infectious diarrhea by probiotic microorganisms (or biotherapeutic agents. Each product was given over 1 mo. or time point (before or during travel) and means (i. alone or used in combination. 4) more evident when probiotics are . B. and flatulence compared with chemically acidified milk without bacteria (37. P < 0. thermophilus to healthy adults (20–65 y old) significantly reduced severity and frequency of mild.44).

Administration of LGG.(80) or radiotherapy (81. pylori eradication therapy led to significantly fewer episodes of diarrhea compared with the placebo group (7 vs. and omeprazol (triple therapy) is a rather mild therapy and leads to diarrheas in only ∼10–20% of cases. difficile– associated diarrhea. Therefore. Although administration of S.g. Antibiotic-associated diarrhea (AAD) is a common clinical problem. strains of L. and 5) significant only in watery diarrhea and viral gastroenteritis but not in invasive bacterial diarrhea. difficile infections. Administration of fermented milk containing 107–108 per day B.71). acidophilus 4 wk before and during a H.5 h and appear to be useful adjuncts to rehydration therapy in the treatment of acute infectious diarrhea (59). at the moment there is not enough evidence from clinical trials to recommend the use of probiotics in the prevention of diarrhea in tube-fed patients. occurring in 25 –30% of patients with 25% of cases caused by C. Side effects were ameliorated by the administration of probiotic bacteria before and during chemo. difficile–associated diarrhea. Clearly fewer randomized controlled trials have been performed in healthy adults. Prevention and treatment of AAD is a frequently used model to test the effectiveness of (potential) food probiotics and the justification of health claims. boulardii during H.bulgaricus had no effect on the frequency or incidence of diarrhea in subjects who were tube-fed <5 d (79). Clostridium difficile) often lead to diarrhea and symptoms related to toxin production. Application of probiotics also significantly decreased the number of relapses after successful treatment of Clostridium difficile infections (72). Bb12. The reasons for this are manifold. and for very severe (dehydrating) diarrhea was less successful. acidophilus) and multiple-strain probiotics (Lactinex. Careful reviews of the literature (74–77) support an efficacy of L. Also. . Whether regular consumption of probiotics exerts beneficial effects in HIV patients has not been studied up to now. S. but it has been shown that probiotic products are well tolerated by these patients (83). pylori eradication did reduce AAD from 11. pylori eradication. In particular. Diarrhea in immunocompromised subjects Chemo. delbrückii ssp.. amoxicillin. results of randomized controlled clinical studies are too conflicting to give specific recommendations for the clinical use of probiotics. placebocontrolled study (78). particularly LGG. In conclusion. Diarrhea in tube-fed patients Diarrhea is a frequent complication in enteral tube feeding.5 to 6. Clostridium difficile infections or relapses). reuteri andL. The use of dietary or medicinal probiotics against other pathogens. boulardii may be effective as an adjunct in the treatment of C.82). in children in Third-World –countries. In conclusion. boulardii did reduce the frequency of diarrhea in critically ill tubefed patients from 20% of enteral feeding days in the placebo to 14% in the treated group (P < 0. In conclusion. acidophilus plus L. animalis ssp. a mixed-strain preparation of L. Of higher importance is the testing of possible clinical applications of selected probiotic microorganisms (LGG.9% of patients (70). S. SF68. although results of a few studies indicate that probiotics can be effective in the prevention of radiation-induced diarrhea. in adults. and other probiotic strains before and during antibiotic treatment reduced the frequency and/or duration of episodes and the severity of symptoms in many cases (60–68) but was not always effective (69). whereas S. toward (nosocomial) rotavirus infections in children are relatively well supported. Alleviation or prevention of diarrhea caused by antibiotic treatment Disturbance or destruction of the indigenous microflora caused by antibiotic treatment as well as a subsequent excessive growth of normally harmless bacteria (e.applied early in the episode. VSL#3) to reduce use of antibiotics for prevention or treatment of undesirable side effects (diarrhea. boulardii is not effective or only moderately effective in the prevention of AAD but more efficacious in prevention and treatment of C. none of the probiotics examined can be recommended without any reservation.and radiotherapy frequently cause severe disturbances of the immune system and the indigenous intestinal microflora accompanied by diarrhea and/or increased cell counts of the mold Candida albicans in the gastrointestinal tract and other organs. there seems to be a potential role for probiotics in prevention of AAD. with respect to the prophylaxis of traveler's diarrhea. but the effectiveness of probiotics has been little studied to date. rhamnosus GG and mixed-strain probiotics in prevention and treatment of AAD in children and adults but not in the treatment of C. Coadministration of S. the preventive and curative effects of certain dietary probiotics.Saccharomyces boulardii. Eradication of the gastric pathogen Helicobacter pylori using clarithromycin. at the moment. The same is true for diarrheas during triple therapy for H. there is not enough evidence from clinical trials to recommend the prophylactic or therapeutic use of probiotics in immunocompromised subjects. A meta-analysis of 23 randomized controlled studies in adults and children with a total of 1917 subjects came to the conclusion that probiotics reduce the mean duration of diarrheal episodes by 30. difficile. particularly because of contradictory study results related to the diversity of travel destinations and to the locale-specific pathogens. boulardii.01) in a randomized. In conclusion. but the analysis of other trials yielded no clear-cut results because of inconsistent data and the heterogeneity in study design and choice of probiotics (73).lactis and L. 22% of the subjects) (44.

diverticulitis. extented gastrointestinal transit time. most frequently.g. and prevent diarrhea (121). although mainly in preliminary studies (98). improvement of gut barrier function (91). partly life-threatening concentrations of D-lactic acid and toxic metabolites of the bacterial protein metabolism. or a mixed culture preparation containing 4 strains of lactobacilli. e. casei to patients with small bowel bacterial overgrowth. Patients with inflammatory bowel diseases (Crohn's disease. or Lactococcus lactis to prevent or treat colitis (84–88). Effects of prebiotics Prebiotics were originally defined by Gibson and Roberfroid (117) as “nondigestible food ingredients that beneficially affect the host by selectively stimulating the growth and/or activity of 1 or a limited number of bacteria in the colon. In other studies LGG and other probiotics failed to induce or maintain remission and did not extend the time to a new relapse in Crohn's disease (99–102). bifidobacteria. produced by partial hydrolysis of inulin or synthetically from the monomers. and other methodological inadequacies. both in the composition and/or activity in the gastrointestinal microflora that confer benefits upon host wellbeing and health. bifidum increased the growth of bifidobacteria but inhibited human pathogenic strains . In conclusion. ulcerative colitis. Investigations in other candidate prebiotics to date did not yield enough meaningful information to make conclusive assessments. poor compliance. and bifidogenic and pH-lowering effects (119. Therefore. or inflammation of an ileal pouch after colectomy) also showed a positive response to probiotics such as LGG. were administered. targets for probiotic effects. especially Clostridium. By this last effect prebiotics inhibit certain strains of potentially pathogenic bacteria. increased immune response (90). and Streptococcus thermophilus (VSL#3). 120). In conclusion. acidophilus and L.” According to these authors. E. accumulating evidence from randomized. infantis spec. in this issue. Irritable bowel syndrome The irritable colon is a functional disorder of the colon without provable biochemical or structural irregularity and is characterized by intermittent abdominal pain and an alternating succession of diarrhea and obstipation. necrotizing enterocolitis. A symbiotic combination of inulin plus oligofructose with L. Other studies failed to confirm significant effects on stool frequency or consistency (111–113). decreased frequency of diarrheas (104) following administration of L. placebo-controlled study on 362 primary-care female patients with IBS showed an improvement in bowel dysfunction and other symptoms only if 10 8cfu of the freeze-dried probiotic bacteria B. In conclusion. However. Beneficial effects were a decreased expression of inflammatory markers ex vivo (89).Inflammatory bowel diseases Although their exact causes are not yet fully understood. and the alleviation of functional diarrhea were found (105–109). a randomized. coliNissle 1917. maintenance of remission (92–96). The main characteristics of a prebiotic are resistance to digestive enzymes in the human gut but fermentability by the colonic microflora. because of small numbers of patients. Small bowel bacterial overgrowth Certain circumstances such as insufficient production of gastric acid (anacidity). Extensive investigations have been performed on the effect of nonfood probiotics. and a lower drug consumption (92. so further investigations are required to advance from hopeful findings to conclusive results (114–116). particularly nonpathogenic strains of Escherichia coli. in the development of inflammatory bowel diseases are needed. plantarumplus B. Studies in experimental animals give a clue about the potential application of lactobacilli. less motility disorder. This is discussed in greater detail in the article by Sheil et al. a mixed strain preparation of lactobacilli plus bifidobacteria was effective in ulcerative colitis and pouchitis. but relatively small clinical studies suggests the potential of probiotics for inducing or maintaining remission in inflammatory bowel diseases. this issue) as “selectively fermented ingredients that allow specific changes. Only a few successful approaches to normalizing the small intestinal microflora have been reported (103). and 2) (trans)galactooligosaccharides. the few reported clinical trials are not yet sufficient to recommend the use of probiotics in the treatment of small bowel bacterial overgrowth. disturbances of the autochthonous intestinal microflora and the stimulation of proinflammatory immunological mechanisms seem to play a role in a number of inflammatory diseases of the intestine. Although in some trials a positive modulation of the intestinal flora.97). resection of the small intestine. further investigations and a deeper insight into the role of the autochthonal microflora and the host immmune system. or.. and thus improve host health. 3 strains of bifidobacteria. and cert ain oligosaccharides). but not at any other dosage level (110). lactulose. In particular. only 2 indigestible oligosaccharides fulfill the criteria for prebiotic classification to date: 1) inulin and inulin-type fructans. They have been redefined by the same group (118. numerous efforts have been undertaken to improve the health and well-being of affected patients by the administration of probiotics with antiinflammatory properties and a proven positive impact on the intestinal flora. All in all fewer symptoms and a higher quality of life of children and adult patients were observed. Reports on effects of probiotics in this disorder are still rather contradictory.” and this criterion is fulfilled only by some indigestible but fermentable carbohydrates (inulin. controlled. currently there is not enough evidence from clinical trials to recommend the routine use of certain probiotic strains in the treatment of IBS. terminal renal failure can lead to an excessive growth of single bacterial strains in the small intestine and to increased.

and Salmonella enteritidis in vitro more than any other carbohydrate tested (122). the combination oftrans-galactooligosaccharides plus bifidobacteria did protect mice against lethal infections with Salmonella enterica serovar typhimurium (123). there is not enough evidence to medically recommend prebiotics for the prevention or treatment of diarrhea.05) were found in the stool. or in cases of a maladapted intestinal flora. or diarrhea. And 10 g/d oligofructose (given 2 wk before and during a 2-wk journey) was only moderately successful in preventing traveler's diarrhea. there was no report of a successful preventive or therapeutic use of prebiotics in patients with diarrhea and/or inflammatory diseases of the gut. Significantly fewer episodes of flatulence (4 vs. partially hydrolyzed guar gum. Bifidobacterium spp. vomiting (0 vs. IBS patients. and fever (5 vs. and AAD in children (135). oligofructose.. Galactooligosaccharides. and despite some promising results of animal experiments. which can sometimes be observed when therapeutic doses of prebiotics are administered to particularly sensitive subjects. in the oligofructose compared with the placebo group (0 vs. E. paracasei strain and oligofructose increased counts ofLactobacillus spp. Inulin and oligofructose (125) or prebiotic treatment with germinated barley foodstuff (126) had beneficial effects on experimental colitis and the composition of the intestinal microflora of rats. on the other hand.of Campylobacter jejuni. decreasing colonization and invasion by pathogenic organisms. reducing the percentage of subjects with diarrhea attacks to 11% compared with 20% in the placebo group ( P = 0. In other studies a prebiotic effect on diarrhea was less clear. pain. and are regulated as dietary supplements and foods. 3 children and 0 vs. compared with the control group (124). uses. Other clinical studies failed to show a significant reduction of diarrhea in IBS (133). Despite the promising results of animal experiments. and total aerobes in the feces of weanling piglets significantly more than a pure L. improved symptoms in constipation-predominant and in diarrhea-predominant IBS (129). Probiotic . and contraindications of probiotics are reviewed. Probiotics are live nonpathogenic microorganisms administered to improve microbial balance. Summary. P < 0. failed to attenuate inflammation in experimental colitis in rats (127). and fewer diarrheal episodes were observed. the bifidogenic effect of prebiotics may be suppressed by the antibiotic. safety. coli. 13) were observed in the oligofructose group as well (128). The pharmacology. despite established positive effects of inulin. In AAD. greater numbers of bifidobacteria (NS) and lower numbers of clostridia ( P < 0. total anaerobes. Similarly. but the same amount of oligofructose failed to protect elderly subjects receiving broad-spectrum antibiotics from AAD (development of diarrhea in 56 of 215 in the oligofructose and in 60 of 220 patients in the placebo group) (131). dosages. water-soluble. compared with 34% in controls (P < 0001) (130). nongelling fiber.08) (132). a bifidogenic. A symbiotic composed of a probiotic L. such as Lactobacillus andBifidobacterium species. Furthermore. This is possibly a result of side effects such as gas. They consist of Saccharomyces boulardiiyeast or lactic acid bacteria. plantarum preparation and significantly decreased fecal concentrations of Clostridium spp. American Journal of Health-System Pharmacy Probiotics Abstract and Introduction Abstract Purpose. andEnterobacterium spp.05). Coadministration of 12 g/d oligofructose during antibiotic therapy reduced the occurrence of relapses of successfully treated C. and galactooligosaccharides on the intestinal microflora.. However. borborygmus. and modifying the host immune response. 27). infantile infectious diarrhea (134). 10). 13 episodes. when small amounts (2 g/d) of oligofructose or a placebo (maltodextrin) were administered over 4 wk to 35 healthy infants (aged 6–24 mo). difficile–associated diarrhea to 8%. particularly in the gastrointestinal tract. including lowering intestinal pH. Fewer children were afflicted with diarrhea. drug interactions. In conclusion. Probiotics exert their beneficial effects through various mechanisms.

Probiotics have demonstrated efficacy in preventing and treating various medical conditions. irritable bowel syndrome. travelers' diarrhea. Increasing clinical evidence supports some of the proposed health benefits related to the use of probiotics."[1]The term probiotic was initially used in the 1960s and comes from a Greek word meaning "for life. Table 1 lists common microorganisms used as probiotics. Bacteria-derived probiotics should be separated from antibiotics by at least two hours. Introduction In recent years.benefits associated with one species or strain do not necessarily hold true for others. They are available as capsules. and pouchitis. Probiotics are generally considered safe and well tolerated. with bloating and flatulence occurring most frequently. ulcerative colitis. tablets. The most widely . Probiotic products may contain a single microorganism or a mixture of several species. consist of yeast or bacteria. it was not until the early 20th century that investigators suggested gut flora could be altered with beneficial bacteria replacing harmful microbes. most commonly due to rotavirus. most commonly yogurt or dairy drinks. which are regulated as dietary supplements and foods. Data supporting their role in other conditions are often conflicting. the beneficial effects of certain foods containing live bacteria have been recognized for centuries. or powders and are contained in various fermented foods. There is no consensus about the minimum number of microorganisms that must be ingested to obtain a beneficial effect. Crohn's disease. Clostridium difficileinfection. Probiotics are defined as "live microorganisms which when administered in adequate amounts confer a health benefit on the host. However. They should be used cautiously in patients who are critically ill or severely immunocompromised or those with central venous catheters since systemic infections may rarely occur. particularly in managing certain diarrheal diseases. both research and consumer interest in probiotics have grown. however. packets.[2–4] Probiotics. More research is needed to clarify the role of probiotics for preventing antibioticassociated diarrhea. particularly those involving the gastrointestinal tract. leading to the concept of probiotics. a probiotic should typically contain several billion microorganisms to increase the chance that adequate gut colonization will occur. The strongest evidence for the clinical effectiveness of probiotics has been in the treatment of acute diarrhea. and vulvovaginal candidiasis." Although a relatively new word. Conclusion.

so a health benefit attributed to one strain is not necessarily applicable to another strain.12. Furthermore. The strongest evidence for . Probiotic organisms must be able to withstand passage through the gastrointestinal tract (i. mainly due to their ability to restore gut flora. specifically Lactobacillus and Bifidobacterium species. The yeastSaccharomyces boulardii also appears to have health benefits. colonize and reproduce in the gut. attach and adhere to the intestinal epithelium.9] The rationale for using probiotics involves restoring microbial balance. survive acid and bile degradation). they must possess certain characteristics.13] Illnesses associated with the gastrointestinal tract have been a common target of probiotics. An appropriate balance of gut flora is generally maintained. Uses Probiotics have been used for the prevention and treatment of various medical conditions and to support general wellness. Some of their beneficial health effects have been validated.[5–7] In order for probiotics to be successful. and not have pathogenic properties. immunosuppressive medications. and greater benefits may be seen with one lot of probiotics versus another due to the complexity of quality control with live microorganisms. while other uses are supported by limited evidence.6. and irradiation can cause an increase in the pathogenic bacteria and disrupt this homeostasis.8] Some microbes are considered beneficial to the human host.8. Probiotics. may restore the microbial balance in the gastrointestinal tract. and stabilize the balance of the gut flora. Not only are probiotic effects strain specific. Furthermore.9– 11] Products containing more than one organism are particularly appealing for two reasons: colonization in some patients may occur with one strain and not another.[2. surgery. combination agents can make it challenging to quantify particular clinical benefits.. which contain beneficial bacteria and yeast. Therefore. generalizations about potential health benefits should not be made. It is noteworthy that probiotic effects tend to be specific to a particular strain. while others are pathogenic. More than 500 different bacterial species reside in the adult gastrointestinal tract. remain viable for the shelf life of the product. antibiotics.[2.e.[2.5. and probiotic mixtures may be synergistic in suppressing pathogens. probiotic strains must be safe and effective in humans. probiotic products may vary from each other.used probiotics include lactic acid bacteria. even within one species. however. [6.

bacteriocins.[2..15] Probiotics have also been studied for their role in treating upper respiratory infections (e. may also respond to probiotics. and Pseudomonas aeruginosa to uroepithelial cells and . difficile toxins A and B.7] Another mechanism of bacterial interference involves the production of various substances. allergic diseases. and atopy. and biosurfactants. ulcerative colitis (UC). bacterial vaginosis. Klebsiella pneumoniae.g. especially rotaviral diarrhea in children.[6.the use of probiotics lies in the treatment of certain diarrheal diseases.[2.. As mentioned previously.[11. irritable bowel syndrome (IBS).g.14] One probiotic with this ability is Lactobacillus species strain GG. and anaerobic bacteria. particularly Lactobacillus and Bifidobacterium species. boosting immune response. These bacteria produce lactic acid. Clinical studies have also supported the role of probiotics in treating pouchitis.[14] Lactobacilli have been shown to inhibit the attachment of Escherichia coli. including various urogenital problems (e. a nonpathogenic yeast. and propionic acid. which lower the intestinal pH and suppress the growth of various pathogenic bacteria. thereby reestablishing the balance of the gut flora. the most frequently used probiotics include lactic acid bacteria.15] Probiotics have also been shown to decrease the symptoms of lactose intolerance.14. may have a role in Clostridium difficileinfection by producing a protease that decreases the toxicity ofC. gram-negative. S. that are toxic to pathogenic microorganisms.8. and preventing dental caries Pharmacology Although the exact mechanisms of action of probiotics are not known. reducing the risk of colon and bladder cancer.6. candidal vaginitis. urinary tract infections).[7. probiotic therapy may also be beneficial in the treatment of Crohn's disease.[2.8.8]Although clinical trial results are conflicting. which has been shown to secrete a low-molecular-weight compound that inhibits a broad spectrum of gram-positive.[20] Probiotics also decrease colonization of pathogenic organisms in the urinary and intestinal tracts by competitively blocking their adhesion to the epithelium. acetic acid.9] Data are inconsistent regarding the efficacy of probiotics for antibiotic-associated diarrhea (AAD) and travelers' diarrhea. acute otitis media). such as hydrogen peroxide. organic acids.15–17] Other illnesses not associated with the gastrointestinal tract or gut microbiota. andHelicobacter pylori infections. several have been proposed.8.10.[19] In addition. boulardii.[5.

and immunoglobulin M response. resulting in a shortened duration of gastroenteritis symptoms. The probiotics most frequently studied for treating acute diarrhea include LGG and Lactobacillus reuteri. duration of diarrhea (58. .2 hours versus 96. Hepatology.03) and a shorter hospital stay (78. [3.[21..7% of those receiving placebo. most commonly due to rotavirus or an unknown pathogen.9. patients treated with LGG were less likely to have persistent diarrhea (i. p = 0.01).18] Kaila et al.24] This article focuses on the more-common uses of probiotics Acute Diarrhea There is convincing evidence from multiple studies supporting the efficacy of probiotics in the treatment of acute diarrhea.8 ± 22. While some of these indications are well documented. probiotics are often used to treat conditions for which data regarding the efficacy of probiotics are lacking or conflicting.3 ± 21.[7] Another proposed mechanism of action of probiotics involves immunomodulation. In addition.6 hours versus 71.9 ± 35. In addition. Patients who were given LGG versus placebo had a shorter mean ±S. lactobacilli strengthen the gut mucosal barrier by stabilizing tight junctions between epithelial cells and decreasing intestinal permeability.15.intestinal epithelial cells.7% versus 10.17] The European Society for Pediatric Gastroenterology.[23] found that children with acute rotaviral diarrhea who were given Lactobacillus rhamnosus strain GG (LGG) had an increased IgA.e.[15. multicenter study involving 287 children age 1–36 months from 10 countries who were admitted to the hospital with moderate-to-severe diarrhea. and Nutrition conducted a double-blind. p = 0.D.3 ± 27. which are high-molecular-weight glycoproteins produced by epithelial cells. the result is the formation of a protective barrier. Animal studies have found that some probiotic strains augment the immune response by stimulating the phagocytic activity of lymphocytes and macrophages. immunoglobulin G.8 hours.[25]The patients were randomized to receive oral re-hydration solution plus placebo or oral rehydration solution plus a live preparation of LGG. Numerous health effects are associated with probiotic use.4 hours.[2.04). diarrhea lasting longer than seven days) (2.22] This inhibition may occur because lactobacilli cause steric hindrance and upregulate intestinal mucins. placebocontrolled. p< 0.[18] Probiotics also increase immunoglobulin A (IgA) and stimulate cytokine production by mononuclear cells.7. especially in children with rotavirus infection.

children who were given LGG or the probiotic mixture also had a significantly lower daily stool output compared with the other groups ( p < 0.001). boulardii. revealed a combined relative risk (RR) of 0.29] The first meta-analysis.5.5 hours). andBifidobacterium bifidum)—were associated with a significantly shorter median duration of diarrhea (78. Difficile Infection There is evidence that probiotics can prevent AAD and treat C. The other three preparations (S. which were prescribed for five days. controlled trials that measured diarrhea duration and the frequency of diarrheal stools on the second day of treatment. In their study. which examined 7 trials (n = 881).57) in favor of a beneficial effect of probiotics for reducing the risk of AAD.[26] conducted a meta-analysis of nine clinical trials (n = 765) involving children younger than three years with acute infectious diarrhea who received Lactobacillus species.14.[5] Two meta-analyses of studies examining the use of probiotics to prevent AAD suggested that concurrent administration of probiotics (most commonly lactobacilli and S. The studies examined were randomized. 571 children age 3 –36 months with acute diarrhea were randomized to one of six different treatment groups: oral rehydration solution alone (control group) or one of five probiotic preparations. AAD and C. Bacillus clausii. however.3–1.13. most frequently LGG. 0. respectively. data are conflicting or inconclusive.Streptococcus thermophilus.[28] The other meta-analysis yielded a . The meta-analysis revealed a reduced mean duration of diarrhea by 0.6 stools per day on day 2 of treatment (95% CI.17] The most common probiotic microorganisms used for these diseases include lactobacilli and S.001) compared with children who received oral rehydration solution alone (115. Only two preparations —LGG and a mixture of four bacterial strains (Lactobacillus delbrueckii var bulgaricus. and Enterococcus faecium SF 68) did not significantly affect the duration and severity of diarrhea.3966 (95% CI.7–2. 0.2 days) and a decrease in diarrhea frequency by a mean of 1. p < 0. difficile infection (CDI). Lactobacillus acidophilus.[27] illustrated this point and emphasized that the particular probiotic preparation should be chosen based on solid efficacy data. blinded.27–0.[28. Canani et al. 0.7 day (95% confidence interval [CI].Van Niel et al. All probiotics are not equally effective in treating acute diarrhea in children.[2. One day after initiation of probiotics. boulardii. boulardii) with antibiotics resulted in a reduced frequency of diarrhea.6 fewer stools) in children who received probiotics.5 and 70 hours.

9%. difficile colonization in 44 critically ill patients receiving antibiotics was significantly reduced by enteral administration of L.[33] While results have been inconsistent. However.[31] It is important to note that this study was stopped prematurely due to the low rate of enrollment and reduced funding. possibly due to the probiotic strain used and the various trip destinations. some studies have indicated that probiotics. were not effective in decreasing CDI recurrence rates.[32] A Cochrane Library review also concluded that there was inadequate evidence to support the adjunctive use of probiotics for CDI.[29] A third meta-analysis reviewed 25 randomized controlled trials (n = 2810) examining the use of probiotics for the prevention of AAD and 6 randomized controlled trials (n = 354) of probiotic therapy for the treatment or prevention of CDI. supporting probiotic treatment over placebo in the prevention of AAD. On the other hand. In contrast to the previous studies that found that probiotics reduced the rate of CDI. and various mixtures of two probiotic strains significantly reduced the frequency of AAD. compared with 7.001) for pooled data from all 9 trials (n = 1214). boulardii in combination with oral vancomycin or metronidazole or both significantly decreased the recurrence of CDI.53.8]Hilton et al. 0. a recent study found that the rate of C. In contrast. the most commonly studied probiotics for travelers' diarrhea include lactobacilli and S.26–0.[34] randomized 245 American tourists traveling to various developing countries to receive LGG or placebo. boulardii. Those travelers who ingested LGG had a mean daily risk of developing diarrhea of 3.4% for travelers taking placebo ( p = 0. boulardii. difficile overgrowth and decrease CDI recurrence. only S.37 (95% CI. McFarland[36] conducted a . plantarum 299v (p < 0. a systematic review of 8 randomized controlled trials did not find sufficient evidence for routine probiotic use in CDI. [30] The metaanalysis revealed that LGG.combined odds ratio of 0.05). Similar to AAD and CDI. especially S. S.[5. p < 0. Other probiotics tested.05). acidophilus or Lactobacillus fermentumstrain KLD did not reduce the frequency of diarrhea among 282 British soldiers deployed to Belize. Travelers' Diarrhea Results of studies evaluating the effectiveness of probiotics for preventing travelers' diarrhea have been inconsistent. Katelaris et al.[35] found that ingestion of L. may prevent C. including LGG andLactobacillus plantarum 299v in combination with oral vancomycin or metronidazole. boulardii.

causing increased fermentation activities and gas production. andBifidobacterium breve). stool frequency) or the effectiveness of specific probiotic strains due to insufficient data. limitations exist in interpreting trial results due to the lack of standardization of strains. and S.[12. boulardii (4 studies).77. MD) has reduced abdominal bloating and flatulence.[38] This meta-analysis was not able to examine other types of individual IBS symptoms (e..78. however.38] Inflammatory Bowel Disease . Bifidobacterium infantis. bloating. VSL Pharmaceuticals. These symptoms may be due to bacterial overgrowth in the small intestine. p < 0.[34. A review of 14 clinical trials also revealed that probiotics (most commonly lactobacilli.35] on the role of probiotics in the prevention of travelers' diarrhea.001).. dosages. a combination product (VSL#3.69– 0.g. IBS IBS is characterized by abdominal pain. L. The types of probiotics in the meta-analysis included S. and L. The probiotics used most frequently in the treatment of IBS include lactobacilli and bifidobacteria. The meta-analysis revealed that probiotics significantly prevented travelers' diarrhea (pooled relative risk [RRpooled]. Towson. 95% CI. plantarum). bulgaricus.[37] Some studies suggest that probiotics may be beneficial in reducing bloating and flatulence associated with IBS.[37.91. and altered bowel habits. and assessment of clinical outcomes. In addition. 95% CI. More data are needed before probiotics can be recommended as typical care in the treatment of IBS. and VSL#3) improved overall symptoms associated with IBS compared with placebo. various types of lactobacilli (6 studies). treatment durations. 0.[37] Although probiotics may be beneficial in treating IBS symptoms. 0. 0. 0. 0. flatulence. 95% CI.79–0. Inc. which included the two above-mentioned studies.24] A recent meta-analysis involving 20 trials (n = 1404) found that probiotics (most commonly lactobacilli and bifidobacteria) improved global IBS symptoms (RRpooled.Lactobacillus casei. thermophilus. acidophilus. This preparation contains eight bacterial organisms in large numbers: three bifidobacteria (Bifidobacterium longum.88) compared with placebo.85. flatulence.62–0. 0. four lactobacilli (L.94) and reduced abdominal pain (RRpooled. the contributing studies had methodological limitations. bloating or distension.meta-analysis of 12 studies (n = 4709). bifidobacteria. and probiotic mixtures (2 studies).

boulardii to mesalamine treatment. providing an appealing alternative to the use of antibiotics. suggesting that the probiotic yeast may be beneficial in the maintenance treatment of Crohn's disease. lack of a control group. may contribute to the inflammation seen with these diseases. Bibiloni et al. coli with UC and reduced levels of bifidobacteria with Crohn's disease. Studies have also investigated the role of probiotics in maintaining remission of Crohn's disease. coli probiotic strain used in these three studies has been shown to colonize the intestine and antagonize the pathogenic bacteria seen with UC. Probiotics may improve the microbial balance of the indigenous flora.[5.25% versus 37. treatment with corticosteroids was not suitable for these patients.04). An imbalance of intestinal microflora.[44]noted that patients with inactive Crohn's disease had a significantly lower clinical relapse rate when receiving a six-month regimen of S.7] Several studies examining the role of probiotics in UC have suggested that they can induce or maintain disease remission. Although studies have been conflicting. was attained in 68% of patients after adding a four-week course of S. Crohn's disease.[43] noted that a six-week course of VSL#3 was also effective in inducing remission or causing a response in 77% of patients with active mild-to-moderate UC that was unresponsive to conventional therapy.Inflammatory diseases of the digestive tract include UC. and openlabel design. Guslandi et al. [39–41] Two of the studies had notable limitations—diverse patient population[39] and short study duration[40]—but the more recent study was methodologically more sound and confirmed the results of the other two studies. Marteau et al.[41] The particular nonpathogenic E. In contrast. suggesting that the probiotic was equivalent to standard therapy with mesalamine in maintaining remission.[42] For various reasons. Clinical remission. probiotics seem to be an attractive option in the treatment and prevention of inflammatory bowel disease. confirmed endoscopically.5%.[40]Another study investigated the use of S. [45] found that a . This openlabel trial also lacked a control group and involved only 34 patients. Three controlled trials compared the probiotic E. boulardii plus mesalamine versus treatment with mesalamine alone (6. coli Nissle 1917 with mesalamine in UC and found that the two therapies were similar in preventing disease relapse. boulardii in 25 patients who developed a mild-to-moderate clinical flare-up of UC while taking standard maintenance therapy with mesalamine. This study was limited by its small sample size. and pouchitis. p = 0. specifically high numbers of enteroadhesive and enterohemorrhagic E.

particularly VSL#3. In addition. Gionchetti et al.[46] In addition to modifying the endogenous flora.[46] found that VSL#3 was significantly more effective than placebo in maintaining remission after nine months. which is formed surgically after an ileal pouch–anal anastomosis from a proctocolectomy. placebo-controlled trial involving 40 patients with chronic relapsing pouchitis. Similar to the previous study. thermophilus increased significantly from baseline in patients treated with VSL#3 (p < 0.0001). Various studies support the use of probiotics. these 17 patients also experienced relapse within four months.[46–48] Although the etiology of pouchitis is unknown.[47. and S. in reducing relapse rates and maintaining remission of pouchitis.six-month regimen of Lactobacillus johnsoniiLA1 was not effective in preventing endoscopic recurrence of Crohn's disease after surgical resection. double-blind. In contrast to those studies with encouraging results using VSL#3 in pouchitis. fecal concentrations of lactobacilli.[49] This trial did not show differences in the mean pouchitis .05) during the first year after pouch formation in this randomized. interferon. When the probiotic was discontinued at the study's end. placebo-controlled study involving 40 patients. Mimura et al. In this study. 17 of the 20 patients treated with VSL#3 remained in remission at one year versus only 1 of 16 patients who received placebo (p < 0. bifidobacteria. VSL#3 alters the immune response in pouchitis by raising tissue levels of the antiinflammatory cytokine interleukin 10 and reducing tissue levels of tumor necrosis factor. All 20 placebo-treated patients experienced a relapse within four months. Gionchetti et al. it may be associated with decreased lactobacilli and bifidobacteria counts as well as increased concentrations of other bacteria. In addition to preventing relapses. while 17 of the 20 patients treated with VSL#3 remained in remission after nine months ( p < 0.[47] showed that the probiotic mixture VSL#3 was significantly more effective than placebo in preventing the occurrence of pouchitis (p < 0.001).001). and matrix metalloproteinase activity. double-blind.[48] confirmed the efficacy of VSL#3 in maintaining remission in patients with recurrent or refractory pouchitis. a three-month trial involving LGG did not show any benefit as primary therapy for ileal pouch inflammation. 36 patients whose pouchitis was in remission were randomized to receive VSL#3 or placebo for one year or until relapse.48] In a randomized. Pouchitis is a nonspecific inflammation of the ileal reservoir. It is characterized by increased stool frequency and abdominal cramping.

was reduced significantly in the infants given probioticsupplemented formulas compared with those who did not receive probiotic supplementation (p = 0.97). 0.33–0.008). all of the women reported an improvement in vaginal symptoms and reduced vaginal .[50] conducted a double-blind.[53] Hilton et al. 0. This cohort was reexamined after four years. the Scoring Atopic Dermatitis index.57.6 months) with atopic eczema received formula supplemented with probiotics (either LGG or Bifidobacterium lactis Bb-12) or the same formula without probiotics. 95% CI. randomized. which reflects the extent and severity of atopic eczema. Genitourinary Infections Abnormal vaginal microbiota may lead to symptomatic infections. overgrowth ofCandida albicans may occur.84. 95% CI. suggesting that the protective effect of this probiotic on atopic eczema in at-risk children continues beyond infancy. After the administration of vaginal suppositories containing LGG twice daily for seven days. and significantly fewer children who had previously received LGG were diagnosed with atopic eczema compared with placebo (26% [14 of 53] versus 46% [25 of 54]. When the normal vaginal microflora is disrupted. causing VVC.002). are the predominant vaginal microorganisms in healthy premenopausal women.51. Restoring the normal flora with lactobacilli may help treat this genital infection. 4. 132 participants completed the trial. Lactobacilli. including vulvovaginal candidiasis (VVC). p = 0. especiallyLactobacillus crispatus and Lactobacillus iners. Allergy Several studies have found that probiotics have a beneficial effect on atopic eczema. 0. 0. Kalliomaki et al. placebocontrolled trial in which 159 pregnant women with a family history of atopic disease were given LGG or placebo daily for two to four weeks before their expected delivery date. RR.disease activity index scores between treatment with LGG and placebo.[54] conducted a study involving 28 women with a history of recurrent VVC who also had signs and symptoms of active VVC. such as with use of broad-spectrum antibiotics. followed by administration of the probiotic or placebo to the newborn infant for 6 months.[51] In another randomized double-blind study.[52] After 2 months.32–0. 27 infants (mean age. RR. and only 40% of patients who received the probiotic had LGG recovered in their fecal flora. There was a 50% reduction in the frequency of atopic eczema during the first two years of the children's lives in those given probiotics compared with placebo (23% [15 of 64] versus 46% [31 of 68].

[56] and more than half of the women in one study had recently completed treatment with antifungal medications. The mean number of candidal infections of the vagina and candidal colonization in the vagina and rectum were significantly lower in the women who consumed yogurt versus the control group (0.38.57] One study analyzed 18 commercially available probiotic products available in the United States and found that 7 (39%) had differences between the stated and actual concentrations of bacteria. quality. Reid et al. p = 0. However.[13. rhamnosus GR-1 and L. or powders) and as fermented dairy products (i. it is difficult to reliably conclude whether probiotics can prevent recurrent VVC.[54] Therefore. Their efficacy relies on their ability to survive passage through the gastrointestinal tract and colonize a tissue section.23.[32] The quantity. inadequate controls. Dosages and Product Selection Probiotics are available as supplements (i. fermentum RC-14 to colonize the vagina in 10 women who were asymptomatic for infection but who had a history of recurrent urogenital infections. The probiotic solution was administered twice daily for 14 days. Hilton et al.001.. 13 of whom completed the protocol. tablets. viable organisms and must be ingested on a regular basis in order to maintain effective concentrations. p = 0. including small sample sizes.38 versus 2. some probiotic preparations may be enteric coated or microencapsulated. these three studies had important methodological limitations.001 and 0. the manufacturing process may cause living organisms to become nonviable. To prevent destruction by gastric acid and intestinal bile salts. and lack of blinding. and purity of the bacteria or yeast in probiotics can vary among products due to the complexity of quality control with live microorganisms and the lack of universal quality-assurance programs.[61] . thus reducing probiotic effectiveness. primarily recurrent VVC. probiotics must contain living. one or both of theLactobaccillus strains were recovered from the vaginas of all 10 women.[54. capsules.erythema and discharge. and no VVC occurred during the study.e.[56]found that consumption of 8 oz of yogurt containing L. yogurt and milk).55] one study had a high attrition rate.[57–60] Unfortunately.84 versus 3.[55] investigated the ability of an orally administered solution containing L. Within one week. respectively). acidophilus daily for six months reduced vaginal colonization and infection by Candida species in a crossover trial involving 33 women with recurrent VVC. Two of the studies lacked detailed statistical analyses. For colonization to occur..54.e.

probiotics are generally considered safe and well tolerated. Although rare.[16] Typically. and VSL#3.63] Adverse Effects and Safety When ingested orally. boulardii. boulardii(Florastor.6 million users. Products should be stored according to the manufacturer's recommendations. B. France). however. Fairfield. Amerifit Brands. France). infantis 35624 (Align.[64] Another theoretical risk associated with probiotics involves . S.[65] It is estimated that the risk of developing bacteremia from ingested lactobacilli probiotics is less than 1 per 1 million users. only those products that have been evaluated in controlled human studies should be recommended. Inc.58] Constipation and increased thirst have also rarely been associated with S. and many preparations contain several different species. boulardii is estimated at 1 per 5..[57] Table 2 summarizes dosing for various probiotic strains based on doses found to be efficacious in human studies. Holland. animalisDN-173 010. these are typically mild and subside with continued use. however. NJ). specifying that the preparation contains a minimum of 100 million viable bacteria per gram at the time of manufacture.Probiotic dosing varies depending on the product and specific indication. preparations may have a limited shelf life. Beauvais. JB Laboratories. boulardii.[62] Yogurt products fermented with probiotics should be labeled with a "Live and Active Cultures" seal. Various probiotics are available in the United States. MI). Paris. a probiotic should contain several billion microorganisms to increase the likelihood of adequate gut colonization. Biocodex. which contains B. so dosing may vary depending on the product. The most common adverse effects include bloating and flatulence."[57. No consensus exists about the minimum number of microorganisms that must be ingested to obtain a beneficial effect.62.[64] One theoretical concern associated with probiotics includes the potential for these viable organisms to move from the gastointestinal tract and cause systemic infections. typical doses used in studies ranged from 1–20 billion colony-forming units per day. [28] For lactobacilli.57. probioticrelated bacteremia and fungemia have been reported. In addition. most studies examined daily doses ranging from 250 to 500 mg.[24. marketed by Dannon/Danone as "Bifidus regularis. An example is Activia yogurt (Dannon/Danone. For S. Some examples of these commercially available preparations include LGG (Culturelle.[66] and the risk of developing fungemia fromS. since some may require refrigeration.

These include sepsis or endocarditis with lactobacilli. previous antibiotic therapy.[65. particularly when used by generally healthy individuals.[69] identified major and minor risk factors for probiotic-associated sepsis. this has not yet been observed.[67] There have been several documented cases of fungemia associated with use of S.[70] Despite a substantial increase in the consumption of LGG-containing . cardiac valvular disease (Lactobacillus probiotics only). to date there have been no reports of bifidobacterial sepsis associated with the use of a probiotic. and administration of probiotics via a jejunostomy tube (this method of delivery could increase the number of viable probiotic organisms reaching the intestine by bypassing the acidic contents of the stomach). In a review of the literature. boulardii.66] Although no serious adverse events have been described in clinical trials. Those at greatest risk include critically ill or highly immunocompromised patients or those with central venous catheters in place. fungemia with S.[69] Fortunately. concurrent administration with broad-spectrum antibiotics to which the probiotic is resistant. Major risk factors included immunosuppression (including a debilitated state or malignancy) and prematurity in infants. boulardii. and liver abscess with LGG. and prior surgical interventions. supporting the low pathogenicity of bifidobacteria species.65] Bacteremia due to lactobacilli rarely occurs. boulardii capsules are opened at the bedside for administration through the nasogastric tube.the possible transfer of antibiotic resistance from probiotic strains to pathogenic bacteria. however. prior hospitalization.[24. It is important to remember that the overall risk of developing an infection from ingested probiotics is very low.[68] Although there have been infrequent reports of lactobacillemia and fungemia. systemic infections associated with specific probiotics have been noted in isolated reports. WhenS. The authors recommended that probiotics be used cautiously in patients with one major risk factor or more than one minor risk factor. LGG has been routinely added to dairy products since 1990. Boyle et al. severe underlying comorbidities. Minor risk factors were the presence of a central venous catheter. most cases of probiotic bacteremia or fungemia have responded well to appropriate antibiotic or antifungal therapy. central venous catheters may become contaminated and serve as the source of entry for the organism. In Finland. but predisposing factors include immunosuppression. impairment of the intestinal epithelial barrier (such as with diarrheal illness).

01) and an increased risk of bowel ischemia in the probiotics group compared with placebo (9 versus 0. Imrie/modified Glasgow score. predicting a severe disease course and putting them at risk for developing infectious complications. concurrent administration of antibiotics could kill a large number of the organisms. Florastor. boulardii.[74] Probiotics should also be used cautiously in patients taking immunosuppressants. A recent study found an increased risk of mortality when probiotics were used to prevent infectious complications in patients with predicted severe acute pancreatitis.004). there was no significant change in the incidence ofLactobacillus-associated bacteremia observed during the surveillance period of 1990–2000. Lactobacillus lactis. reducing the efficacy of this probiotic. including infected pancreatic necrosis. such as cyclosporine. acidophilus. S.[73] According to the manufacturer. bifidum.Lactobacillus salivarius.[71] These patients had acute pancreatitis and an elevated Acute Physiology and Chronic Health Evaluation (APACHE) II score. reducing the efficacy of the Lactobacillus and Bifidobacterium species.[58.72] Similarly. and chemotherapeutic agents. or C-reactive protein value.72. This multicenter. since probiotics could cause an infection or pathogenic colonization in immunocompromised patients. administered enterally twice daily for a maximum of 28 days. randomized.products from 1995 through 2000.[58. Drug Interactions Since probiotics contain live microorganisms. p = 0. The study found that this combination of six probiotic strains did not decrease infectious complications in patients with predicted severe acute pancreatitis but rather was associated with significantly more deaths than was placebo (24 versus 9. The authors stated that probiotics should not be routinely given to patients with predicted severe acute pancreatitis and should be used cautiously in critically ill patients or those at risk for nonocclusive mesenteric ischemia. lactis) or placebo. and B. L. boulardii might interact with antifungals. which contains S. p = 0. casei. B. Patients should be instructed to separate administration of antibiotics from these bacteria-derived probiotics by at least two hours. azathioprine. placebo-controlled trial involved 298 patients who received a multispecies probiotic preparation ( L.73] Precautions and Contraindications . double-blind. tacrolimus. should not be taken with any oral systemic antifungal products.

possibly due to altered gut integrity. .73] Caution is also warranted in patients with central venous catheters. Future research needs to encompass more welldesigned clinical trials in larger populations and for longer durations to better evaluate the efficacy of probiotics. Probiotic strains of Lactobacillus have also been reported to cause bacteremia in patients with short-bowel syndrome. particularly those involving the gastrointestinal tract. the results from many probiotic studies should be interpreted cautiously due to methodological limitations.73] Lactobacillus preparations are contraindicated in persons with a hypersensitivity to lactose or milk. since contamination leading to fungemia has been reported when Saccharomycescapsules were opened and administered at the bedside.[73. particularly in critically ill or severely immunocompromised patients. blinding. this may have important implications when interpreting meta-analyses. There is also heterogeneity among studies. As a result.[75] S. Therefore. individuals may obtain a product that is ineffective or that contains varying quantities of bacteria or yeast. Published studies involving probiotics have often utilized small sample sizes and lacked appropriate randomization.[57.Since probiotics contain live microorganisms. A challenge with these products involves the complexity of quality control with live microorganisms. Conclusion Probiotics have demonstrated efficacy in preventing and treating various medical conditions. there is a slight chance that these preparations might cause pathological infection. or control groups.58. since most species are considered nonpathogenic and nontoxigenic Limitations Probiotics are regulated as dietary supplements and not subjected to the same rigorous standards as medications. boulardii is contraindicated in patients with a yeast allergy.[68. Data supporting their role in other conditions are often conflicting. treatment durations. particularly if strain designations were not provided. since different probiotic doses.72. Since probiotic effects are specific to a particular strain. and patient populations may have been used. strains.76] No contraindications are listed for bifidobacteria.

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