Scientific Name(s): Lactobacillus spp., (eg, L. acidophilus , L. casei , L. rhamnosus , L. bulgaricus , L. plantarum , L. helveticus ), Bifidobacterium spp. (eg, B. bifidum , B. longum , B. breve , B. infantis ), Sacchromyces boulardii , Streptococcus salvarius , Enterococcus faecium
Common Name(s): Probiotics , yogurt , sour milk , VSL-3 , Indian yogurt , various commercial preparations
Sufficient clinical trials have been conducted to enable meta-analyses to be conducted for several clinical conditions. Evidence exists to support the use of probiotics in bacterial vaginosis, diarrhea (acute infectious, antibiotic-associated, and persistent), irritable bowel syndrome (IBS), necrotizing enterocolitis in neonates, and ventilator-associated pneumonia. Meta-analyses have shown no effect of probiotics in Crohn disease, eczema, pancreatitis, ulcerative colitis, or in patients in intensive care.
Daily intake of oral probiotic preparations is usual practice, although some trials have used twice-weekly dosing. Preparation strength is commonly measured as colony-forming units per capsule.
The use of probiotics is not advised in patients at risk of opportunistic infections and in those with badly damaged GI tracts.
Information regarding safety and efficacy of specific preparations in pregnancy and lactation is lacking. Trials investigating probiotics have been conducted in pregnant women without obvious problems.
None well documented.
Probiotics are considered relatively safe. There are isolated reports linking probiotics to adverse reactions.
No data are available.
The use of probiotic preparations is evident throughout history. Abraham's longevity, as described in the Bible's Old Testament, may have been the result of drinking sour milk. Roman history (76 BC) describes fermented milk as a remedy for gastroenteritis. In 1916, experiments were conducted to implant Escherichia coli as a means of fighting pathogenic intestinal flora.
In 1965, the term probiotic was first used when describing “substances secreted by one microorganism which stimulates the growth of another.” 1 Revised versions of the definition have appeared in literature to accommodate mechanisms of action and components other than bacteria. An all-encompassing version has been proposed as follows: “A preparation of or a product containing viable, defined microorganisms in sufficient numbers, which alter the microflora (by implantation or colonization) in a compartment of the host, and by that exert beneficial health effects in this host.” 1 Related concepts of prebiotics and synbiotics also have been discussed. 1 , 2
Uses and Pharmacology
The potential mechanisms by which probiotics may exert their action include production of pathogen-inhibitory substances, inhibition of pathogen attachment, inhibition of the action of microbial toxins, stimulation of immunoglobulin A, and trophic effects on intestinal mucosa.
Each agent or preparation may have unique actions, with some strains more or less effective than others. Trials included in meta-analyses are heterogeneous, especially with respect to the strain of probiotic used. 2 , 3 , 4 , 5 , 6Animal data
Widespread usage of probiotics, together with a largely safe adverse event profile, makes data from animal experimentation largely redundant. Sufficient clinical trials have been conducted to enable meta-analyses to be conducted for certain clinical conditions.Bacterial vaginosis
A meta-analysis of clinical trials conducted through December 2007 has found evidence of effect for short-course therapy (5 days) of Lactobacillus versus metronidazole in the treatment of bacterial vaginosis. 7 Long-term administration (6 months of once-weekly vaginal applications) of Lactobacillus rhamnosus has been compared with a single course of metronidazole (7-day course), and an impact on the restoration of normal vaginal flora was found even at 12 months. 8Candidiasis, vaginal
Long-term trials investigating the effect of oral hydrogen peroxide–producing Lactobacillus acidophilus in preventing candidiasis have shown mixed results following long-term use (6 months), but were limited due to the high loss to follow-up of trial participants. 2 , 9 A large, randomized, placebo-controlled, double-blind trial of oral or vaginal L. rhamnosus and Bifidobacterium longum over 10 days showed no effect in treating post-antibiotic candidiasis compared with placebo. 10 In another placebo-controlled, double-blind trial, daily oral intake of L. rhamnosus and Lactobacillus fermentum modified the vaginal flora and decreased the amount of yeast and coliforms. 11Crohn disease
Meta-analyses have consistently shown no effect of probiotics on clinical response in Crohn disease and a failure to have an impact on maintaining remission or on recurrent episodes. 12 , 13 , 14 , 15 One meta-analysis found a slightly increased risk of relapse for Lactobacillus versus placebo (relative risk [RR] clinical relapse, 1.15 [95% confidence interval [CI], 0.9 to 1.48]). 13Diarrhea, acute infectious
Alongside rehydration, probiotics appear to have a role in acute infectious diarrhea. Trials are generally heterogeneous in nature, and further studies might provide more information about the efficacy of specific strains and appropriate regimens. 4Clinical data
Trials conducted through 2010 evaluating the effect of probiotics on acute infectious diarrhea have been included in a Cochrane meta-analysis. Probiotics were found to be safe and to shorten both the mean duration of diarrhea (mean difference, 24.76 hours [95% CI, 15.9 to 33.6 hours]) and the likelihood of ongoing diarrhea after 4 days (RR, 0.41 [95% CI, 0.32 to 0.53]). 4
Results of trials investigating the effect of probiotics on Clostridium difficile infection are conflicting. Some trials suggest a positive effect (using S. boulardii or L. acidophilus with Bifidobacterium bifidum ), 2 , 16 and others show no effect (with L. acidophilus and Bifidobacterium lactis ) 17 or a trend toward an effect (with L. rhamnosus ). 2Diarrhea, antibiotic-associated
Meta-analyses of clinical trials evaluating the effect of antibiotic-associated diarrhea provide equivocal data. As the condition is generally self-limiting, the use of probiotics should be reserved for those patients in whom diarrhea would be a clinically important adverse effect of antibiotic use, and then an adequate dosage should be used. 3Clinical data
A meta-analysis of 6 clinical trials conducted in children (N = 766) found a reduction in the incidence of diarrhea when probiotics were used compared with placebo (RR, 0.44 [95% CI, 0.25 to 0.77]), and the number needed to treat (NNT) to prevent 1 incidence of diarrhea was determined to be 7. Effect on duration of diarrhea was not fully reported in the studies. Strength of effect was determined to be greatest with S. boulardii . 3
Similarly, a further meta-analysis found strong evidence (RR, 0.36 [95% CI, 0.25 to 0.53]) for a reduction in the incidence in diarrhea when doses of greater than 5 billion units of single strain probiotics were used. Analysis of all included trials, including lower dosages, found no difference when intent-to-treat analysis was used. 18
For Lactobacillus trials only, a meta-analysis of trials conducted among children (4 trials) found no effect, whereas the adult trials (6 trials) found a positive effect for Lactobacillus probiotic use in the prevention of antibiotic-associated diarrhea. 19Diarrhea, persistent
Persistent (lasting more than 14 days) diarrhea is an important issue in undernourished children or other children at risk.Clinical data
A Cochrane meta-analysis of 4 trials (N = 464) found a decrease in the duration of diarrhea (mean difference, 4.02 days [95% CI, 4.61 to 3.43]) and a decrease in stool frequency. The reviewers noted the limited availability of quality trials for analysis. 20Eczema/Allergic dermatitis
A Cochrane review of clinical trials conducted in children with eczema found no effect of probiotics on symptom severity or participant/parent preference for treatment option. Important heterogeneity exists among the 12 included trials, except for 3 trials using the same probiotic strain ( L. rhamnosus GG), which were consistently negative. Subgroup analysis did not reveal any populations that might benefit from use of probiotics. 21 , 22
The use of probiotics for the prevention of eczema or atopic dermatitis remains unclear. 22Helicobacter pylori eradication
Clinical trials to date have not shown probiotics to be effective in eradicating H. pylori , with only a trend toward increased eradication when used in conjunction with antibiotic therapy. Lactobacillus casei and B. lactis have shown in vitro activity against H. pylori . However, evidence for activity of L. acidophilus is conflicting. 23 , 24 , 25
A reduction in the incidence of adverse reactions (diarrhea, bleeding, taste disturbances) from triple and quadruple H. pylori treatment regimens, and consequently improved compliance, has been demonstrated with preparations containing Bifidobacterium and L. casei . 26 , 27 , 28Intensive care patients, adults
A meta-analysis of clinical trials evaluating the effect of probiotics added to enteral feeds in critically ill patients found no changes in length of intensive care unit stay, incidence of nosocomial infections or pneumonia, or mortality. 29 , 30Irritable bowel syndrome
Meta-analysis have been conducted in clinical trials through 2007 31 and May 2008. 32 Probiotics perform better than placebo in reducing symptoms of IBS (RR, 0.71 [95% CI, 0.57 to 0.88]). A reduction in overall symptoms, abdominal pain, and flatulence can be demonstrated, 31 , 32 and the NNT to prevent 1 occurrence of overall symptoms has been calculated to be 4. 32Necrotizing enterocolitis, neonates
The role of probiotics in treating necrotizing enterocolitis is now well established. Further clinical trials are now required to establish efficacy of different strains and dosage regimens. Placebo-controlled trials are unnecessary. 33 , 34 Mechanisms of action are suggested to include colonization of the gut by beneficial organisms and the prevention of colonization by pathogens, improved maturity of the mucosal barrier, and modulation of relevant enzyme systems. 33 , 34Clinical data
A meta-analysis of 11 clinical trials conducted through March 2009 of the effect of probiotics in preterm very low birth weight neonates (N = 2,176) found a reduced risk of all-cause mortality (RR, 0.42 [95% CI, 0.29 to 0.62]) and an NNT to prevent 1 death (all cause) of 20. 33 A Cochrane meta-analysis of 9 trials conducted through December 2006 (N = 1,425) found a significant decrease in the incidence of severe (stage II or more) necrotizing enterocolitis (RR, 0.32 [95% CI, 0.17 to 0.6]) and a significant decrease in mortality (RR, 0.43 [95% CI, 0.25 to 0.75]). No effect was found on the incidence of nosocomial sepsis or on total days of total parenteral nutrition. No adverse effects of probiotic use were found. 34Pancreatitis
Meta-analyses, including clinical studies conducted through March 2010, have studied the effect of probiotics in acute pancreatitis. No reduction of clinical outcomes, including complications from infections, multiple organ failure, length of antibiotic therapy, surgical interventions, or mortality, has been found for probiotic use. 35 , 36 , 37Pneumonia, ventilator-associated
A meta-analysis including trials conducted through April 2009 found a lower incidence of ventilator-associated pneumonia (odds ratio [OR], 0.61 [95% CI, 0.41 to 0.91]) and a lower incidence of colonization with Pseudomonas aeruginosa (OR, 0.35 [95% CI, 0.13 to 0.93]) for probiotics. No effect was found on all-cause mortality. 38Respiratory tract infections/otitis media
Studies among healthy adults and children using the oral probiotics Lactobacillus reuteri , L. casei , and L. rhamnosus have shown a reduction in missed work/school days because of respiratory illness. The need for antibiotic intervention was also reduced. 39 , 40 , 41 , 42 , 43 Probiotics ingested for 3 weeks reduced nasal colonization with pathogenic bacteria and demonstrated efficacy in treating acute otitis media. 44 , 45Ulcerative colitis
A meta-analysis of 13 clinical trials conducted through August 2009 found no additional benefit for probiotics in inducing remission. A more favorable profile than placebo was suggested in maintaining remission. 46 With regard to preventing pouchitis (a nonspecific inflammation of the ileal reservoir), evidence from meta-analyses suggest a potential role for probiotics in preventing relapse following anastomosis in chronic ulcerative colitis (OR, = 0.039 [95% CI, 0.011 to 0.142]). 47 , 48 Based on limited clinical data, VSL#3 ( Lactobacillus , Bifidobacterium , and Streptococcus ) may be more effective than single strain Lactobacillus . 48Urinary tract infections
Few quality trials on the effect of probiotics in preventing recurrent or chronic urinary tract infections exist. A phase I study of Lactobacillus crispatus vaginal suppositories found positive results for the prevention of urinary tract infections in women versus placebo 49 ; whereas other trials have produced equivocal results. 2Other uses
Despite positive in vitro studies showing decreased carcinogenic aflatoxins and beta-glucuronidase, efficacy studies in humans are lacking. 50 , 51 The combination of L. acidophilus and lactulose appears beneficial in the therapy of radiotherapy-related intestinal adverse reactions. 52Cystic fibrosis
Six months of Lactobacillus supplementation (6 billion units daily) reduced pulmonary exacerbations and hospital admissions in children with cystic fibrosis versus placebo. 53General GI conditions
Probiotics increased fecal Bifidobacterium counts, reduced fecal blood and pH ( Bifidobacterium , L. acidophilus , and Enterococcus ), and decreased the incidence of fecal Clostridium ( Bacillus subtilis and E. faecium ) in patients with liver cirrhosis. 54 L. acidophilus reduced the length of hospital stay and the need for surgery in patients with partial adhesive small bowel obstruction 55 ; however, no effect was found for probiotics in patients undergoing elective abdominal surgery. 56 Postprandial gas-related intestinal symptoms were demonstrated to be reduced with probiotic use in a clinical trial. 57Immunity
Limited studies suggest more rapid gastric emptying times and decreased symptoms of colic with probiotic use in infants. No difference in weight gain, stool frequency, incidence of constipation, or regurgitations was found. 63 , 64Insulin
A study conducted among patients with type 2 diabetes found a positive effect of L. acidophilus in maintaining insulin sensitivity versus placebo. 65Lipid profile
It has been suggested that appropriately selected probiotics may be useful adjuncts in controlling hypercholesterolemia because of the bacteria's ability to assimilate cholesterol and grow well in the presence of bile. 66 However, evidence of effect remains equivocal. 67 , 68 , 69 , 70 , 71 , 72 , 73Mastitis
Trials have evaluated the effect of probiotics as an alternative to antibiotic therapy in infectious mastitis. Greater reductions in bacterial count and pain score have been found for L. fermentum , Lactobacillus salvarius , and Lactobacillus gasseri in 1 large (n = 352) and 1 smaller study (n = 20). 74 , 75Nutrition/Lactose intolerance
Milk and yogurts containing L. acidophilus have been studied in patients with lactose intolerance, but controversy regarding its efficacy in aiding lactose digestion remains. 76 , 77 The need for adequate, live bacteria, which may account for the variation of results in other studies, has been demonstrated in lactose-intolerant adults. 78Oral health
Studies in some, but not all, populations have reported decreases in yeast counts and incidence of hyposalivation, suggesting a potential role in the prevention of oral candidiasis among elderly patients. 79 , 80 In orthodontic adolescents, probiotics decreased the count of salivary Streptococcus mutans , 81 while a review found a generally positive effect for probiotics on oral health, especially with regard to cariogenic and periodontal pathogens. 80Reproductive hormones
A small trial found improvements in patient pain assessment scores and pain scales for Bacillus coagulans versus placebo. 85
Daily intake of oral probiotic preparations is usually recommended, but some trials have used twice-weekly dosing. Preparation strength is usually described as million/billion colony-forming units per capsule.Necrotizing enterocolitis, neonates
Dosages used in clinical trials for necrotizing enterocolitis in neonates include the use of Bifidobacterium breve 0.5 billion to 1.6 billion units daily and L. casei GG and L. acidophilus 6 billion units daily; however, specific trials are required for definite recommendations. 33Irritable bowel syndrome
Up to 5 billion units daily taken for 4 to 6 weeks has been used in clinical trials. 31
Information regarding safety and efficacy of the different strains of probiotics in pregnancy and lactation is lacking, despite studies being conducted in pregnant women for the prevention of atopic eczema in children and for the treatment of bacterial vaginosis.
A meta-analysis has been conducted regarding the safety of Lactobacillus and Bifidobacterium species used in pregnancy. 86 Of the 11 included trials (conducted through September 2007), no evidence of miscarriage or malformations was found. No effect on the incidence of caesarian section, birth weight, or gestational age was found either. 86
None well documented. One study evaluated the effect of 2 weeks consumption of probiotics on vitamin B levels in healthy women. Vitamin B 1 (thiamine) and B 2 (riboflavin) levels were enhanced; however, no effect was observed on vitamin B 6 . 87
Probiotics are considered relatively safe for use, even with low birth weight infants and neonates, but caution is advised for patients at risk of opportunistic infections and in those with badly damaged GI tracts. 2 , 34 There are isolated case reports linking probiotics to adverse reactions. 88 , 89 , 90
Research reveals little or no information regarding toxicology. No adverse reactions were found in a study examining the safety of B. longum in healthy adults. 91
Bibliography1. Schrezenmeir J, de Vrese M. Probiotics, prebiotics, and synbiotics—approaching a definition. Am J Clin Nutr . 2001;73(2)(suppl):361S-364S.
2. Elmer GW. Probiotics: “living drugs.” Am J Health Syst Pharm . 2001;58(12):1101-1109.
3. Szajewska H, Ruszczyński M, Radzikowski A. Probiotics in the prevention of antibiotic-associated diarrhea in children: a meta-analysis of randomized controlled trials. J Pediatr . 2006;149(3):367-372.
4. Allen SJ, Martinez EG, Gregorio GV, Dans LF. Probiotics for treating acute infectious diarrhoea. Cochrane Database Syst Rev . 2010;(11):CD003048.
5. Oelschlaeger TA. Mechanisms of probiotic actions - A review. Int J Med Microbiol . 2010;300(1):57-62.
6. Ohland CL, Macnaughton WK. Probiotic bacteria and intestinal epithelial barrier function. Am J Physiol Gastrointest Liver Physiol . 2010;298(6):G807-G819.
7. Oduyebo OO, Anorlu RI, Ogunsola FT. The effects of antimicrobial therapy on bacterial vaginosis in non-pregnant women. Cochrane Database Syst Rev . 2009;(3):CD006055.
8. Marcone V, Rocca G, Lichtner M, Calzolari E. Long-term vaginal administration of Lactobacillus rhamnosus as a complementary approach to management of bacterial vaginosis. Int J Gynaecol Obstet . 2010;110(3):223-226.
9. Van Kessel K, Assefi N, Marrazzo J, Eckert L. Common complementary and alternative therapies for yeast vaginitis and bacterial vaginosis: a systematic review. Obstet Gynecol Surv . 2003;58(5):351-358.
10. Pirotta M, Gunn J, Chondros P, et al. Effect of lactobacillus in preventing post-antibiotic vulvovaginal candidiasis: a randomised controlled trial. BMJ . 2004;329(7465):548.
11. Reid G, Burton J, Devillard E. The rationale for probiotics in female urogenital healthcare. MedGenMed . 2004;6(1):49.
12. Rahimi R, Nikfar S, Rahimi F, et al. A meta-analysis on the efficacy of probiotics for maintenance of remission and prevention of clinical and endoscopic relapse in Crohn's disease. Dig Dis Sci . 2008;53(9):2524-2531.
13. Shen J, Ran HZ, Yin MH, Zhou Tx, Xiao Ds. Meta-analysis: the effect and adverse events of Lactobacilli versus placebo in maintenance therapy for Crohn disease. Intern Med J . 2009;39(2):103-109.
14. Rolfe VE, Fortun PJ, Hawkey CJ, Bath-Hextall F. Probiotics for maintenance of remission in Crohn's disease. Cochrane Database Syst Rev . 2006;(4):CD004826.
15. Doherty G, Bennett G, Patil S, Cheifetz A, Moss AC. Interventions for prevention of post-operative recurrence of Crohn's disease. Cochrane Database Syst Rev . 2009;(4):CD006873.
16. Plummer S, Weaver MA, Harris JC, Dee P, Hunter J. Clostridium difficile pilot study: effects of probiotic supplementation on the incidence of C. difficile diarrhoea. Int Microbiol . 2004;7(1):59-62.
17. Sullivan A, Barkholt L, Nord CE. Lactobacillus acidophilus , Bifidobacterium lactis and Lactobacillus F19 prevent antibiotic-associated ecological disturbances of Bacteroides fragilis in the intestine. J Antimicrob Chemother . 2003;52(2):308-311.
18. Johnston BC, Supina AL, Vohra S. Probiotics for pediatric antibiotic-associated diarrhea: a meta-analysis of randomized placebo-controlled trials. [published correction appears in CMAJ 2006;175(7):777.] CMAJ . 2006;175(4):377-383.
19. Kale-Pradhan PB, Jassal HK, Wilhelm SM. Role of Lactobacillus in the prevention of antibiotic-associated diarrhea: a meta-analysis. Pharmacotherapy . 2010;30(2):119-126.
20. Bernaola Aponte G, Bada Mancilla CA, Carreazo Pariasca NY, Rojas Galarza RA. Probiotics for treating persistent diarrhoea in children. Cochrane Database Syst Rev . 2010;(11):CD007401.
21. Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang ML. Probiotics for the treatment of eczema: a systematic review. Clin Exp Allergy . 2009;39(8):1117-1127.
22. Boyle RJ, Bath-Hextall FJ, Leonardi-Bee J, Murrell DF, Tang ML. Probiotics for treating eczema. Cochrane Database Syst Rev . 2008;(4):CD006135.
23. Wang KY, Li SN, Liu CS, et al. Effects of ingesting Lactobacillus - and Bifidobacterium -containing yogurt in subjects with colonized Helicobacter pylori . Am J Clin Nutr . 2004;80(3):737-741.
24. Horie K, Horie N, Abdou AM, et al. Suppressive effect of functional drinking yogurt containing specific egg yolk immunoglobulin on Helicobacter pylori in humans. J Dairy Sci . 2004;87(12):4073-4079.
25. Sgouras D, Maragkoudakis P, Petraki K, et al. In vitro and in vivo inhibition of Helicobacter pylori by Lactobacillus casei strain Shirota . Appl Environ Microbiol . 2004:70(1);518-526.
26. Sheu BS, Wu JJ, Lo CY, et al. Impact of supplement with Lactobacillus - and Bifidobacterium -containing yogurt on triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther . 2002;16(9):1669-1675.
27. Tursi A, Brandimarte G, Giorgetti GM, Modeo ME. Effect of Lactobacillus casei supplementation on the effectiveness and tolerability of a new second-line 10-day quadruple therapy after failure of a first attempt to cure Helicobacter pylori infection. Med Sci Monit . 2004;10(12):CR662-CR666.
28. Zou J, Dong J, Yu X. Meta-analysis: Lactobacillus containing quadruple therapy versus standard triple first-line therapy for Helicobacter pylori eradication. Helicobacter . 2009;14(5):97-107.
29. Watkinson PJ, Barber VS, Dark P, Young JD. The use of pre- pro- and synbiotics in adult intensive care unit patients: systematic review. Clin Nutr . 2007;26(2):182-192.
30. Barraud D, Blard C, Hein F, et al. Probiotics in the critically ill patient: a double blind, randomized, placebo-controlled trial. Intensive Care Med . 2010;36(9):1540-1547.
31. Hoveyda N, Heneghan C, Mahtani KR, Perera R, Roberts N, Glasziou P. A systematic review and meta-analysis: probiotics in the treatment of irritable bowel syndrome. BMC Gastroenterol . 2009;9:15.
32. Moayyedi P, Ford AC, Talley NJ, et al. The efficacy of probiotics in the treatment of irritable bowel syndrome: a systematic review. Gut . 2010;59(3):325-332.
33. Deshpande G, Rao S, Patole S, Bulsara M. Updated meta-analysis of probiotics for preventing necrotizing enterocolitis in preterm neonates. Pediatrics . 2010;125(5):921-930.
34. Alfaleh K, Bassler D. Probiotics for prevention of necrotizing enterocolitis in preterm infants. Cochrane Database Syst Rev . 2008;(1):CD005496.
35. Petrov MS, Loveday BP, Pylypchuk RD, McIlroy K, Phillips AR, Windsor JA. Systematic review and meta-analysis of enteral nutrition formulations in acute pancreatitis. Br J Surg . 2009;96(11):1243-1252.
36. Zhang MM, Cheng JQ, Lu YR, Yi ZH, Yang P, Wu XT. Use of pre-, pro- and synbiotics in patients with acute pancreatitis: a meta-analysis. World J Gastroenterol . 2010;16(31):3970-3978.
37. Sun S, Yang K, He X, Tian J, Ma B, Jiang L. Probiotics in patients with severe acute pancreatitis: a meta-analysis. Langenbecks Arch Surg . 2009;394(1):171-177.
38. Siempos II, Ntaidou TK, Falagas ME. Impact of the administration of probiotics on the incidence of ventilator-associated pneumonia: a meta-analysis of randomized controlled trials. Crit Care Med . 2010;38(3):954-962.
39. Hatakka K, Savilahti E, Pönkä A, et al. Effect of long term consumption of probiotic milk on infections in children attending day care centres: double-blind, randomised trial. BMJ . 2001;322(7298):1327.
40. Tubelius P, Stan V, Zachrisson A. Increasing work-place healthiness with the probiotic Lactobacillus reuteri : a randomised, double-blind placebo-controlled study. Environ Health. 2005;4:25.
41. Saavedra JM, Abi-Hanna A, Moore N, Yolken RH. Long-term consumption of infant formulas containing live probiotic bacteria: tolerance and safety. Am J Clin Nutr . 2004;79(2):261-267.
42. Lin JS, Chiu YH, Lin NT, et al. Different effects of probiotic species/strains on infections in preschool children: a double-blind, randomized, controlled study. Vaccine . 2009;27(7):1073-1079.
43. Leyer GJ, Li S, Mubasher ME, Reifer C, Ouwehand AC. Probiotic effects on cold and influenza-like symptom incidence and duration in children. Pediatrics . 2009;124(2):e172-e179.
44. Skovbjerg S, Roos K, Holm SE, et al. Spray bacteriotherapy decreases middle ear fluid in children with secretory otitis media. Arch Dis Child . 2009;94(2):92-98.
45. Hatakka K, Blomgren K, Pohjavuori S, et al. Treatment of acute otitis media with probiotics in otitis-prone children-a double-blind, placebo-controlled randomised study. Clin Nutr . 2007;26(3):314-321.
46. Sang LX, Chang B, Zhang WL, Wu XM, Li XH, Jiang M. Remission induction and maintenance effect of probiotics on ulcerative colitis: a meta-analysis. World J Gastroenterol . 2010;16(15):1908-1915.
47. Elahi B, Nikfar S, Derakhshani S, Vafaie M, Abdollahi M. On the benefit of probiotics in the management of pouchitis in patients underwent ileal pouch anal anastomosis: a meta-analysis of controlled clinical trials. Dig Dis Sci . 2008;53(5):1278-1284.
48. Holubar SD, Cima RR, Sandborn WJ, Pardi DS. Treatment and prevention of pouchitis after ileal pouch-anal anastomosis for chronic ulcerative colitis. Cochrane Database Syst Rev . 2010;(6):CD001176.
49. Czaja CA, Stapleton AE, Yarova-Yarovaya Y, Stamm WE. Phase I trial of Lactobacillus crispatus vaginal suppository for prevention of recurrent urinary tract infection in women. Infect Dis Obstet Gynecol . 2007;2007:35387.
50. Reid G, Jass J, Sebulsky MT, McCormick JK. Potential uses of probiotics in clinical practice. Clin Microbiol Rev. 2003;16(4):658-672.
51. Marteau P, Pochart P, Flourié B, et al. Effect of chronic ingestion of a fermented dairy product containing Lactobacillus acidophilus and Bifidobacterium bifidum on metabolic activities of the colonic flora in humans. Am J Clin Nutr . 1990;52(4):685-688.
52. Salminen S, Salminen E. Lactulose, lactic acid bacteria, intestinal microecology and mucosal protection. Scand J Gastroenterol Suppl . 1997;222:45-48.
53. Bruzzese E, Raia V, Spagnuolo MI, et al. Effect of Lactobacillus GG supplementation on pulmonary exacerbations in patients with cystic fibrosis: a pilot study. Clin Nutr . 2007;26(3):322-328.
54. Zhao HY, Wang HJ, Lu Z, Xu SZ. Intestinal microflora in patients with liver cirrhosis. Chin J Dig Dis . 2004;5(2):64-67.
55. Chen SC, Yen ZS, Lee CC, et al. Nonsurgical management of partial adhesive small-bowel obstruction with oral therapy: a randomized controlled trial. CMAJ . 2005;173(10):1165-1169.
56. Anderson AD, McNaught CE, Jain PK, MacFie J. Randomised clinical trial of synbiotic therapy in elective surgical patients. Gut . 2004;53(2):241-245.
57. Kalman DS, Schwartz HI, Alvarez P, Feldman S, Pezzullo JC, Krieger DR. A prospective, randomized, double-blind, placebo-controlled parallel-group dual site trial to evaluate the effects of a Bacillus coagulans -based product on functional intestinal gas symptoms. BMC Gastroenterol . 2009;9:85.
58. Marcos A, Wärnberg J, Nova E, et al. The effect of milk fermented by yogurt cultures plus Lactobacillus casei DN-114001 on the immune response of subjects under academic examination stress. Eur J Nutr . 2004;43(6):381-389.
59. Haddad PS, Azar GA, Groom S, Boivin M. Natural health products, modulation of immune function and prevention of chronic diseases. Evid Based Complement Alternat Med . 2005;2(4):513-520.
60. Gill HS, Rutherfurd KJ, Cross ML, Gopal PK. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. Am J Clin Nutr . 2001;74(6):833-839.
61. Wheeler JG, Shema SJ, Bogle ML, et al. Immune and clinical impact of Lactobacillus acidophilus on asthma. Ann Allergy Asthma Immunol . 1997;79(3):229-233.
62. Boge T, Rémigy M, Vaudaine S, Tanguy J, Bourdet-Sicard R, van der Werf S. A probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials. Vaccine . 2009;27(41):5677-5684.
63. Savino F, Cordisco L, Tarasco V, et al. Lactobacillus reuteri DSM 17938 in infantile colic: a randomized, double-blind, placebo-controlled trial. Pediatrics . 2010;126(3):e526-e533.
64. Indrio F, Riezzo G, Raimondi F, Bisceglia M, Cavallo L, Francavilla R. Effects of probiotic and prebiotic on gastrointestinal motility in newborns. J Physiol Pharmacol . 2009;60(suppl 6):27-31.
65. Andreasen AS, Larsen N, Pedersen-Skovsgaard T, et al. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects. Br J Nutr . 2010;104(12):1831-1838.
66. Gilliland SE, Walker DK. Factors to consider when selecting a culture of Lactobacillus acidophilus as a dietary adjunct to produce a hypocholesterolemic effect in humans. J Dairy Sci . 1990;73(4):905-911.
67. Greany KA, Nettleton JA, Wangen KE, Thomas W, Kurzer MS. Probiotic consumption does not enhance the cholesterol-lowering effect of soy in postmenopausal women. J Nutr . 2004;134(12):3277-3283.
68. Xiao SD, Zhang DZ, Lu H, et al. Multicenter, randomized, controlled trial of heat-killed Lactobacillus acidophilus LB in patients with chronic diarrhea. Adv Ther . 2003;20(5):253-260.
69. Xiao JZ, Kondo S, Takahashi N, et al. Effects of milk products fermented by Bifidobacterium longum on blood lipids in rats and healthy adult male volunteers. J Dairy Sci . 2003;86(7):2452-2461.
70. Lin SY, Ayres JW, Winkler W Jr, Sandine WE. Lactobacillus effects on cholesterol: in vitro and in vivo results. J Dairy Sci . 1989;72(11):2885-2899.
71. Schaafsma G, Meuling WJ, van Dokkum W, Bouley C. Effects of a milk product, fermented by Lactobacillus acidophilus and with fructo-oligosaccharides added, on blood lipids in male volunteers. Eur J Clin Nutr . 1998;52(6):436-440.
72. Ataie-Jafari A, Larijani B, Alavi Majd H, Tahbaz F. Cholesterol-lowering effect of probiotic yogurt in comparison with ordinary yogurt in mildly to moderately hypercholesterolemic subjects. Ann Nutr Metab . 2009;54(1):22-27.
73. Kadooka Y, Sato M, Imaizumi K, et al. Regulation of abdominal adiposity by probiotics ( Lactobacillus gasseri SBT2055) in adults with obese tendencies in a randomized controlled trial. Eur J Clin Nutr . 2010;64(6):636-643.
74. Arroyo R, Martín V, Maldonado A, Jiménez E, Fernández L, Rodríguez JM. Treatment of infectious mastitis during lactation: antibiotics versus oral administration of Lactobacilli isolated from breast milk. Clin Infect Dis . 2010;50(12):1551-1558.
75. Jiménez E, Fernández L, Maldonado A, et al. Oral administration of Lactobacillus strains isolated from breast milk as an alternative for the treatment of infectious mastitis during lactation. Appl Environ Microbiol . 2008;74(15):4650-4655.
76. Lin MY, Yen CL, Chen SH. Management of lactose maldigestion by consuming milk containing Lactobacilli . Dig Dis Sci . 1998;43(1):133-137.
77. Saltzman JR, Russell RM, Golner B, Barakat S, Dallal GE, Goldin BR. A randomized trial of Lactobacillus acidophilus BG2FO4 to treat lactose intolerance. Am J Clin Nutr . 1999;69(1):140-146.
78. Pelletier X, Laure-Boussuge S, Donazzolo Y. Hydrogen excretion upon ingestion of dairy products in lactose-intolerant male subjects: importance of the live flora. Eur J Clin Nutr . 2001;55(6):509-512.
79. Hatakka K, Ahola AJ, Yli-Knuuttila H, et al. Probiotics reduce the prevalence of oral Candida in the elderly—a randomized controlled trial. J Dent Res . 2007;86(2):125-130.
80. Flichy-Fernández AJ, Alegre-Domingo T, Peñarrocha-Oltra D, Peñarrocha-Diago M. Probiotic treatment in the oral cavity: an update. Med Oral Patol Oral Cir Bucal . 2010;15(5):e677-e680.
81. Cildir SK, Germec D, Sandalli N, et al. Reduction of salivary mutans Streptococci in orthodontic patients during daily consumption of yoghurt containing probiotic bacteria. Eur J Orthod . 2009;31(4):407-411.
82. Nettleton JA, Greany KA, Thomas W, Wangen KE, Adlercreutz H, Kurzer MS. Plasma phytoestrogens are not altered by probiotic consumption in postmenopausal women with and without a history of breast cancer. J Nutr . 2004;134(8):1998-2003.
83. Nettleton JA, Greany KA, Thomas W, Wangen KE, Adlercreutz H, Kurzer MS. The effect of soy consumption on the urinary 2:16-hydroxyestrone ratio in postmenopausal women depends on equol production status but is not influenced by probiotic consumption. J Nutr . 2005;135(3):603-608.
84. Bonorden MJ, Greany KA, Wangen KE, et al. Consumption of Lactobacillus acidophilus and Bifidobacterium longum do not alter urinary equol excretion and plasma reproductive hormones in premenopausal women. Eur J Clin Nutr . 2004;58(12):1635-1642.
85. Mandel DR, Eichas K, Holmes J. Bacillus coagulans : a viable adjunct therapy for relieving symptoms of rheumatoid arthritis according to a randomized, controlled trial. BMC Complement Altern Med . 2010;10:1.
86. Dugoua JJ, Machado M, Zhu X, Chen X, Koren G, Einarson TR. Probiotic safety in pregnancy: a systematic review and meta-analysis of randomized controlled trials of Lactobacillus , Bifidobacterium , and Saccharomyces spp. J Obstet Gynaecol Can . 2009;31(6):542-552.
87. Fabian E, Majchrzak D, Dieminger B, Meyer E, Elmadfa I. Influence of probiotic and conventional yoghurt on the status of vitamins B 1 , B 2 and B 6 in young healthy women. Ann Nutr Metab . 2008;52(1):29-36.
88. Griffiths JK, Daly JS, Dodge RA. Two cases of endocarditis due to Lactobacillus species: antimicrobial susceptibility, review, and discussion of therapy. Clin Infect Dis . 1992;15(2):250-255.
89. Day AS, Abbott GD. D-lactic acidosis in short bowel syndrome. N Z Med J . 1999;112(1092):277-278.
90. Hoa NT, Baccigalupi L, Huxham A, et al. Characterization of Bacillus species used for oral bacteriotherapy and bacterioprophylaxis of gastrointestinal disorders. Appl Environ Microbiol . 2000;66(12):5241-5247.
91. Mäkeläinen H, Tahvonen R, Salminen S, Ouwehand AC. In vivo safety assessment of two Bifidobacterium longum strains. Microbial Immunol . 2003;47(12):911-914.
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