Risk difference data were available for the 10 studies (963 patients; 498 in the treatment group and 465 in the control group). The pooled risk difference was 0.10 (95% CI 0.05–0.15; P<0.0001) by the fixed effects model (Cochran's Q=13.41; P=0.144).
The pooled difference was in the change of C-UBT values (three studies; 227 subjects-treatment group 119, control group 108) between the two groups (standardized by change in SD score). The results showed that C-UBT values decreased in the supplemented group with a standardized mean difference of −0.460 (95% CI −0.726 to −0.195) by fixed effects model (Cochran's Q=1.235; P=0.539). No evidence of asymmetry on the funnel plot (Egger's weighted least squares P=0.729).
Data on number of patients with one or more adverse effects was available for 719 patients (six studies; treatment group=375; control group=344) [20,21,23,25,27,29]. The pooled OR by random effects model (DerSimionian and Liard weighting method;  heterogeneity by Cochran's Q=68.5; P<0.0001) was 0.51 (95% CI, 0.10–2.57; P=0.41) (Fig. 4). No evidence of publication bias was found for this measure (Egger's weighted least squares P=0.171). Exclusion sensitivity analysis revealed that exclusion of any one of the trials did not significantly change the outcome. Details of the adverse effects were provided in four studies. Two studies by Sheu et al. [21,28] documented a lower incidence of diarrhoea, nausea, taste disturbance and constipation in the supplemented group. Studies by Cats et al.  and Felley et al.  have reported only one case each of diarrhoea in the supplemented group with none in the control group.
Predefined sensitivity analysis was conducted to study the efficacy of the intervention by age group and for symptomatic versus asymptomatic patients. The fixed effect pooled subanalysis OR for asymptomatic patients and children was of borderline significance (P=0.055 and P=0.072). However, there was no significant difference between the subgroups (overlapping CIs).
Univariate metaregression analysis was performed to evaluate the effect of quality of trial, bacterial preparation (Lactobacillus sp., L. acidophilus, L. casei, Bifidobacterium) duration of supplementation (in weeks), effect of cointervention (any other drug for H. pylori eradication vs. none) and age group (adult vs. child) using the meta-regression by the maximum likelihood method (Table 2). A trend towards better eradication with Lactobacillus sp. but none of the differences reached statistical significance was observed. None of the other variables were found to have a significant impact on the results.
The main conclusion about improvement in eradication rates was drawn on the basis of a comprehensive systematic review including non-English journals. The results remained stable across a wide spectrum of subanalyses and exclusion sensitivity analyses. Nevertheless, several limitations merit consideration. The conclusions are primarily based on eradication data using author-defined cutoffs. Two of the included studies have only been published as abstracts from conference proceedings [26,27]. Hence, they were not peer-reviewed and details of the methodology were not available despite efforts. Most of the trials did not specifically evaluate change in C-UBT values. For the secondary analysis on C-UBT change imputation of data using graphs was necessitated in two of the studies and follow-up value had to be assumed in the third study.
The results have important clinical implications and provide direction for future research. Several studies in the past have evaluated the benefit of probiotics in a capsule/sachet-based form or fermented milk product form with variable results. Fermented milk contains several potentially active biological components with documented anti-helicobacter properties. Of these, bovine lactoferrin has been the most evaluated with several authors [10–14] documenting an improvement in eradication rates on addition to standard regimens, whereas one trial documented insignificant improvement. Glycomacropeptide and α-lactalbumin are other biologically active components deserving further exploration [16,17]. Lactic acid produced by the fermenting bacteria itself has been documented to have anti-helicobacter properties . Thus, it is important to differentiate the fermented milk-based formulations from capsule/sachet-based probiotic bacteria.
J.N. developed the idea for review, prepared the protocol, applied the search strategy, A.S. and J.N. retrieved the articles and extracted data. J.N. did the statistical analysis. Both the authors contributed to the drafting of the final version of the paper. J.N. will be the guarantor for the paper. This study was supported by intramural funding by Sitaram Bhartia Institute of Science and Research, New Delhi.
Conflict of interest: none declared.
1. Go MF. Review article: natural history and epidemiology of Helicobacter pylori
infection. Aliment Pharmacol Ther 2002; 16 (Suppl 1):3–15. [PMID: 11849122].
2. Rauws EA, Tytgat GN. Cure of duodenal ulcer associated with eradication of Helicobacter pylori
. Lancet 1990; 335:1233–1235. [PMID: 1971318].
3. Brenes F, Ruiz B, Correa P, Hunter F, Rhamakrishnan T, Fontham E, Shi TY. Helicobacter pylori
causes hyperproliferation of the gastric epithelium: pre- and post-eradication indices of proliferating cell nuclear antigen. Am J Gastroenterol 1993; 88:1870–1875. [PMID: 7901989].
4. Boot H, De Jong D, Van Heerde P, Taal B. Role of Helicobacter pylori
eradication in high-grade MALT lymphoma. Lancet 1995; 346:448–449. [PMID: 7623599].
5. Chey WD, Wong BC. Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology Guideline on the Management of Helicobacter pylori
Infection. Am J Gastroenterol 2007; 102:1808–1825. [PMID: 17608775].
6. Malfertheiner P. Compliance, adverse events and antibiotic resistance in Helicobacter pylori
treatment. Scand J Gastroenterol Suppl 1993; 196:34–37. [PMID: 8341989].
7. Gotteland M, Brunser O, Cruchet S. Systematic Review: are probiotics useful in controlling gastric colonization by Helicobacter pylori
? Aliment Pharmacol Ther 2006; 23:1077–1086. [PMID: 16611267].
8. Hamilton-Miller JMT. The role of probiotics in the treatment and prevention of Helicobacter pylori
infection. Int J Antimicrob Agents 2003; 22:360–366. [PMID: 14522098].
9. Tong JL, Ran ZH, Shen J, Zhang CX, Xiao SD. Meta-analysis
: the effect of supplementation with probiotics on eradication rates and adverse events during Helicobacter pylori
eradication therapy. Aliment Pharmacol Ther 2007; 25:155–168. [PMID: 17229240].
10. De Bortoli N, Leonardi G, Ciancia E, Merlo A, Bellini M, Costa F, et al. Helicobacter pylori
eradication: a randomized prospective study of triple therapy versus triple therapy plus lactoferrin and probiotics. Am J Gastroenterol 2007; 102:951–956. [PMID: 17313499].
11. Di Mario F, Aragona G, Dal Bó N, Cavallaro L, Marcon V, Olivieri P, et al. Gastrointestinal Study Unit (GISU). Bovine lactoferrin for Helicobacter pylori
eradication: an open, randomized, multicentre study. Aliment Pharmacol Ther 2006; 23:1235–1240. [PMID: 16611285].
12. Okuda M, Nakazawa T, Yamauchi K, Miyashiro E, Koizumi R, Booka M, et al. Bovine lactoferrin is effective to suppress Helicobacter pylori
colonization in the human stomach: a randomized, double-blind, placebo-controlled study. J Infect Chemother 2005; 11:265–269. [PMID: 16369731].
13. Di Mario F, Aragona G, Dal Bò N, Cavestro GM, Cavallaro L, Iori V, et al. Use of bovine lactoferrin for Helicobacter pylori
eradication. Dig Liver Dis 2003; 35:706–710. [PMID: 14620619].
14. Di Mario F, Aragona G, Bò ND, Ingegnoli A, Cavestro GM, Moussa AM, et al. Use of lactoferrin for Helicobacter pylori
eradication. Preliminary results. J Clin Gastroenterol 2003; 36:396–398. [PMID: 12702979].
15. Zullo A, De Francesco V, Scaccianoce G, Manes G, Efrati C, Hassan C, et al. Helicobacter pylori
eradication with either quadruple regimen with lactoferrin or levofloxacin-based triple therapy: a multicentre study. Dig Liver Dis 2007; 39:806–810. [PMID: 17644057].
16. Ushida Y, Shimokawa Y, Matsumoto H, Toida T, Hayasawa H. Effects of bovine alpha-lactalbumin on gastric defense mechanisms in naive rats. Biosci Biotechnol Biochem 2003; 67:577–583. [PMID: 12723606].
17. Brody EP. Biological activities of bovine glycomacropeptide. Br J Nutr 2000; 84 (Suppl 1):S39–S46. [PMID: 11242445].
18. Aiba Y, Suzuki N, Kabir AM, Takagi A, Koga Y. Lactic acid-mediated suppression of Helicobacter pylori
by the oral administration of Lactobacillus salivarius
as a probiotic in a gnotobiotic murine model. Am J Gastroenterol 1998; 93:2097–2101. [PMID: 9820379].
19. Higgins JPT, Green S, editors. Assessment of study quality. Cochrane Handbook for Systematic Reviews of Interventions 4.2.6 [updated September 2006]; Section 6. In: The Cochrane Library, Issue 4. Chichester: John Wiley & Sons; 2006.
20. Juni P, Altman DJ, Egger M. Assessing the quality of randomized controlled trials. In: Egger M, Smith GD, Altman DG, editors. Systematic reviews in health care: meta-analysis
in context. London: BMJ Publishing; 2001. pp. 87–108.
21. Sheu BS, Wu JJ, Lo CY, Wu HW, Chen JH, Lin YS, Lin MD. Impact of supplement with Lactobacillus- and Bifidobacterium-containing yogurt
on triple therapy for Helicobacter pylori
eradication. Aliment Pharmacol Ther 2002; 16:1669–1675. [PMID: 12197847].
22. Sýkora J, Valecková K, Amlerová J, Siala K, Dedek P, Watkins S, et al. Effects of a specially designed fermented milk
product containing probiotic Lactobacillus casei
DN-114 001 and the eradication of H. pylori
in children: a prospective randomized double-blind study. J Clin Gastroenterol 2005; 39:692–698. [PMID: 16082279].
23. Goldman CG, Barrado DA, Balcarce N, Rua EC, Oshiro M, Calcagno ML, et al. Effect of a probiotic food as an adjuvant to triple therapy for eradication of Helicobacter pylori
infection in children. Nutrition 2006; 22:984–988. [PMID: 16978844].
24. Felley CP, Corthésy-Theulaz I, Rivero JL, Sipponen P, Kaufmann M, Bauerfeind P, et al. Favorable effect of an acidified milk (LC-1) on Helicobacter pylori
gastritis in man. Eur J Gastroenterol Hepatol 2001; 13:25–29. [PMID: 11204805].
25. Park MJ, Kim SJ, Yim JY, Jung HC, Song IS, Yu ES, et al. The suppressive effect of a fermented milk
containing lactobacilli on helicobacter pylori
in human gastric mucosa. Gastroenterology 2001; 38:233–240.
26. Kim M, Kim N, Lee D, Jung H, Song I. The effects of probiotics on the PPI triple therapy for Helicobacter pylori
eradication: Abstract no.: P087. Helicobacter
27. Song HJ, Lee HE, Kim SG, Kim JS, Kim WS, Jung HC, Song IS. The effect of a Lactobacilli-containing fermented milk
on Helicobacter pylori
eradication therapy: double-blind, placebo controlled, randomized study: WO047 [abstract]. J Gastroenterol Hepat 2005; 20 (Suppl 2):A308.
28. Sheu BS, Cheng HC, Kao AW, Wang ST, Yang YJ, Yang HB, Wu JJ. Pretreatment with Lactobacillus- and Bifidobacterium-containing yogurt
can improve the efficacy of quadruple therapy in eradicating residual Helicobacter pylori
infection after failed triple therapy. Am J Clin Nutr 2006; 83:864–869. [PMID: 16600940].
29. Cats A, Kuipers EJ, Bosschaert MA, Pot RG, Vandenbroucke-Grauls CM, Kusters JG. Effect of frequent consumption of a Lactobacillus casei
-containing milk drink in Helicobacter pylori
-colonized subjects. Aliment Pharmacol Ther 2003; 17:429–435. [PMID: 12562457].
30. Miki K, Urita Y, Ishikawa F, Iino T, Shibahara-Sone H, Akahoshi R, et al. Effect of Bifidobacterium bifidum fermented milk
on Helicobacter pylori
and serum pepsinogen levels in humans. J Dairy Sci 2007; 90:2630–2640. [PMID: 17517703].
31. Sullivan A, Bennet R, Viitanen M, Ann-Chatrin P, Carl-Erik N. Influence of Lactobacillus F19 on intestinal microflora in children and elderly persons and impact on Helicobacter pylori
infections. Microb Ecol Health Dis 2002; 14:17–21.
32. Sgouras D, Maragkoudakis P, Petraki K, Martinez-Gonzalez B, Eriotou E, Michopoulos S, et al. In vitro and in vivo Inhibition of Helicobacter pylori
by Lactobacillus casei
Strain Shirota. Appl Environ Microbiol 2004; 70:518–526. [PMID: 14711683].
33. Wendakoon CN, Thomson ABR, Ozimek L. Lack of therapeutic effect of a specially designed yogurt
for the eradication of Helicobacter pylori
infection. Digestion 2002; 65:16–20. [PMID: 11961338].
34. Cindoruk M, Erkan G, Karakan T, Dursun A, Unal S. Efficacy and safety of Saccharomyces boulardii
in the 14-day triple anti-Helicobacter pylori
therapy: a prospective randomized placebo-controlled double-blind Study. Helicobacter
2007; 12:309–316. [PMID: 17669103].
35. Sykora J, Valeekova K, Amlerova J, Siala K, Dedek P, Watkins S, et al. 1, 6 Omeprazole based triple therapy with amoxicillin and clarithromycin supplemented with fermented milk
containing special probiotic (Lactobacillus casei
DN-114 001) in the eradication of H. pylori
colonized children: a prospective randomised controlled trial. Helicobacter
36. Pantoflickova D, Corthesy-Theulaz I, Dorta G, Stolte M, Isler P, Rochat F, et al. Favorable effect of regular intake of fermented milk
containing Lactobacillus johnsonii
on Helicobacter pylori
associated gastritis. Aliment Pharmacol Ther 2003; 18:805–813. [PMID: 14535874].
37. Opekun AR, Yen CW, Opekun JL, Graham DY. In vivo tests of natural therapy, tibetan yogurt
or fresh broccoli, for Helicobacter pylon
infection. Methods Find Exp Clin Pharmacol 2005; 27:327–329. [PMID: 16082421].
38. Wang KY, Li SN, Liu CS, Perng DS, Su YC, Wu DC, et al. Effects of ingesting Lactobacillus- and Bifidobacterium-containing yogurt
in subjects with colonized Helicobacter pylori
. Am J Clin Nutr 2004; 80:737–741. [PMID: 15321816].
39. Horie K, Horie N, Abdau AM, Yang JO, Yun SS, Chun HN, et al. Suppressive effect of functional drinking yogurt
containing specific egg yolk immunoglobulin on Helicobacter pylori
in humans. J Dairy Sci 2004; 87:4073–4079. [PMID: 15545368].
40. Miyaji M, Yasue N, Hayakawa T, Higashi K, Kimura M, Tsukada K, et al. Yogurt
containing Lactobacillus gasseri
OLL2716 (LG21) ameliorates gastric mucosal inflammation in Helicobacter pylori
infected patients with upper gastrointestinal symptoms. Jpn Pharmacolo Ther 2006; 34:91–96.
41. Kawai T, Takagi A, Uemura N, Inoue K, Nakajima S, Koga Y. Randomized double blind controlled trial of the efficacy of Lactobacillus ghasseri
OLL2716 (LG21) for suppression of Helicobacter pylori
: G.08. Helicobacter
2006; 11 (Suppl 2):40.
42. Takagi A, Koga Y. Therapeutic effect of Lactobacillus gasseri
and plaunotol on the triple therapy for Helicobacter pylori
eradication: abstract no. 15[middle dot] 05. Helicobacter
43. Gotteland M, Poliak L, Cruchet S, Brunser O. Effect of regular ingestion of Saccharomyces boulardii
plus inulin or Lactobacillus acidophilus
LB in children colonized by Helicobacter pylori
. Acta Paediatr 2005; 94:1747–1751.
44. Takagi A, Koga Y. Therapeutic effect of Lactobacillus gasseri
and Plaunotol on Helicobacter pylori
infection: abstract no. 11.27. Helicobacter
. 2005; 10:536–537.
45. Imoto I, Okuda M, Nakazawa T, Miyashiro E, Yamauchi K, Teraguchi S, et al. Suppressive effect of bovine lactoferrin against Helicobacter pylori
46. Shimizu T, Haruna H, Hisada K, Yamashiro Y. Effects of Lactobacillus gasseri
OLL 2716 (LG21) on Helicobacter pylori
infection in children. J Antimicrob Chemother 2002; 50:617–618. [PMID: 12356815].
47. Sakamoto I, Igarashi M, Kimura K, Takagi A, Miwa T, Koga Y. Suppressive effect of Lactobacillus gasseri
OLL 2716 (LG21) on Helicobacter pylori
infection in humans. J Antimicrob Chemother 2001; 47:709–710. [PMID: 11328791].
48. Oh Y, Osato MS, Han X, Bennett G, Hong WK. Folk yoghurt kills Helicobacter pylori
. J Appl Microbiol 2002; 93:1083–1088. [PMID: 12452966].
49. Cruchet S, Obregon MC, Salazar G, Diaz E, Gotteland M. Effect of the ingestion of a dietary product containing Lactobacillus johnsonii
La1 on Helicobacter pylori
colonization in children. Nutrition 2003; 19:716–721. [PMID: 12921879].
50. Hashimoto K, Aoki T, Ishikawa F, Lino T, Nagoaka M, Shimakawa Y, et al. Effect of Bifidobacterium bifidum
strain Yakult-containing fermented milk
on Helicobacter pylori
-positive healthy volunteers. Assoc J Jpn Soc Med Use Funct Foods 2005; 2:203–213.
52. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22:719–748.
53. DerSimonian R, Laird N. Meta-analysis
in clinical trials. Control Clin Trials 1986; 7:177–188.
54. Guo JB, Yang PF, Wang MT. The application of clostridium to the eradication of Helicobacter pylori
. Chin J Celiopathy 2004; 4:163–165.
55. Cao YJ, Qu CM, Yuan Q. Control of intestinal flora alteration induced by eradication therapy of Helicobacter pylori
infection in the elders. Chin J Gastroenterol Hepatol 2005; 14:195–199.
56. Nista EC, Candelli M, Cremonini F, Cazzato IA, Zocco MA, Franceschi F, et al. Bacillus clausii
therapy to reduce side-effects of anti-Helicobacter pylori
treatment: randomized, double-blind, placebo controlled trial. Aliment Pharmacol Ther 2004; 20:1181–1188. [PMID: 15569121].
57. Armuzzi A, Cremonini F, Bartolozzi F, Canducci F, Candelli M, Ojetti V, et al. The effect of oral administration of Lactobacillus GG on antibiotic-associated gastrointestinal side-effects during Helicobacter pylori
eradication therapy. Aliment Pharmacol Ther 2001; 15:163–169. [PMID: 11148433].
58. Armuzzi A, Cremonini F, Ojetti V, Bartolozzi F, Canducci F, Candelli M, et al. Effect of Lactobacillus GG supplementation on antibiotic-associated gastrointestinal side effects during Helicobacter pylori
eradication therapy: a pilot study. Digestion 2001; 63:1–7. [PMID: 11173893].
59. Cremonini F, Di Caro S, Covino M, Armuzzi A, Gabrielli M, Santarelli L, et al. Effect of different probiotic preparations on anti-helicobacter pylori
therapy-related side effects: a parallel group, triple blind, placebo-controlled study. Am J Gastroenterol 2002; 97:2744–2749. [PMID: 12425542].
60. Myllyluoma E, Veijola L, Ahlroos T, Tynkkynen S, Kankuri E, Vapaatalo H, et al. Probiotic supplementation improves tolerance to Helicobacter pylori
eradication therapy – a placebo-controlled, double-blind randomized pilot study. Aliment Pharmacol Ther 2005; 21:1263–1272. [PMID: 15882248].
61. Canducci F, Armuzzi A, Cremonini F, Cammarota G, Bartolozzi F, Pola P, et al. A lyophilized and inactivated culture of Lactobacillus acidophilus
increases Helicobacter pylori
eradication rates. Aliment Pharmacol Ther 2000; 14:1625–1629. [PMID: 11121911].