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Effect of fermented milk-based probiotic preparations on Helicobacter pylori eradication: a systematic review and meta-analysis of randomized-controlled trials

Sachdeva, Aarti; Nagpal, Jitender

European Journal of Gastroenterology & Hepatology: January 2009 - Volume 21 - Issue 1 - p 45-53
doi: 10.1097/MEG.0b013e32830d0eff
Original Articles: Upper Gastrointestinal Disorders

Objective To evaluate the effect of fermented milk-based probiotic preparations on Helicobacter pylori eradication.

Design Systematic review of randomized controlled trials.

Data sources Electronic databases and hand search of reviews, bibliographies of books and abstracts and proceedings of international conferences.

Review methods Included trials had to be randomized or quasi-randomized and controlled, using fermented milk-based probiotics in the intervention group, treating Helicobacter-infected patients and evaluating improvement or eradication of H. pylori as an outcome.

Results The search identified 10 eligible randomized controlled trials. Data were available for 963 patients, of whom 498 were in the treatment group and 465 in the control group. The pooled odds ratio (studies n=9) for eradication by intention-to-treat analysis in the treatment versus control group was 1.91 (1.38–2.67; P<0.0001) using the fixed effects model; test for heterogeneity (Cochran's Q=5.44; P=0.488). 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 odds ratio for the number of patients with any adverse effect was 0.51 (95% CI 0.10–2.57; P=0.41; random effects model; heterogeneity by Cochran's Q=68.5; P<0.0001).

Conclusion Fermented milk-based probiotic preparations improve H. pylori eradication rates by approximately 5–15%, whereas the effect on adverse effects is heterogeneous.

Department of Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, New Delhi, India

Correspondence to Dr Jitender Nagpal, Pediatrics and Clinical Epidemiology, Sitaram Bhartia Institute of Science and Research, New Delhi-110016, India

Tel: +91 11 42111111; e-mail: jitendernagpal@gmail.com

Received 28 April 2008 Accepted 16 June 2008

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Introduction

Helicobacter pylori infection is a significant public health problem with reported prevalence rates of up to 70–90% in developing countries [1]. Eradication of H. pylori is often necessary in the management of gastric and duodenal ulcers, gastroesophageal reflux atrophic gastritis and other H. pylori-related complications [2–4]. Standard triple therapy (proton pump inhibitor with clarithromycin with amoxicillin/nitroimidazole) achieves eradication rates ranging from 55 to 90%; 10–45% of patients will fail to eradicate the bacteria and remain H. pylori positive [5]. The second-line quadruple regimens are further limited by poor patient compliance because of side effects, number of tablets per day and long duration [5,6].

Several studies in the recent past have sought to determine the efficacy of various probiotic preparations in H. pylori eradication with or without cointerventions. Recent reviews [7,8] and a meta-analysis [9] have documented a beneficial effect of probiotic preparations (including three studies using fermented milk-based products [9]) on the eradication of H. pylori when used in combination with triple or quadruple therapy. Fermented milk-based probiotics (FMPs) probably differ from capsule/sachet-based bacteria-only preparations (CBOP) with various components (bovine lactoferrin [10–15], α-lactalbumin [16], glycomacropeptide [17], lactic acid [18]) of fermented milk documented to have an inhibitory effect on the Helicobacter in-vivo and in-vitro. In addition, FMPs offer potential benefits in terms of compliance and expense. Thus, with the increasing commercial availability of traditional and probiotic-enriched fermented milk products, we conducted the current systematic review to determine the efficacy of these products, alone or in combination with standard regimens.

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Methods

Searches

We conducted searches in Medline, Extended Medline (1950 to 19 December 2007) using the following search words (Helicobacter or H. pylori) and (Fermented Milk or Yogurt or Curd) with limits pertaining to ‘human’ participants for clinical trial, review, meta-analysis, and randomized controlled trial. We conducted similar searches in EMBASE (1980 to week 50, 2007), AMED (1985 to 19 December 2007), CIAP Full Text Articles, SCOPUS (1869 to 19 December 2007), KoreaMed (1997 to 19 December 2007), MEDIND (19 December 2007) and Cochrane Controlled Trials register (fourth quarter, 2007). We imposed no age or language restrictions. We also reviewed reference lists of identified articles and hand-searched reviews, bibliographies of books, and abstracts. Furthermore, we had searched abstracts of major gastroenterological meetings, such as the Digestive Disease, Week of the American Gastroenterological Association, the World Congress of Gastroenterology, European, and Helicobacter Study Group. Authors of some identified trials were asked whether they knew of additional studies, including unpublished randomized studies. We scanned the titles and abstracts of the trials identified in the computerized search to exclude studies that were obviously irrelevant. We scrutinized the full texts of the remaining studies and identified trials that fulfilled the inclusion criteria.

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Selection criteria

To be included, trials had to be randomized or quasi-randomized and controlled, using a FMP in the intervention group, treating Helicobacter-infected patients (confirmed on urea breath test or histology or stool antigen test; symptomatic or asymptomatic) and evaluating improvement or eradication of H. pylori as an outcome (confirmed on urea breath test or histology or stool antigen test). We considered studies in which other drugs were simultaneously administered to be eligible if the only difference between the intervention and control groups was the FMP. Studies using milk fermented with any strain of Lactobacillus, Bifidobacterium or other bacteria were considered eligible.

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Validity assessment

We assessed the quality of trials by using recommended criteria [19,20]. We categorized randomization into randomized, quasirandomized, not stated or unclear. We classified concealment of allocation as adequate, unclear, or inadequate. To assess attrition, studies were divided by the percentage of participants lost to follow-up (<4.9%, 5–9.9%, 10–19.9%, and ≥20%). For the purpose of this calculation, we considered the number of patients available at the last follow-up (at which data were retrievable). We graded blinding as double blinding, single blinding, no blinding, or unclear.

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Data abstraction

Standardized data abstraction sheets were prepared. Data were extracted for study quality, type and duration of treatment, anti-H. pylori regimens, and the number and age of enrolled patients, diagnostic methods of testing H. pylori infection before enrolling and after completing study and documented side effects. The key outcome data recorded included eradication rates, adverse events including occurrence of diarrhoea, nausea, taste disturbance, or constipation were abstracted from all included studies. All articles were examined independently for eligibility by two reviewers (A.S. and J.N.). The data included in this review were derived from the published studies or published abstracts or provided by the authors. If needed, and wherever possible, we contacted the authors for clarification. When the results of a particular study were reported in more than one publication, only the most recent and complete data were included in the meta-analysis.

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Statistical analysis

Data were entered into the Comprehensive Metaanalysis Software Version 2 (Biostat, Englewood, New Jersey, USA) and MIX v 1.61 software (Kitasato Clinical Research Center, Evidence Synthesis Division – MIX, Sagamihara, Kanagawa, Japan). The outcome measure examined was the odds ratios (ORs) for improving H. pylori eradication rates and reducing side effects with FMP versus without FMP combining with specified treatment regimens. Eradication rates were used as directly specified (eight studies [21–28]) or imputed using pre-C urea breath test (C-UBT) and post-(C-UBT) values (from scatter graphs in two studies [29,30]) and an assumed C-UBT eradication value of approximately 5‰ (two studies [29,30]). Heterogeneity between the studies was assessed by Cochran's Q-test and by visual inspection of the confidence intervals (CIs) on the forest plot. Statistical significance for the test of heterogeneity was set at 0.10. Eradication rates were analyzed based on a fixed effects model both by an intention-to-treat and as per protocol. To evaluate the stability of the results of this meta-analysis, we performed an exclusion sensitivity analysis. We used funnel plot asymmetry to detect any publication bias in the meta-analysis, and Egger's regression test (weighted least squares) to measure funnel plot asymmetry. Subanalyses for the meta-analysis were planned depending on symptoms before enrollment and age of patients.

For the calculation of pooled estimates for C-UBT test we needed the mean C-UBT at the beginning, the end of intervention, the two standard deviations and the correlation between the pretest and posttest values. For most studies C-UBT values were not stated (seven studies [21–27]). In the case of two of the studies [29,30] the values of individual patients could be imputed from the presented graphs of C-UBT/δ-C-UBT to a minimal count of approximately 1‰ and the required values calculated using the Student's t-test. For one study the follow-up values of the control group had to be assumed to be equal to those at baseline in the absence of available data [28].

OR for the number of patients with adverse effects was also evaluated as a secondary outcome measure.

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Results

The bibliographic search yielded a total of 146 results from all specified sources after excluding duplicates. These articles were screened for relevance and fulfillment of selection criteria. Of the 31 potentially relevant clinical trials, 21 were excluded [12,31–50] as specified in Fig. 1 (interrater agreement for eligibility κ=0.946). We therefore evaluated 10 trials [21–30] evaluating H. pylori eradication rates in this systematic review. One study by Cats et al. [29] had to be excluded from the primary outcome analysis as none of the patients in the treatment (n=14) or control groups (n=6) achieved imputed C-UBT values of approximately less than 5‰ at follow-up.

Fig. 1

Fig. 1

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Study characteristics

Table 1 summarizes the baseline characteristics of the included studies. As depicted, most studies were conducted on symptomatic and asymptomatic H. pylori-positive adults. C-UBT with or without endoscopy was used as the initial screening tool as well as for confirmation of eradication in all studies. One study [27] was done in duodenal ulcer patients and another was conducted in patients with treatment failure of the standard triple therapy regimen [28]. Four of the studies [21–23,26,28] used yogurt, whereas in the remainder fermented milk was used. Seven of the studies coadministered various triple (five), [21–23,26,27] quadruple (one) [28] or single-drug therapy regimens [23]. Seven studies were conducted in high-income countries [22,24–27,29,30], one in an upper middle-income country [23] and two studies were from Taiwan where the income status was not specified [21,28] (World Bank list of economies) [51]. Four studies used Bifidobacterium species, [21,23,28,30] five studies used Lactobacillus casei strains [22,23,25,26,29] and four used Lactobacillus acidophilus [21,24,25,28], strains for fermentation of the milk alone or as a combination. Six of the studies [22–25,27,30] were placebo controlled.

Table 1

Table 1

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Eradication rates

Eradication OR was available for 943 patients (nine studies; 484 in the treatment group and 459 in the control group). The pooled OR by intention-to-treat analysis in the treatment versus control group was 1.91 (1.38–2.67; P<0.0001) using the fixed effects model (Mantel and Haenszel method; [52] Fig. 2). The fixed effects model was used as there was insignificant heterogeneity [Cochran's Q=5.44; P=0.488; I^2=0% (95% CI 0–70.81%)]. The results were further examined by an exclusion sensitivity plot to determine the impact of exclusion of one of the studies. No significant change in the results was observed on exclusion of any of the studies. We found no evidence of publication bias on the funnel plot (Fig. 3). This was confirmed by the Egger's (weighted least squares) method (P for bias=0.74).

Fig. 2

Fig. 2

Fig. 3

Fig. 3

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).

Similar results were obtained with per protocol analysis (six studies; N=711; treatment group=369; control group=342 [21,22,24,26–28]). The pooled OR of eradication was 2.35 (95% CI 1.54–3.58) by the fixed effects model (Cochran's Q=7.93; P=0.541). Exclusion of any one of the studies did not impact the results and there was no evidence of publication bias (Egger's weighted least squares P=0.837).

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Change in C-urea breath test values

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).

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Adverse effects

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; [53] 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. [29] and Felley et al. [24] have reported only one case each of diarrhoea in the supplemented group with none in the control group.

Fig. 4

Fig. 4

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Sensitivity analysis

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.

Table 2

Table 2

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Discussion

The results suggest that fermented milk product-based probiotic preparations potentially improve H. pylori eradication rates by approximately 10%. They have no significant impact on the treatment-associated adverse effects. No difference between the studies using yogurt or fermented milk in children or in adults was observed.

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Strengths and limitations

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.

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Implications

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 [18]. Thus, it is important to differentiate the fermented milk-based formulations from capsule/sachet-based probiotic bacteria.

As documented in this analysis, FMP preparations improve H. pylori eradication rates, whereas their impact on adverse effects of standard eradication regimens is heterogeneous. The magnitude of the benefit is comparable with that obtained in a meta-analysis in 2006 [n=1074; pooled OR 1.84 (1.34–2.54) vs. 1.91 (1.38–2.67) in this study] using a mix of CBOP (eight studies [54–61]) and FMP (three studies) preparations in combination with triple therapy by intention-to-treat analysis and higher by per protocol analysis [pooled OR 1.82 (1.30–2.56) vs. 2.35 (1.54–3.58) in this study]. As an exploratory exercise we subanalysed the studies from the meta-analysis to differentiate between preparations using CBOP [OR 1.57 (1.06–2.32)] and FMP preparations [OR 2.51 (1.43–3.51)]. Furthermore, the subanalysis on CBOP preparations (eight studies [54–61]) fails on exclusion sensitivity analysis with the exclusion of one study by Canducci et al. [61] (OR 1.36). These findings allow speculation of equivalent or better efficacy of fermented milk-based products but further research is necessary directly comparing fermented milk-based preparations with capsule/sachet-based preparations given the potentially better compliance with fermented milk-based preparations. It is necessary to document strain and preparation-specific effects in symptomatic and asymptomatic patients receiving first-line or eradication failure regimens. Individual adverse effects and potential benefits in compliance need to be detailed in future studies. Further work is also necessary to explore the potential of long-term intake of FMPs for the prevention and/ or treatment of H. pylori infections. The findings also need to be confirmed in developing countries where interference with other bacteria might be an important confounder.

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Conclusion

Although the results suggest that FMP preparations potentially improve H. pylori eradication rates by approximately 5–15%, more trials are necessary to further validate the results. The limited evidence available and the marginal quality of some of the trials preclude a more robust conclusion. Available data are also inadequate to define a preferred preparation, preferred bacterial species, clinical setting, and effects on compliance or role in eradication failure.

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What is already known on this topic?

Probiotics are effective in improving H. pylori eradication rates and decreasing adverse effects of eradication therapy.

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What this study adds

  • (1) FMP preparations improve H. pylori eradication rates by approximately10%.
  • (2) The impact on adverse effects is heterogeneous.
  • (3) The magnitude of the benefit is comparable or better than that reported for CBOP.
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Acknowledgements

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.

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Keywords:

fermented milk; Helicobacter; meta-analysis; yogurt

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