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. 2025 Jul 23;57(1):2533431. doi: 10.1080/07853890.2025.2533431

Efficacy of probiotics pretreatment in Helicobacter pylori eradication therapy: a systematic review and meta-analysis of clinical outcomes

Yinghui Zhang a, Mengtian Tu b, Ping Long a, Jing Zheng a, Guanghong Du c, Shiyu Xiao a,✉, Caiping Gao a,d,✉
PMCID: PMC12288164  PMID: 40697099

Abstract

Background

Probiotics inhibit Helicobacter pylori (H. pylori) growth and alter gut microbiome, in addition to alleviating the side effects of H. pylori eradication. It has also been reported that H. pylori be eradicated after fecal microbiota transplantation in some cases. However, whether probiotics used before H. pylori eradication improves the eradication rate remains unclear. This study evaluates their role through a systematic review and meta-analysis.

Methods

We searched PubMed, EMBASE, the Cochrane Library, and the Conference Proceedings Citation Index up to January 31, 2024, to identify randomized controlled studies (RCTs) assessing the efficacy of probiotics used before H. pylori eradication. Meta-analyses of eradication rates were performed.

Results

Twelve eligible RCTs with 2,144 participants were included. The intention-to-treat analysis revealed that the overall eradication rate of H. pylori was higher in the probiotics pretreatment group compared to the control group (80.34% vs. 70.49%), with a risk ratio (RR) of 1.14 (95% CI: 1.08 to 1.19; I2 = 36%) and side effects were less (16.0% vs. 28.3%, RR = 0.59, 95% CI 0.41 to 0.84). The per-protocol analysis yielded similar results (86.43% vs. 76.88%, RR = 1.12, 95% CI: 1.08 to 1.17; I2 = 57%). Subgroup analyses, considering factors like geographic location, eradication regimens, and probiotic combinations, consistently confirmed the benefits. Finally, probiotics pretreatment durations of 14 days or more, as well as the study designs pre vs. free and pre and combine vs. free, demonstrated significant effects. Shorter durations and other study designs with fewer studies did not show significant effects.

Conclusion

There is moderate to high evidence to suggest that probiotics pretreatment improves H. pylori eradication rate and reduces side effects. These findings highlight the potential value of gut microbiome modulation in H. pylori treatment and offer a new direction for addressing the challenges of antibiotic resistance and treatment failure.

Keywords: Helicobacter pylori, pretreatment, probiotics, microbiome, meta-analysis

Introduction

The global prevalence of Helicobacter pylori (H. pylori) infection remains above 40% [1]. H. pylori infection, which invariably causes gastritis, is difficult to clear naturally unless treated with eradication therapies consisting of antibiotics and acid suppressants [2]. Persistent infection can lead to chronic atrophic gastritis, peptic ulcers, gastric cancer, gastric mucosa-associated lymphoid tissue lymphoma etc. H. pylori has also been linked to an increased risk of colorectal cancer and Alzheimer’s disease [3,4]. However, the rise in antibiotic resistance, fueled by widespread antibiotic use, has caused H. pylori eradication rate to decline [5]. Additionally, H. pylori eradication therapies also induce an increase in long-term resistant bacteria communities in the gut [6].

Probiotics, live microorganisms that bring health benefits, have emerged as a potential adjunct to H. pylori therapy. Randomized controlled trials (RCTs) and meta-analyses suggest that probiotics can reduce side effects associated with H. pylori eradication treatments, though their impact on H. pylori eradication rate remains unclear [7–14]. Emerging evidence highlights the gut microbiome’s role in H. pylori clearance. Probiotics may inhibit H. pylori growth through producing antibacterial substances, competing for ecological niches, and modulating the immune system [15–18]. Probiotics also modulate the microbiome across the digestive tract [19–22], potentially altering the environment in which H. pylori thrives and leading to the decolonization of pathogenic bacteria [23]. Furthermore, faecal microbiota transplantation (FMT) has even been reported to clear H. pylori in some cases, underscoring the microbiome’s importance [24].

Despite these findings, it remains unclear whether using probiotics before H. pylori eradication therapy improves outcomes. This study aims to address this gap by evaluating the efficacy of probiotics administered prior to H. pylori treatment through a systematic review and meta-analysis.

Methodology

Registration of review protocol

This systematic review and meta-analysis were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline [25]. The study protocol was registered on the International Prospective Register of Systematic Reviews (CRD42021233382; 22 Feb 2021; Updated 07 Jan 2024).

Search strategy

A comprehensive literature search of PubMed, EMBASE, the Cochrane Library, and the Conference Proceedings Citation Index was carried out up till January 2024 with the following search strategy (Helicobacter pylori OR H. pylori OR Campylobacter Pylori) AND (probiotic OR probiotics OR yeast OR yeasts OR yogurt OR Lactobacillus OR Bifidobacterium OR Saccharomyces OR Streptococcus OR Enterococcus OR Bacillus OR prebiotics OR Lactococcus OR fermented milk OR Clostridium butyricum OR Bacillus subtilis OR Bacillus licheniformis OR Curd). We also manually checked the reference lists of RCTs and systematic reviews identified by previous searches to include other potentially eligible studies.

Eligibility criteria

The title and abstract were used to assess the eligibility of the records. Eligible records were screened for duplicates. Data were extracted from these eligible articles independently by two authors (TM and SX), and any disagreements were resolved through discussion with a third reviewer (ZY). RCTs that compared the pretreatment of probiotics for H. pylori eradication (pretreatment group) with current mainstream guideline-recommended therapies (control group) [7,26], with or without the use of probiotics, were included. Reviews, meta-analyses, comments, letters, case reports, case series, animal studies, and studies without controls were excluded. Additionally, studies that did not report the H. pylori eradication rate, used serological tests to diagnose active H. pylori infection, had an interval of less than 4 weeks for H. pylori re-check, or did not report the interval were also excluded.

Risk of bias assessment

Two investigators (TM and ZY) separately rated the risk of bias in the included RCTs according to the risk of bias assessment tool (RevMan 5.4, Nordic Cochrane Center, Cochrane Collaboration, Copenhagen, Denmark). The assessment covered the following bias domains: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and others. Each domain was categorized as having a low, high, or uncertain risk of bias. If RCTs ≥ 10 was included in the meta-analysis, funnel plots were constructed to assess the risk of publication bias.

Data extraction

We extracted the following information from the included studies: (a) year of publication, region, first author, study design, participants’ characteristics, number of patients in each treatment arm, methods used to confirm H. pylori infection; (b) the type, dose, and duration of probiotics used; (c) initial or rescue therapy, regimen of eradication, eradication rates, side effects, number of patients in whom H. pylori infection was successfully eradicated (either provided directly or calculated from the intention-to-treat [ITT] and the per-protocol [PP] analyses).

Data synthesis and analysis

The endpoints of interest in this meta-analysis were the H. pylori eradication rate. To evaluate the heterogeneity among the included studies, the inconsistency index (I2) statistic was performed. An I2 value larger than 50% indicated a high degree of heterogeneity, and a random-effects model was used to pool studies for analyses. Otherwise, a fixed-effects model was used [27]. Statistical heterogeneity was assessed using sensitivity analyses to determine whether any clinical heterogeneity contributed to such a statistical difference.

Both ITT and PP analyses were used to determine the clinical outcomes. Subgroup analyses were performed to compare the H. pylori eradication rates across studies from different countries, eradication regimens, H. pylori group, probiotic types (single probiotic strains or combinations of probiotics), durations of probiotics used before H. pylori eradication therapies, and study designs of probiotics pretreatment. We summed dichotomous outcome measures as the risk ratio (RR) along with 95% confidence interval (CI) using RevMan 5.4. The results of this meta-analysis were reported as forest plots.

Results

Study selection

A flow diagram of this study is presented in Figure 1. Initially, 867 articles were identified through the primary literature search. Of these, 605 were excluded due to being duplicates, irrelevant to the analysis, or not RCTs. A total of 262 articles were retrieved for further review.

Figure 1.

Figure 1.

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Preferred Reporting Items for systematic Reviews and meta-analyses flow diagram of study selection.

Eight studies were excluded because they were either incomplete or unpublished after registration. 153 articles were excluded as they did not involve the use of probiotics prior to H. pylori eradication treatment. Further exclusions included 52 articles that lacked current mainstream guideline-recommended therapies as controls, 29 articles that did not involve probiotics, and two similar studies published by authors from the same institution within a year. Two articles were excluded for not reporting the H. pylori eradication rate, and two others were excluded because the H. pylori re-check interval was either less than four weeks or not reported. One article was excluded as it was a conference report, and the final report of the same study had already been published. Another article was excluded for using non-viable probiotics. Finally, twelve studies involving 2,144 patients met the inclusion criteria and were included in the meta-analysis [28–39].

Characteristics of eligible studies

The characteristics of the included studies are summarized in Table 1. All studies involved adults, with no pediatric participants. Six studies from China included 1,156 patients, while six studies from Japan, the United States, Italy, Iraq, Iran, and the UAE included 988 patients. The studies covered both initial and rescue therapies for H. pylori infection, with four studies not specifying the therapy type and one including both. Six studies used standard triple therapy, and six used bismuth quadruple therapy. Nine studies used a combination of probiotics, while three used a single probiotic. Probiotic duration varied: 3-7 days (3 studies), 14 days (6 studies), and 21 days or longer (3 studies). The most common pretreatment comparisons were pre vs. free (7 studies) and pre and combine vs. free (4 studies), with fewer studies exploring other variations.

Table 1.

The characteristics of included studies.

Study Subgroup(n) Male/ Female Age (years) Hp infection. Initial diagnosis / Re-check Hp group Regimen of eradication Probiotics used before Hp eradication treatment / Dose / Duration Eradication rate (ITT/PP, %)
Sheu
(2006, China) [28]		 Pre (69) 37/31 48.9 UBT / UBT Rescue BQT L. acidophilus La5, Bifidobacterium lactis Bb12, Lactobacillus bulgaricus, Streptococcus thermophilus / 2 × 1011 CFU / 14d 85.5/90.8
Free (69) 38/30 46.4   71.0/76.6
Deguchi (2012, Japan) [29] Pre + combine (115) 76/39 55.9 Culture, RUT, histology /UBT, SAT, culture Initial STT Lactobacillus gasseri/ ≥109 / 21 d 82.6/85.6
Free (114) 66/48 57.8 69.3/74.5
Du
(2012, China) [30]		 Pre (78) 32/44 44.9 ± 13.8 UBT, RUT, histology / UBT Initial STT Acidophilus, Streptococcus faecalis, Bacillus subtilis /≥4.5 × 107/ 7d 79.5/81.6
Free (79) 33/45 48.0 ± 13.3 60.8/61.5
After (77) 26/48 48.2 ± 12.2 79.2/82.4
Dajani (2013, United Arab) [31] Pre + combine (95) 47/48 19-61 RUT, histology, UBT, SAT / UBT Initial or rescue STT Bifidobacterium infantis / 6 × 109 CFU/ 14d 90.5/90.5
Free (106) 51/55 17-64 68.9/68.9
Combine (100) 51/49 17-62 83.0/83.0
Francavilla (2014, United States) [32] Pre (50) 18/32 22-65 UBT / UBT Not report STT L. reuteri DSM 17938 and ATCC PTA 6475 /2 × 108 CFU / 28d 75.0/76.7
Free (50) 21/29 18-61 65.9/67.4
Wang F (2014, China) [33] Pre (90) 66/24 42 ± 14 UBT, histology / UBT Rescue BQT Lactobacillus acidophilus, Streptococcus faecalis and Bacillus subtilis / >3 × 107 CFU / 14d 66.7/81.1
Free (90) 68/22 40 ± 14 75.6/78.2
Peng (2016, China) [34] Pre (48) 27/21 42.7 ± 15.0 UBT / UBT Rescue STT Bifidobacterium, Lactobacillus bulgaricus and Streptococcus thermophilus / >6 × 107 CFU / 14d 81.3/83.0
Free (48) 38/18 47.4 ± 16.7 60.4/69.0
Combine (48) 31/17 45.0 ± 15.7 83.3/83.3
Shafaghi (2016, Iran) [35] Pre + combine (38) 18/20 43.7 ± 13.3 Histology / UBT Not report BQT Lactobacillus, Bifidobacterium, Streptococcus thermophilus /4 × 108 CFU/ 3d 92.1/92.1
Combine (38) 17/21 43.3 ± 12.2 63.2/100
Jin (2018, China) [36] Pre (70) 37/33 18-70 UBT / UBT Rescue BQT Bifidobacterium, Lactobacillus bulgaricus and Streptococcus thermophilus / >6 × 107 CFU / 28d 75.7/84.1
Pre + combine (70) 41/29 77.1/84.4
Free (70) 43/27 62.9/72.1
Combine (70) 39/31 71.4/79.4
Wang L (2018, China) [37] Pre (60) 34/26 40.3 ± 11.5 UBT / UBT Rescue BQT Lactobacillus acidophilus, Streptococcus faecalis and Bacillus subtilis / >3 × 107 CFU / 14d 91.7/91.7
Free (60) 36/24 39.5 ± 10.4 65.0/65.0
Combine (60) 33/27 38.6 ± 12.3 80.0/80.0
Ameen (2019, Iraq) [38] Pre + combine (37) Not report 17-70 SAT and UBT / SAT or UBT Not report STT lactobacillus acidophilus, lactobacillus salivarius, bifidobacterium bifidum and streptococcus thermophillus / 1 × 109 CFU/ 14d 45.9/89.5
Free (31) 41.9/76.5
Combine (38) 47.4/78.3
After (24) 62.5/83.3
Marinelli (2022, Italy) [39] Pre + combine + after (66) 23/43 50.0–59.3 UBT, histology, / UBT Not report BQT Lactobacillus rhamnosus GG / 6 × 107 CFU / 7d 74.2/94.2
Free (98) 20/78 53.9–62.0 83.7/96.5
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BQT: bismuth quadruple therapy; CFU: colony forming unit; Hp: Helicobacter pylori; ITT: intention-to-treat; PP: per-protocol; Pre: pretreatment; RUT: rapid urease test; SAT: stool antigen test; STT: standard triple therapy; UBT: urea Breath Test.

Outcomes of overall eradication rate

The eradication rate of H. pylori was evaluated across twelve studies involving 2,144 patients. By ITT analysis, the pooled eradication rate was 80.34% (707/880) in the pretreatment group and 70.49% (891/1,264) in the control group. Pretreatment with probiotics significantly improved the eradication rate (RR = 1.14, 95% CI 1.08 to 1.19, p < 0.001), with low heterogeneity observed between studies (I2 = 36%) (Figure 2). Similarly, PP analysis revealed a pooled eradication rate of 86.43% (707/818) in the pretreatment group and 76.88% (891/1,159) in the control group. Probiotics pretreatment also improved the eradication rate (RR = 1.12, 95% CI 1.08 to 1.17, p < 0.001), although heterogeneity was higher (I2 = 57%) (Figure 3).

Figure 2.

Figure 2.

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Forest Plot of randomized controlled trials of H. pylori eradication therapy: Efficacy on H. pylori eradication rate (intention-to-treat analysis).

Figure 3.

Figure 3.

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Forest Plot of randomized controlled trials of H. pylori eradication therapy: Efficacy on H. pylori eradication rate (per-protocol analysis).

Subgroup analysis for H. pylori eradication rate by region

In ITT analysis, studies from China (6 studies) showed a higher eradication rate in the pretreatment group (RR = 1.14, 95% CI 1.07 to 1.22, p < 0.001, I2 = 0%), while studies outside China (6 studies) also demonstrated higher rates (RR = 1.13, 95% CI 1.05 to 1.22, p < 0.001, I2 = 60%). In PP analysis, studies from China reported similar results (RR = 1.13, 95% CI 1.07 to 1.20, p < 0.001, I2 =0%), whereas studies outside China showed higher rates (RR = 1.11, 95% CI 1.05 to 1.18, p < 0.001, I2 = 74%). Both subgroups had consistent findings, with lower heterogeneity in studies from China (Table 2, Supplement Figures S1–S2).

Table 2.

Summary of Forest plot for subgroup analysis.

Sub-group No. of studies Intention-to-treat analysis
 Per-protocol analysis
Pretreatment
 Control
 Risk Ratio I2 Test Pretreatment
 Control
 Risk Ratio I2 Test
Events Total Events Total MH, Fixed,95%CI Events Total Events Total MH, Fixed,95%CI
Country studies from China 6 391 485 476 671 1.14 [1.07, 1.22] 0% 391 460 476 637 1.13 [1.07, 1.20] 0%
studies from outside China 6 316 395 415 593 1.13 [1.05, 1.22] 60% 316 358 415 522 1.11 [1.05, 1.18] 74%
Regimen of eradication STT 6 332 417 488 709 1.15 [1.07, 1.23] 0% 332 391 488 655 1.15 [1.08, 1.22] 0%
BQT 6 375 463 403 555 1.13 [1.05, 1.21] 66% 375 427 403 504 1.10 [1.04, 1.16] 75%
H. pylori group initial 2 157 193 188 270 1.17[1.05, 1.30] 0% 157 187 188 258 1.14[1.04, 1.26] 0%
rescue 5 329 407 367 515 1.14[1.06, 1.23] 12% 329 384 367 485 1.13[1.06, 1.21] 12%
unclear 5 221 280 336 479 1.11[1.02, 1.21] 67% 221 247 336 416 1.10[1.04. 1.17] 77%
Probiotic type combination of probiotics 8 414 526 466 690 1.15 [1.07, 1.23] 20% 414 484 466 610 1.12 [1.05, 1.18] 53%
certain probiotic 4 293 354 425 574 1.12 [1.05, 1.20] 63% 293 334 425 549 1.13 [1.07, 1.20] 73%
Probiotics pretreatment duration 3d-7d 2 85 104 105 136 1.06 [0.93, 1.22] 89% 85 90 105 109 0.98 [0.92, 1.04] 32%
14d 7 387 477 584 830 1.14 [1.08, 1.21] 5% 387 447 584 777 1.15 [1.09, 1.22] 0%
> =21d 3 235 299 202 298 1.16 [1.05, 1.28] 0% 235 281 202 273 1.13 [1.04, 1.23] 0%
Study design pre vs. free 7 370 459 306 460 1.21[1.12, 1.31] 25% 370 439 306 436 1.20[1.11, 1.29] 16%
pre vs. combine 3 147 178 138 178 1.07[0.96, 1.18] 0% 147 170 138 171 1.07[0.97, 1.18] 0%
pre vs. after 1 62 78 61 77 1.00[0.85, 1.18] / 62 76 61 74 0.99[0.85, 1.15] /
pre + combine vs. free 4 252 317 209 321 1.23[1.12, 1.36] 0% 252 289 209 290 1.21[1.11, 1.32] 0%
pre + combine vs. combine 4 192 240 175 246 1.13[1.02, 1.24] 36% 192 216 175 210 1.06[0.98, 1.14] 48%
pre + combine vs. after 1 17 37 15 24 0.74[0.46, 1.17] / 17 19 15 18 1.07[0.83, 1.39] /
pre + combine + after vs. free 1 50 66 81 98 0.92[0.78, 1.08] / 50 52 81 85 1.01[0.94, 1.08] /
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BQT: bismuth quadruple therapy, pre: pretreatment, STT: standard triple therapy.

Subgroup analysis for H. pylori eradication rate by eradication regimen

In ITT analysis, standard triple therapy (6 studies) showed a higher eradication rate in the pretreatment group (RR = 1.15, 95% CI: 1.07–1.23; I2 = 0%), while the bismuth quadruple therapy (6 studies) also demonstrated higher rates (RR = 1.13, 95% CI: 1.05–1.21; I2 = 66%). In PP analysis, standard triple therapy yielded similar results (RR = 1.15, 95% CI: 1.08–1.22; I2 = 0%), whereas bismuth quadruple therapy showed slightly lower rates (RR = 1.10, 95% CI: 1.04–1.16; I2 = 75%). Both regimens were effective (Table 2, Supplement Figures S3–S4).

Subgroup analysis for H. pylori eradication rate by H. pylori group

In ITT analysis, consistent results were observed across different H. pylori groups (initial therapy, rescue therapy, and unclear). The initial H. pylori group (2 studies) exhibited a higher eradication rate in the pretreatment group (RR = 1.17, 95% CI: 1.05 to 1.30; I2 = 0%). The rescue H. pylori group (5 studies) also showed increased eradication rates (RR = 1.14, 95% CI: 1.06 to 1.23; I2 = 12%). Similarly, the unclear H. pylori group (5 studies) demonstrated higher efficacy (RR = 1.11, 95% CI: 1.02 to 1.21; I2 = 67%). PP analysis reported similar results (Table 2, Supplement Figures S5–S6).

Subgroup analysis for H. pylori eradication rate by probiotic types

In ITT analysis, the combination of probiotics (8 studies) showed a higher eradication rate in the pretreatment group (RR = 1.15, 95% CI: 1.07–1.23; I2 = 20%), while a certain probiotic (4 studies) also demonstrated higher rates (RR = 1.12, 95% CI: 1.05–1.20; I2 = 63%). In PP analysis, the combination of probiotics yielded similar results (RR = 1.12, 95% CI: 1.05–1.18; I2 = 53%), whereas the certain probiotic showed comparable rates (RR = 1.13, 95% CI: 1.07–1.20; I2 = 73%). Both probiotic types were effective (Table 2, Supplement Figures S7–S8).

Subgroup analysis for H. pylori eradication rate by probiotics pretreatment duration

In ITT analysis, the duration of probiotics pretreatment prior to H. pylori eradication therapy yielded inconsistent results. Pretreatment for 3 to 7 days did not significantly improve the eradication rate (RR = 1.06, 95% CI 0.93 to 1.22, p = 0.39, I2 = 89%). However, pretreatment for 14 days significantly enhanced the eradication rate (RR = 1.14, 95% CI 1.08 to 1.21, p < 0.001, I2 = 5%). Similarly, pretreatment for 21 days or longer also improved the eradication rate (RR = 1.16, 95% CI 1.05 to 1.28, p = 0.003, I2 = 0%). PP analysis reported similar results. (Table 2, Supplement Figures S9–S10).

Subgroup analysis for H. pylori eradication rate by study design

In ITT analysis, significant improvements were observed in pre vs. free (RR = 1.21, 95% CI 1.12 to 1.31, p < 0.001, I2 = 25%) and pre and combine vs. free (RR = 1.23, 95% CI: 1.12–1.36; I2 = 0%), while other study designs with fewer studies did not show significant effects. In PP analysis, pre vs. free (RR = 1.20, 95% CI: 1.11 to1.29; I2 = 16%) and pre and combine vs. free (RR = 1.21, 95% CI: 1.11 to1.32; I2 = 0%) remained significant, with other designs yielding non-significant findings. Pretreatment before H. pylori eradication therapy showed consistent efficacy, particularly in comparison to free regimens (Table 2, Supplement Figures S11–S12).

Side effects

The main reported side effects included nausea, diarrhea, constipation and metallic taste et al. Some studies reported that side effects were similar, and some studies did not report side effects. According to available data from eight studies (1551 patients), side effects were less likely in the probiotics pretreatment group compared to the control group (16.0% vs. 28.3%, RR = 0.59, 95% CI 0.41 to 0.84, p < 0.005, Figure 4).

Figure 4.

Figure 4.

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Forest Plot of randomized controlled trials of H. pylori eradication therapy: side effects.

Risk of bias and sensitivity analysis

The risk of bias summary was shown in Figure 5. The risks for bias were shown in Supplement Figure S13. In the sensitivity analysis, after deleting one study at a time, the statistical significance of the combined RR remained unchanged.

Figure 5.

Figure 5.

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Risk of bias summary.

Publication bias

Funnel plot showed no significant publication bias among the twelve studies included in this meta-analysis (Supplement Figure S14).

Quality of evidence through GRADEPro analysis

The quality of evidence from the included studies was assessed using the Cochrane review tool GRADEpro GDT (https://gdt.gradepro.org/app/), focusing on the efficacy of probiotics pretreatment in H. pylori eradication therapy. As shown in Table 3, the certainty of the overall effects of probiotics pretreatment (n = 12) was high (⊕⊕⊕⊕) in the ITT analysis, demonstrating the effectiveness of probiotics in improving H. pylori eradication rates. However, the certainty decreased from high to moderate in PP analysis. Across all subgroup analyses, the certainty of evidence for probiotics pretreatment remained either high or moderate. Detailed GRADEpro assessments for all subgroups are provided in Supplement (Supplement Table S1).

Table 3.

GRADEpro Summary of findings for assessing the quality of evidence as assessed separately by two reviewers.

Certainty assessment
 № of patients
 Effect
 Certainty Importance
№ of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Pretreatment of probiotics control Relative
(95% CI)		 Absolute
(95% CI)
Total: intention-to-treat analysis (ITT)
12 randomised trials not serious not serious not serious not serious none 707/880 (80.3%) 891/1264 (70.5%) RR 1.14
(1.08 to 1.19)		 99 more per 1,000
(from 56 more to 134 more)		 ⊕⊕⊕⊕
High		 CRITICAL
Total: per-protocol analysis (PP)
12 randomised trials not serious serious not serious not serious none 707/818 (86.4%) 891/1159 (76.9%) RR 1.12
(1.12 to 117.00)		 92 more per 1,000
(from 92 more to 1,000 more)		 ⊕⊕⊕○
Moderate		 CRITICAL
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CI: confidence interval; RR: risk ratio.

4. Discussion

This systematic review and meta-analysis investigated the efficacy of probiotics pretreatment in improving H. pylori eradication rate. Unlike previous studies, which primarily focused on probiotics administered during or after H. pylori eradication therapies, this study explored the role of probiotics as a pretreatment strategy. Probiotics pretreatment significantly increased eradication rate (80.34% vs. 70.49%, RR = 1.14, 95% CI 1.08–1.19, p < 0.001). Subgroup analyses confirmed benefits across regions and eradication regimens, H. pylori group, with both single and combined probiotics showing efficacy. However, pretreatment duration was critical: 14 days or longer improved eradication rates, while shorter durations (3–7 days) did not. Study designs pre vs. free and pre and combine vs. free further validated probiotic pretreatment’s efficacy in improving H. pylori eradication rate. These results suggest that probiotics, when administered prior to H. pylori eradication therapy, may play a beneficial role in improving treatment outcomes.

Two previous meta-analyses examined the efficacy of probiotics administered at different timings (before, during, after) in H. pylori eradication therapy. Lv et al. found that probiotics used before and after the treatment regimen improved eradication rates [40], while Shi et al. reported that probiotics administered before and throughout eradication therapy enhanced efficacy [10]. These meta-analyses included 4 or 5 RCTs with probiotics used before H. pylori eradication, and 1or 2 RCTs did not meet the current study’s eligibility criteria; and their findings align with our study results. These findings contrast with earlier research, which suggested that while certain probiotics, such as Lactobacillus, can inhibit H. pylori growth, adhesion, and colonization through mechanisms like autolysin secretion and reduced binding to glycolipid receptors,16-18 they do not clear H. pylori infection on their own [41]. For instance, single probiotic strains have been shown to reduce urease activity in H. pylori-infected patients but fail to eradicate the pathogen [21,42].

The potential mechanisms underlying the benefits of probiotics pretreatment may involve biofilm formation and gut microbiome modulation. Some probiotics can bind to and produce biofilms in cultured cells, significantly reducing H. pylori binding and colonization [43,44]. Additionally, supplementing with probiotics alters the gut microbiome, which may create an environment less conducive to H. pylori survival [19–21]. This is supported by studies showing that FMT cleared H. pylori in 40.6% of patients, highlighting the gut microbiome’s potential role in H. pylori treatment [24]. Furthermore, a meta-analysis involving patients with inflammatory bowel disease (IBD), a condition associated with significant gut microbiome changes, found a reduced H. pylori infection rate in IBD patients, further emphasizing the interplay between the gut microbiome and H. pylori clearance [45].

The gut microbiome is increasingly recognized as a critical factor in maintaining intestinal homeostasis and immune function, offering hope for the treatment of infectious diseases. For example, FMT has proven effective against Clostridium difficile infection and shows promise in treating human immunodeficiency virus infection [46–48]. Similarly, probiotic supplementation has been associated with reduced mortality in COVID-19 patients and may help decolonize pathogenic bacteria from the gut [49]. These findings, along with our results, suggest that modulating the gut microbiome—whether through probiotics, FMT, or other methods—could be a valuable strategy for addressing multidrug-resistant H. pylori and the long-term resistant bacterial communities that arise from eradication therapies. However, the mechanisms underlying these effects, such as the migration of gut-licensed immune cells to other tissues, require further investigation [50].

Despite these promising findings, this study has several limitations. First, the meta-analysis included only twelve RCTs with varying probiotic strains, doses, durations, and combinations, which may affect the reliability of the conclusions. Second, six of the included studies were conducted in China, and although studies from other regions supported the same conclusions, more diverse populations are needed to generalize the findings. Third, this study did not evaluate the simultaneous use of probiotics during eradication therapies or their supplementation after treatment, as these topics have been extensively covered in previous umbrella meta-analyses [9]. Future research should investigate key factors affecting probiotic efficacy, including strain selection, dosage optimization, antimicrobial interactions, and ethnic/age-specific responses through rigorous clinical trials and omics technologies.

In conclusion, this meta-analysis provides evidence that probiotics pretreatment significantly improves H. pylori eradication rate and reduces side effects, particularly when probiotics is used for an adequate duration. These findings highlight the potential value of gut microbiome modulation in H. pylori treatment and offer a new direction for addressing the challenges of antibiotic resistance and treatment failure. Further studies are needed to elucidate the mechanisms involved and to develop standardized protocols for probiotic use in H. pylori eradication therapies.

Acknowledgements

Supplementary Material

Clean copy - Supplementary_Materials - IANN-2025-1474.R2.docx
IANN_A_2533431_SM2739.docx (4.3MB, docx)
PRISMA_2020_checklist.docx
IANN_A_2533431_SM2738.docx (32.3KB, docx)

Acknowledgments

We are grateful to Professor Xing-Xiang He from the First Affiliated Hospital of Guangdong Pharmaceutical University for his help in reconfirming that none of the patients who were cleared of H. pylori after FMT tested positive for H. pylori until April 2024. Yinghui Zhang and Mengtian Tu are joint first authors. Shiyu Xiao and Caiping Gao are joint senior authors. CRediT: Yinghui Zhang: Validation, Investigation, Methodology, Visualization, Writing – original draft; Mengtian Tu: Data curation, Investigation, Formal analysis, Software, Writing – original draft; Ping Long: Data curation; Jing Zheng: Data curation; Guanghong Du: Data curation; Shiyu Xiao: Investigation, Methodology, Software, Visualization, Writing – review & editing; Caiping Gao: Conceptualization, Data curation, Funding acquisition, Project administration, Writing – review & editing. All authors have read and approved the final work.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Funding Statement

This work was supported by the [National Natural Science Foundation of China #1] under Grant [number 82170579]; and [Science and Technology Department of Sichuan Province #2] under Grant [number 2023YFS0286].

Ethics statement

This meta-analysis is based on existing published RCTs. The Ethics Committee of Sichuan Academy of Science & Sichuan Provincial People’s Hospital hereby declares that this meta - analysis is exempt from ethical review.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data will be made available from the corresponding author [Caiping Gao] on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Clean copy - Supplementary_Materials - IANN-2025-1474.R2.docx
IANN_A_2533431_SM2739.docx (4.3MB, docx)
PRISMA_2020_checklist.docx
IANN_A_2533431_SM2738.docx (32.3KB, docx)

Data Availability Statement

The data will be made available from the corresponding author [Caiping Gao] on reasonable request.

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