Probiotics versus Rifaximin as Adjuvant Therapy for Helicobacter pylori Eradication

INTRODUCTION

Helicobacter pylori (H. pylori), a gram-negative bacterium with a global prevalence exceeding 50% [1], is typically asymptomatic. However, it contributes to dyspeptic symptoms, peptic ulcer disease, and is associated with more severe conditions including gastric cancer, mucosa-associated lymphoid tissue (MALT) lymphoma, and extra-gastrointestinal diseases [2,3]. Non-invasive diagnostic techniques, such as the H. pylori stool antigen test and urea breath test, offer excellent sensitivity and specificity [4]. Nevertheless, accurate testing requires discontinuation of antibiotics for four weeks and proton pump inhibitors (PPIs) for two weeks prior to testing [5].

Most guidelines recommend a "test-and-treat" strategy for H. pylori in specific clinical scenarios [3]. Eradication regimens typically combine antibiotics with acid suppression therapy (PPIs or potassium-competitive acid blockers) for 14 days [6]. Standard triple therapy (double-dose PPI, clarithromycin, and amoxicillin for 14 days) achieves eradication rates exceeding 70% [7].

Triple therapy is often associated with side effects such as nausea, vomiting, abdominal pain, and diarrhea [8]. These symptoms can persist for weeks post-treatment. The pathophysiology of diarrhea likely involves antibiotic-induced alterations in gut microbiota [9]. Probiotics, including Bacillus clausii, are commonly used to treat viral diarrhea in children and mitigate antibiotic-associated side effects [10]. B. clausii spores withstand gastric pH, germinate in the intestine, adhere to the intestinal wall, and colonize the mucosa [11].

Rifaximin, a Rifamycin-class antibiotic structurally similar to rifampicin, exhibits potent luminal antibacterial activity [12]. It may also reduce bacterial virulence factors, inhibit adhesion, and attenuate mucosal inflammation [13].

Studies evaluating the addition of probiotics or rifaximin to H. pylori eradication therapy have yielded conflicting results regarding their impact on side effects and eradication rates [14,15]. Probiotics incorporated into various regimens appear beneficial for reducing gastrointestinal adverse effects, particularly diarrhea, but do not consistently improve eradication rates [16]. Similarly, rifaximin supplementation does not enhance H. pylori eradication rates [17], and evidence regarding its efficacy in alleviating therapy-associated gastrointestinal side effects is insufficient [18]. Furthermore, direct head-to-head comparisons of rifaximin and probiotics as adjuvant therapies are lacking.

Aims:

1. Primary: To examine the effects of adding a probiotic (Bacillus clausii) or a locally active antibiotic (rifaximin) to standard triple therapy on reported gastrointestinal side effects (diarrhea, abdominal pain, vomiting, nausea).
2. Secondary: To examine the H. pylori eradication rate when incorporating either adjuvant into triple therapy.

PATIENTS AND METHODS

This open label, randomized clinical trial was conducted in the outpatient clinic of the Tertiary Hospital for Gastroenterology and Hepatology between April 2024 and April 2025, following approval by the institutional review board (IRB No. 04-2024-300490) in April 2024.

1. Participants: Two hundred and twenty-five patients with dyspeptic symptoms and confirmed H. pylori infection (positive stool antigen test) was enrolled. Patients with alarm symptoms, aged over 60 years, or asymptomatic were excluded.
2. Randomization: After obtaining written informed consent, participants were randomized (1:1:1) using a computerized random number generator and sealed opaque envelopes into three groups (n=75 )each.
3. Sample Size: Based on a previous study [19],Guarino, Alfredo et al., 2015, a sample size of 180 was calculated to detect a ≥20% difference in diarrhea incidence between the three groups with 80% power and a two-sided 5% significance level. To account for potential dropouts, each group size was increased to 75.
4. Interventions (14 days for all groups):

    * C-Triple (Control): Standard triple therapy (pantoprazole 20 mg BID, amoxicillin 1000 mg BID, clarithromycin 500 mg BID).

    * R-Triple (Rifaximin): Standard triple therapy + rifaximin 550 mg BID.

    * P-Triple (Probiotic): Standard triple therapy + probiotic (2 billion Bacillus clausii spores BID).

1. Follow-up:

    * Side Effects: Participants recorded daily gastrointestinal symptoms (abdominal pain, nausea, vomiting, diarrhea) on provided sheets throughout treatment.

    * Eradication Confirmation: Successful eradication was assessed via stool antigen testing 4 weeks after completing antibiotic therapy.

1. Statistical Analysis: Data were analyzed using SPSS Version 21 (SPSS Inc.). Non-normally distributed variables (assessed via normality tests) were analyzed using non-parametric tests. Categorical adverse event data are presented as percentages; associations between groups were assessed using the chi-square test.

RESULTS

Baseline Characteristics and Medical Characteristics of the Studied Groups (Table 1): The three groups (n=75 each) showed no significant differences in baseline demographics or clinical characteristics (age, sex, BMI, smoking status, NSAID use, diabetes, hypertension).

Gastrointestinal Side Effects During Treatment of the Studied Groups (Table 2): Diarrhea: Incidence was 20% (15/75) in C-Triple, 4% (3/75) in P-Triple, and 17.3% (13/75) in R-Triple. The difference between groups was statistically significant (p=0.023). Pairwise comparison showed a significant difference between P-Triple and R-Triple (p=0.037). Abdominal Pain: Incidence was 14.7% (11/75), 4% (3/75), and 9.3% (7/75) in C-Triple, P-Triple, and R-Triple, respectively (p=0.08, NS). Nausea/Vomiting: No significant differences were observed between groups.

Comparison of Probiotic Vs. Rifaximin as Adjuvant Therapy in Preventing Gastrointestinal Side Effects of the Studied Groups (Table 3): The incidence of gastrointestinal (GI) side effects was compared between the P-triple group (probiotic adjuvant) and the R-triple arm (Rifaximin adjuvant) during treatment. Abdominal pain was reported in 4% (n=3) of the probiotic group vs. 9.3% (n=7) in the Rifaximin group (p=0.16). Nausea occurred in 9.3% (n=7) of the probiotic group compared to 17.3% (n=13) in the Rifaximin group (p=0.22). Vomiting was observed in 5.3% (n=4) of the probiotic group vs. 13.3% (n=10) in the Rifaximin group (p=0.07). Diarrhea was significantly lower in the probiotic group (5.7%, n=4) than in the Rifaximin group (17.3%, n=13) (p=0.037).

While most GI symptoms showed a trend toward lower incidence with probiotics, only diarrhea reached statistical significance (p < 0.05).

Eradication Rates of Helicobacter pylori of the Studied Groups (Table 4): Eradication rates were 72% (54/75) for C-Triple, 80% (60/75) for P-Triple, and 85.3% (64/75) for R-Triple. The difference was not statistically significant (p=0.15).  

Table 1 Baseline clinical and medical characteristics of the studied groups.

Note: BMI (body mass index). M (male). F(female). DM (diabetes mellitus).

HTN (hypertension). NSAID (non-steroidal anti-inflammatory drugs). N (number) .

SD standard deviation

Table 2: Gastrointestinal Side Effects During Treatment of the Studied Groups

Table 3: Comparison of Probiotic Vs. Rifaximin as Adjuvant Therapy in Preventing

Gastrointestinal Side Effects of the Studied Groups.

Table 4: Eradication rate of Helicobacter pylori in the groups studied.

DISCUSSION

This randomized trial demonstrates that neither rifaximin nor Bacillus clausii significantly improves the H. pylori eradication rate of standard triple therapy. However, B. clausii significantly reduced the incidence of diarrhea compared to both standard therapy and Rifaximin supplementation.

Although most H. pylori therapy-related gastrointestinal side effects are self-limiting, severe cases can impact treatment adherence. The observed reduction in diarrhea with probiotics aligns with the proposed pathophysiology involving antibiotic-induced gut microbiota alterations. Our findings support previous RCTs, such as Plomer et al. [20], which reported antidiarrheal benefits of B. clausii combined with triple therapy. While our study relied on symptom event reporting versus Plomer's symptom-free-day analysis, both found no improvement in eradication rates with probiotics (eradication was not assessed by Plomer et al.).

The literature on probiotics for H. pylori eradication remains inconsistent. While some meta-analyses [e.g., Lü Muhan et al. [21]] suggested a positive effect on eradication, others and our study found no significant benefit. This discrepancy may relate to probiotic strain, timing of administration, and regimen type. Wang et al. [22] highlighted significant variations in efficacy between strains and formulations (e.g., Bifidobacterium-Lactobacillus combinations showing superior eradication rates in some analyses). The concurrent administration of probiotics with antibiotics in our study may also explain the lack of eradication benefit.

Rifaximin, despite its luminal antibacterial activity and efficacy in other diarrheal conditions, showed no benefit for either H. pylori eradication or prevention of therapy-associated diarrhea in this study. This aligns with a large meta-analysis by Wang et al. [23] concluding Rifaximin offers no role in H. pylori eradication regimens. Rifaximin's limited impact on commensal gut microbiota may explain its inferiority to probiotics in preventing diarrhea.

To our knowledge, this is the first head-to-head trial comparing rifaximin and probiotics as adjuvants in H. pylori eradication. It highlights their lack of effect on eradication rates and demonstrates the ineffectiveness of adding rifaximin specifically for side effect reduction. This provides evidence against the unnecessary inclusion of rifaximin in such regimens. Limitations include potential H. pylori strain variation influencing eradication, lack of gut microbiota analysis, and possible bias in patient-reported symptoms (especially abdominal pain and nausea).

Further randomized, double-blind, multicenter studies are needed to confirm the role of specific probiotics in reducing triple-therapy-associated diarrhea, evaluate optimal strains and administration timing, and correlate effects with gut microbiota changes.

CONCLUSION

The addition of either Bacillus clausii or rifaximin to standard triple therapy did not significantly improve H. pylori eradication rates. However, B. clausii significantly reduced the incidence of diarrhea associated with treatment. Rifaximin provided no significant benefit in alleviating gastrointestinal side effects compared to standard triple therapy alone.

Ethical considerations: This open label, randomized clinical trial was conducted in the outpatient clinic of the Tertiary Hospital for Gastroenterology and Hepatology between April 2024 and April 2025, following approval by the institutional review board (IRB No. 04-2024-300490) in April 2024.                                         

List of abbreviations:

C-Triple                  Standard therapy: pantoprazole, amoxicillin, clarithromycin

GI                            Gastrointestinal

H pylori                   Helicobacter pylori

MALT                      Mucosa-associated lymphoid tissue

PPI                          Proton pump inhibitors

P-Triple                 Standard therapy plus B. clausii 2 billion spores      

R-Triple                 Standard therapy plus Rifaximin                         

Acknowledgement                                                None

Declaration of Conflicting interest

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.                          

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

CRediT authorship contribution statement

Bahaa Osman taha : Conceptualization, Ethical approval procedures, literature search, methodology, and writing the manuscript. Mohammed Ezz-Eldin: literature search, methodology, coding of the data and data presentation & commenting on results, and writing the manuscript. Tarek Abdelrahman: consultation and follow up of the research steps and supervision.

All the authors have read and approved the final manuscript.

The data are available as requested.