Helicobacter pylori (H. pylori) is a spiral-shaped Gram-negative bacterium that colonizes the gastric mucosa and affects more than 50% of the global population (Burucoa and Axon, 2017; Camilo et al., 2017; Duan et al., 2025). It is strongly associated with a wide range of gastrointestinal diseases, including chronic gastritis, peptic ulcer disease, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer (Duan et al., 2025; Maleki Kakelar et al., 2019; Mentis et al., 2019). Despite the widespread use of bismuth-containing quadruple therapy as a first-line eradication regimen, recurrence following treatment remains a substantial clinical challenge, particularly in areas with high reinfection rates and increasing antibiotic resistance (Ding et al., 2023; Zhou et al., 2024).

The recurrence of H. pylori infection may result from either true recrudescence or reinfection and is influenced by host immunity, environmental factors, and disruption of the gut microbial ecosystem caused by broad-spectrum antibiotics (Xue et al., 2019). These microbiota disturbances can impair mucosal defenses, increase gastric pH, and reduce colonization resistance, thus creating a favorable niche for H. pylori to reestablish (Xu et al., 2024). In recent years, probiotics—live microorganisms that confer health benefits when administered in adequate amounts—have gained attention for their role in restoring intestinal microbial balance, modulating host immunity, and reducing gastrointestinal side effects during and after antibiotic therapy (Xu et al., 2024).

Several randomized controlled trials and meta-analyses have suggested that probiotic supplementation may enhance eradication rates, improve patient tolerance, and reduce treatment-related adverse effects such as bloating and diarrhea (Gupta et al., 2024; Kim et al., 2021; Samara et al., 2022; Aragona et al., 2024). However, most studies have focused on the role of probiotics during eradication therapy, with limited data available on their potential in preventing recurrence after successful treatment. Moreover, heterogeneity in probiotic strains, dosage, treatment duration, and study designs has led to inconclusive evidence regarding long-term benefits.

To address this knowledge gap, the present study investigates the real-world effectiveness of probiotic supplementation in reducing H. pylori recurrence following classic quadruple therapy. Using a retrospective cohort design with propensity score matching (PSM) to minimize baseline bias, we compared recurrence rates and secondary outcomes—including gastrointestinal symptoms and treatment adherence—between patients who received probiotics and those who did not. We hypothesize that probiotic use may not only reduce recurrence risk but also contribute to better treatment tolerance and post-treatment gut health. By clarifying the role of probiotics in recurrence prevention, this study aims to support the development of evidence-based strategies for H. pylori management in clinical practice.

Patients in the probiotic group received oral probiotic supplements containing viable strains of Lactobacillus spp. and Bifidobacterium spp., at a minimum dose of 1 × 10⁹ CFU/day. Supplementation began concurrently with quadruple therapy and continued for 4 weeks following treatment completion. Patients were instructed to take probiotics at least 2 h apart from antibiotics to minimize antimicrobial interference. Adherence was monitored through follow-up calls and medication return.

The control group received standard quadruple therapy without probiotic support. Both groups were treated using a 14-day bismuth-containing quadruple regimen composed of a proton pump inhibitor (PPI), bismuth potassium citrate, tetracycline, and metronidazole, administered as per national guidelines.

The primary outcome of this study was recurrence of H. pylori infection within 12 months after eradication therapy. The recurrence rate in the probiotic group was significantly lower than that in the control group (9.2% vs. 19.2%, P = 0.021). These findings suggest that adjunctive probiotic supplementation may contribute to more sustained bacterial clearance after standard therapy.

In terms of treatment tolerability, patients in the probiotic group experienced significantly fewer self-reported gastrointestinal adverse effects during and after treatment. The incidence of bloating was 12.5% in the probiotic group compared to 22.5% in the control group (P = 0.041), while antibiotic-associated diarrhea was reported in 7.5% versus 18.3% of patients, respectively (P = 0.013). Other side effects, such as nausea, abdominal pain, and taste disturbance, were reported with similar frequencies between groups and did not reach statistical significance.

Importantly, patients receiving probiotics exhibited significantly better treatment adherence, with 91.7% of patients completing ≥90% of their prescribed medications, compared to 83.3% in the control group (P = 0.038). Adherence is a critical determinant of eradication success, and this finding underscores the practical benefit of probiotic use in real-world settings. No serious adverse events were reported in either group. These outcome data are summarized in Table 2.

As shown in Table 4, the probiotic group had a lower rate of unplanned hospital revisits (2.5% vs. 7.5%) and 30-day reconsultations for symptoms (3.3% vs. 8.3%) compared to the control group, though these differences were not statistically significant. However, therapy discontinuation was significantly less frequent in the probiotic group (1.7% vs. 6.7%, P = 0.040), indicating better treatment adherence and tolerability.

Helicobacter pylori remains one of the most prevalent and persistent bacterial infections worldwide, with well-established links to peptic ulcer disease, gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric cancer (Gong and Yuan, 2018; Hanafiah and Lopes, 2020; Matsuo et al., 2017; Sabbagh et al., 2019). While standard quadruple therapy is effective for initial eradication, recurrence remains a significant concern, particularly in regions with high reinfection rates, poor treatment adherence, and widespread antibiotic resistance. This study assessed the impact of probiotic supplementation on recurrence rates and treatment-related outcomes, and our findings suggest that probiotics are associated with reduced recurrence and improved treatment tolerance.

Our results demonstrated that patients who received probiotic supplementation during and after quadruple therapy had a significantly lower recurrence rate of H. pylori infection within 12 months compared to those receiving standard care alone. These findings are consistent with prior research indicating that probiotics help restore gut microbiota balance, prevent recolonization by pathogenic organisms, and modulate mucosal immunity (Guo et al., 2023; Luo et al., 2024; Quigley, 2019; Bock et al., 2024). In particular, strains of Lactobacillus and Bifidobacterium have shown the ability to inhibit H. pylori adherence, reduce inflammation, and promote gastric mucosal healing (Messaoudi et al., 2011).

Furthermore, probiotic use was associated with a reduction in gastrointestinal side effects such as bloating and antibiotic-associated diarrhea—two of the most common reasons for poor adherence and premature treatment discontinuation. Our data also showed that patients in the probiotic group had significantly higher medication adherence rates, which is critical for ensuring successful eradication and preventing antibiotic resistance. These findings are in agreement with meta-analyses by Paoluzi et al. and Kingkaew et al., which concluded that probiotics enhance tolerance and adherence to H. pylori eradication regimens (Kingkaew et al., 2023; Paoluzi et al., 2015).

In addition to their immunomodulatory and microbiota-restoring properties, probiotics may also exert indirect benefits by improving patient-reported quality of life during and after eradication therapy. Several studies have shown that gastrointestinal discomfort—particularly bloating, abdominal distension, and altered bowel habits—can significantly impair daily functioning and reduce willingness to complete therapy (Neyrinck et al., 2021; Wood, 2007). By alleviating these symptoms, probiotics not only promote treatment adherence but may also enhance patient satisfaction and long-term health behavior. These patient-centered benefits are increasingly recognized as important indicators of therapeutic value, especially in the context of outpatient care and self-administered regimens. Given the growing interest in microbiome-based interventions, our findings support the integration of probiotics into standard H. pylori management protocols as part of a broader, personalized care model.

Importantly, logistic regression analysis confirmed probiotic supplementation as an independent protective factor against H. pylori recurrence. Additionally, receiver operating characteristic (ROC) analysis indicated that probiotic use is moderately associated with lower recurrence risk, improved adherence, and reduced adverse events—further supporting its clinical utility as an adjunct therapy.

Despite these encouraging results, several limitations must be acknowledged. First, the retrospective design inherently limits the ability to infer causality. Although propensity score matching was used to balance observed baseline characteristics, the potential for unmeasured or residual confounding cannot be excluded. Therefore, the findings of this study should be interpreted as observational and exploratory in nature. Future prospective, multicenter randomized controlled trials are necessary to validate the causal role of probiotic supplementation in reducing H. pylori recurrence. Second, probiotic strains and dosages were not standardized across all patients, which may introduce heterogeneity in treatment effects. Third, recurrence was only monitored for 12 months, and long-term reinfection rates or resistance patterns were not evaluated. Additionally, the study was conducted at a single center, which may limit generalizability.

Future multicenter, prospective randomized controlled trials with longer follow-up durations are warranted to validate our findings, determine optimal probiotic formulations, and explore cost-effectiveness. Investigating the role of specific probiotic strains and duration of administration in different populations could further inform precision-based adjunctive strategies for H. pylori eradication.

In conclusion, this study provides real-world evidence that probiotic supplementation during and after standard quadruple therapy is associated with lower Helicobacter pylori recurrence rates, fewer gastrointestinal side effects, and higher treatment adherence. These findings support the incorporation of probiotics as a complementary strategy to enhance eradication durability and improve patient tolerance. Structured probiotic use may represent a simple, safe, and effective intervention to optimize H. pylori management in clinical practice. Further high-quality prospective studies are needed to confirm these results and define best-practice guidelines for probiotic integration into eradication protocols.