Introduction

Helicobacter pylori is a gram-negative infective bacterium affecting more than half of the world's population [1]. H. pylori infection contributes to etiology of a variety of diseases, such as gastric ulcer disease, dyspepsia, lymphoma, and gastric cancer [2,3,4]. Treatment of H. pylori infection is still being debated around the world, owing to emergence of multidrug-resistant strains of H. pylori. At the present, the most effective treatment options for H. pylori infection are complete pathogen eradication using multiple combinations of proton pump inhibitors (PPI) and two or three antibiotics [5,6,7]. This complicated approach carries a high risk of adverse effects (AEs), antibiotic resistance, and incompatibility [8, 9]. Reduced H. pylori load in the stomach by selective bacterial-bacterial surface interaction indicates a novel treatment approach to mitigating the danger posed by this human infection. Bacterial accumulation has previously been discussed in terms of infection elimination via specific binding to pathogens and formation of co-aggregates [10,11,12]. Many observations support the use of probiotics with bioactive components in people infected with H. pylori, recommending the use of multiplex probiotic microorganisms in control and treatment of infections caused by H. pylori [13, 14]. It has been proposed that Lactobacillus supplementation may be effective in accelerating removal of H. pylori in first-time patients, as well as having a positive effect on some AEs associated with H. pylori treatment [15]. To date, saccharomyces boulardii and several Lactobacillus reuteri strains have been used alone or in combination with various H. pylori treatment regimens in clinical studies [16,17,18,19,20,21,22,23,24,25,Statistical analysis

After entering the SPSS 24 software, the data were described using central and dispersion indices for quantitative variables and frequency and agreement tables for qualitative variables. Homogeneity of groups was assessed using analysis of variance (ANOVA) and Chi-Square tests. Marginal logistic model with generalized estimating equation (GEE) approach was used for modeling the changes in complications during the study. In the tests, significance level was set at 0.05.

Results

Patients

A total of 156 subjects with confirmed H. pylori infection completed the treatment protocol in all groups by the end of the study. The study included 60.9 percent female participants and 39.1% male participants, with a mean age of 47.76 ± 13.92 years old (age range of 16–74 years old). They were randomly assigned into three study arms: 52 patients were assigned into the L. Reuteri group (Group P), 52 patients were assigned into the S. boulardii group (Group S), and 52 patients were assigned into the placebo group (Group C). The majority of our patients (93.6%) were from rural areas, housewife (46.8%), and non-smokers (76.9%). Dyspepsia was the most common reason for undergoing an endoscopy procedure (64.7%). At the time of the first endoscopy, the majority of patients had antral gastritis. Antral and corpus predominant gastritis were found in 88.5and 27.6% of patients, respectively. The three treatment groups were similar in terms of their demographic, clinical, and endoscopic characteristics at baseline (Table 1) (p > 0.05).

Table 1 Characteristics of the all groups
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Eradication rate

The highest rate of H. pylori eradication occurred in all groups in the second week after treatment. Totally, 86.5, 94.2, and 92.3% of eradication was observed in the control, S, and P groups, respectively. In general, eradication rate in the studied groups was not statistically significant in the second and sixth weeks, (with P = 0.46 in the second week and P = 0.53 in the sixth week, respectively) (Fig. 3).

Fig. 3
figure 3

Rate of eradication of H. pylori infection in the studied groups

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Patients compliance and adverse effects

Headache, abdominal pain, and anxiety were significantly reduced in the Group S (who received saccharomyces boulardii probiotic-DAILYEAST®). But in Group P, headache and abdominal pain were significantly reduced and anxiety was significantly increased (p < 0.05). However, none of the study groups experienced significant changes in vomiting, insomnia, bitter taste in the mouth, or epigastric discomfort (p > 0.05) (Table 2). According to Table 2, after adjusting the effect of time, in the Group S, chance of develo** symptoms of headache (OR = 10.51), abdominal pain (OR = 3.21), and anxiety (OR = 3.58) was significantly lower than control group (p < 0.05). Also, except for headache (OR = 3.75), the Group P did not differ significantly from the control group in incidence of complications (p > 0.05) (Fig. 4). For more details, see Additional file 1.

Table 2 Generalized estimating equations (GEE) logistic model of the association between the treatment group and complications
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Fig. 4
figure 4

Distribution frequency of AEs observed in the study groups

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Discussion

Treatment of H. pylori infection is becoming increasingly important, particularly in develo** countries. Despite availability of various therapeutic regimens, treatment failure has remained a growing problem in daily clinical practices. Several factors could contribute to failure of eradication, but the most important factors are antibiotic resistance and clinical efficacy [31]. According to findings of the current study, there was no statistically significant difference between the study results at the second and sixth weeks after treatment. These findings were in agreement with the Zojaji et al. study that evaluated the efficacy and safety of adding S. boulardii to standard triple therapy in 160 adult patients with biopsy confirmed H. pylori infection. They randomized patients into two treatment regimens: patients in group A (n = 80) were given amoxicillin, clarithromycin, omeprazole, and a probiotic of Saccharomyces boulardii for 14 days. Moreover, patients in group B (n = 80) were given amoxicillin, clarithromycin, and omeprazole for 14 days. After the second week, the success rate for H. pylori eradication in group A was higher at 75 (87.5%) than in group B at 65 (81.2%), but the difference between the two groups was not significant [27]. Furthermore, Cindoruk et al., in a study on assessing the effect of S. boulardii on eradication of H. pylori infection and reduction of AEs reported no significant difference in H. pylori eradication between the study groups (71% in the S. boulardii-treated group and 60% in the placebo group), which was consistent with our findings [32]. Also, Shavakhi et al., found that using a combination of probiotics containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus species along with a standard quadruple therapy had no beneficial effect in treating H. pylori infection. This could be due to the probiotic diet's low dose or high frequency of upper gastrointestinal AEs, which can reduce H. pylori eradication [33]. On the other hand, Poonyam et al., indicated that eradication of H. pylori was significantly increased compared to the control group when Lactobacillus reuteri was used in combination with a standard quadruple therapy [34]. Moreover, Yu et al. demonstrated that Lactobacillus can significantly eradicate H. pylori in a meta-analysis with a sample size of 724 patients to investigate the probiotic effect of Lactobacillus in combination with a triple eradication regimen [35]. In addition, Zhou et al., in a meta-analysis showed that S. boulardii can significantly increase eradication of H. pylori [36], all these studies were not in agreement with our findings. Among the reasons for this mismatch, one can mention a difference in the type of probiotic used in the studies in terms of the strains used or the large sample size and multi-center nature of these studies are reasons for the inconsistency between the findings.

With the widespread use of probiotics in clinical practice in recent years, the concept of "treating bacteria with probiotics" has been proposed as a new strategy to eradicate H. pylori. However, the mechanism underlying L. reuteri and S. Bouvardia’s eradication of H. pylori has not been fully elucidated. Several potential mechanisms have been proposed, including the following:

  1. 1.

    The volume of S. boulardii is 10 times larger than that of common bacterial strains of probiotics, which increases the surface area and can better adhere to pathogenic bacteria, affecting the colonization of H. pylori in the gastric mucosa [37]. S. boulardii comprises neuraminidase activity selective for alpha (2–3)‐linked sialic acid, and acts as a ligand binding to H. pylori adhesin, which in turn inhibits the adhesion of H. Pylori in the duodenum [38].

  2. 2.

    Increasing antimicrobial substances, such as short‐chain fatty acids, inhibiting the growth and proliferation of H. pylori [39].

  3. 3.

    S. boulardii may stimulate an increase in secretory IgA and immunoglobulin levels [40], strengthening the mucosal immune barrier. H. pylori infection can stimulate gastric epithelial cells to produce inflammatory mediators such as interleukin (IL) and tumor necrosis factor (TNF) [41, 42].

  4. 4.

    Reducing the incidence of adverse effects and, subsequently, compliance may improve, which may indirectly improve the H. pylori eradication rates.

In the case of L. reuteri, In vitro and in artificial gastric juice, H. pylori specifically co-aggregates with H. pylori without interfering with other commensal intestinal flora bacteria [43]. This specific binding may obscure H. pylori surface structures and impair Helicobacter motility. Pathogens that have aggregated are presumably no longer adhered to the gastric mucosa and are cleared from the stomach. Competition for specific binding proteins could be another mode of action [44].

According to findings of our study, distribution frequency of some AEs in the subjects receiving S. boulardii probiotic was significantly reduced after the intervention but, except for headache, no significant change was observed in the Lactobacillus reuteri-treated group. According to the findings, the most common AEs in the first week were vomiting, bitter taste in the mouth, epigastric discomfort, and insomnia, which were decreased after that time. However, no statistically significant difference was found between the studied groups at different times. Our findings were consistent with those of the studies by Pourmasoumi et al., and Lv et al., who showed that probiotic administration can reduce the AEs of anti H. pylori treatment [

Conclusion

In general, our findings revealed that the use of probiotic supplements containing S. boulardii could significantly reduce some of the AEs of H. pylori eradication therapy. But, the effectiveness of Lactobacillus reuteri (DSMZ 17648 strain) on these cases was not significant, and only the headache was remarkably reduced, which was in accordance with the previous evidence in the literature. Therefore, it is recommended to conduct future research with a larger sample size in order to investigate the effect of S. boulardii supplementation on eradicating H. pylori infection and reducing treatment AEs.