Investigating the effect of quadruple therapy with Saccharomyces boulardii or Lactobacillus reuteri strain (DSMZ 17648) supplements on eradication of Helicobacter pylori and treatments adverse effects: a double-blind placebo-controlled randomized clinical trial

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 [2‐4]. 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 [5‐7]. 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 [10‐12]. 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 [16‐29]. Previous studies have explored the effects of Saccharomyces boulardii and Lactobacillus Reuteri on the eradication of H. pylori and the elimination of AEs associated with the four-drug treatment separately or in comparison. However, very few studies have been done to compare the effects of Lactobacillus reuteri (DSMZ 17648) and Saccharomyces boulardii on this topic.

Therefore, purpose of this study was investigating whether adding saccharomyces boulardii (DAILY EAST®) probiotic or a supplement of DSMZ 17648 Lactobacillus reuteri (PYLOSHOT®) to the standard quadruple treatment for H. pylori infection after 14 days increases eradication rate and reduces the AEs. Due to lack of sufficient studies in this field, there is a need for a clinical trial and it is hoped that the results of this study will be useful in improving treatment of H. pylori.

A total of 156 patients were included in the current study. A total of 156 patients were included in the current study. The sample size was calculated based on Zojaji et al. [27] by using a sample size formula for comparison proportion. In this study, the percentage of improvement in group A (amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, omeprazole 20 mg twice daily, and probiotic Saccharomyces bulardi 250 mg twice daily) was 0.875, and in group B (amoxicillin 1 g twice daily, clarithromycin 500 mg twice daily, omeprazole 20 mg twice daily) was 0.812.

At the end of the treatment period, all the subjects continued to take proton pump inhibitor (PPI) alone for 14 days, and then no medication was given for 2 weeks again. During follow-up, gastrointestinal symptoms were assessed using an evaluation scale (Glasgow dyspepsia questionnaire (GDQ)), and Adverse effects were assessed at 7, 14, 21, and 28 days.

Treatment of H. pylori infection is becoming increasingly important, particularly in developing 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:

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 [26, 28]. Also, Zojaji et al., discovered that using S. boulardii supplement significantly reduces AEs, such as nausea, diarrhea, epigastric discomfort, and bloating in the first and second weeks of treatment [27]. Furthermore, Cindoruk et al., in a study found that the AEs of epigastric discomfort and dyspepsia were significantly reduced in the group that received S. boulardii [32]. Moreover, Shavakhi et al., reported that incidence of diarrhea was significantly lower in the group that consumed combined probiotics containing Lactobacillus, Bifidobacterium, and Streptococcus thermophilus than the placebo group. On the other hand, incidence of abdominal pain was significantly higher in the probiotic group than the placebo group [33]. On the contrary, Frequency of nausea, vomiting, epigastric discomfort, and bitter taste was significantly reduced in the group that received oral supplement of Lactobacillus reuteri compared to the placebo group in the study by Poonyam et al. [34]. Also, Yu et al., in a meta-analysis found that Lactobacillus reduces treatment-related AEs [35]. Furthermore, Zhou et al., discovered that S. boulardii could significantly reduce treatments AEs, particularly diarrhea and constipation [36]. which were not in line with the results of our study.

One of the study's limitations is that it does not investigate the severity of Adverse effects caused by antibiotics. Furthermore, the term "Adverse effects" in this study is defined differently than its usual definition and refers to patients' symptoms and complaints about the side effects of the antibiotics during treatment and their persistence until two weeks after stopping antibiotics. Furthermore, in our country, simply receiving the code of ethics is sufficient to begin research, and for this reason, we began collecting samples after the ethics committee's approval.

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.