ABSTRACT
Background
Saccharomyces boulardii CNCM I‐745 (Sb) is one of the most widely used probiotics in clinical practice. The aim of this study was to assess the impact of adding Sb to Helicobacter pylori eradication therapy on treatment outcomes (effectiveness and safety) in routine European gastroenterology clinical practice.
Materials and Methods
Treatment‐naive cases from the European registry on H. pylori management (Hp‐EuReg) collected from 2013 to 2023 at AEG‐REDCap were analyzed. Effectiveness was assessed by modified intention‐to‐treat, by treatment and geographic regions. Multivariate analysis identified factors independently associated with eradication success and adverse event incidence.
Results
Among 69,922 cases, probiotics were used in 16,528 (24%) treatments, of which 4404 (27%) included Sb. Sb use was significantly associated with an increase in effectiveness (OR = 2.32; 95% confidence interval, 1.38–4.03; p < 0.01) only when prescribed with concomitant therapy encompassing a proton pump inhibitor plus clarithromycin‐amoxicillin‐metronidazole. In addition, a significant reduction in the overall incidence of at least one adverse event was observed in the Sb group (OR = 0.803; 0.66–0.97; p < 0.05). Specifically, diarrhea, nausea, dyspepsia, abdominal pain, asthenia, anorexia, heartburn, and dysgeusia occurred significantly less frequently with Sb. Treatment compliance was high in both groups (with and without Sb).
Conclusions
In Europe, the addition of Sb to first‐line regimens in clinical practice was associated with higher effectiveness when combined with concomitant therapy with clarithromycin‐amoxicillin‐metronidazole and with fewer overall adverse events, supporting its role as a beneficial adjunct in H. pylori eradication therapy.
Registration Number
ClinicalTrials.gov identifier: NCT02328131
Keywords: effectiveness, eradication therapy, Helicobacter pylori , hp‐EuReg, probiotics, saccharomyces boulardii, safety
1. Introduction
Helicobacter pylori ( H. pylori ) infects over half of the global population and is the most important risk factor for peptic ulcer and gastric cancer development, making eradication a key public health goal.
The currently recommended first‐line empirical therapies include the administration of a proton pump inhibitor (PPI) together with at least two antibiotics [1], but increasing antibiotic resistance [2, 3], and treatment‐related adverse events (AEs) limit effectiveness [4].
Adjunctive strategies, such as the use of statins [5] or probiotics [2, 6, 7, 8], including Saccharomyces boulardii CNCM I‐745 (Sb), have shown promise in reducing gastrointestinal side effects and improving eradication rates [9, 10, 11, 12, 13]. The Maastricht VI/Florence Consensus Report [1] recommends probiotics, including Saccharomyces boulardii, to reduce gastrointestinal symptoms during eradication therapy through microbiome regulations [14] and lowering therapy‐related AEs [12, 13, 15]. While meta‐analyses support Sb's benefits [12], real‐world European data are limited. The present study uses the multinational European Registry on H. pylori Management (Hp‐EuReg) database to evaluate Sb's effectiveness and safety in routine clinical practice.
2. Materials and Methods
2.1. European Registry on H. pylori Management (Hp‐EuReg)
Hp‐EuReg (www.hpeureg.com) is a multicenter, prospective, non‐interventional registry promoted by the European Helicobacter and Microbiota Study Group, enrolling H. pylori ‐infected adult patients since 2013 [16]. The study adheres to the Declaration of Helsinki [17] and was approved by the Ethics Committee of Hospital Universitario de La Princesa (NCT02328131). Data were recorded at e‐CRF AEG‐REDCap [18, 19]. Further details on variables and country selection are detailed in the protocol [16].
2.2. Data Management, Selection Criteria and Statistical Analysis
Data were cleaned and quality checked, and only adults receiving first‐line empirical therapy were included; treatments were categorized by probiotic use with Sb (S. boulardii CNCM I‐745) as a single strain adjunct identified, while non‐probiotic users (i.e., patients not receiving any probiotic) served as controls. All probiotic prescriptions were independently reviewed and coded by strain.
Clinical and geographic variables were categorized: European regions (Table S1), with ≥ 100 treatments and where Sb was marketed; PPIs were standardized to omeprazole equivalents and classified by dose (low, standard, and high [20, 21]); and treatment duration grouped into 7, 10, or 14 days.
Effectiveness was assessed using a modified ITT (mITT), and per protocol (PP) analyses, with the current study focusing on mITT as the measure closest to real‐world practice. mITT included patients with completed follow‐up and a confirmatory test regardless of compliance; PP included those with completed follow‐up and ≥ 90% treatment adherence.
Safety was assessed by the incidence of at least one AE occurring during eradication therapy. Adherence was defined as taking ≥ 90% of prescribed drugs.
Univariate sub‐analyses assessed effectiveness and safety using Chi2 test or Fisher's exact tests followed by backward stepwise logistic regression to identify independent predictors of mITT eradication and AEs, including age, sex (female [reference] vs. male), indication (non‐ulcer [reference] vs. ulcer), duration of treatment (7 days [reference] vs. 10 or 14 days), PPI dosage (low [reference] vs. standard or high dose), compliance (No [reference] vs. Yes), geographic region, Sb use (No [reference]; Yes), and first‐line regimens (six categories): (1) triple therapy with clarithromycin (C) and either amoxicillin (A) or metronidazole (M) [reference]; (2) triple therapy with A and levofloxacin (L); (3) non‐bismuth quadruple concomitant therapy with C, A and either M or tinidazole (T), (4) bismuth‐based quadruple therapy encompassing either the classical format with M, tetracycline (Tc) all given separately or all together in a three‐in‐one single capsule (Pylera); (5) bismuth‐based quadruple concomitant therapy with C and A; and (6) ‘other regimens’ (≤ 10% of the regimens overall). Results were reported as odds ratios (OR) and 95% confidence intervals (CIs) (p < 0.05).
3. Results
3.1. Population Characteristics and Treatment Patterns
From May 2013 to December 2023, the Hp‐EuReg recorded 69,922 first‐line empirical eradication treatments. Of these, 53,394 were administered without probiotics (control group) and 16,528 (31%) with at least one (Figure 1); and 4404 treatments used Sb (6% of all treatments; 27% of probiotic combined treatment). Among the 57,798 eligible treatments (Sb and control), 41,298 were included in the mITT population (Figure 1).
FIGURE 1.
Study flow chart. mITT: Modified Intention‐To‐Treat (population); N, number of treatments; Sb, saccharomyces boulardii CNCM I‐745 (single‐strain).
Patients were mostly female (60%), Caucasian (88%), and aged between 31 and 70 years (79%) (Table 1). Treatments were mainly for non‐investigated dyspepsia or dyspepsia with normal endoscopy (70%); with 9% and 7% for duodenal and gastric ulcers, respectively. One‐third (34%) of patients took concomitant medication including PPIs (37%) and statins (27%); with < 5% on daily non‐steroidal anti‐inflammatory drugs (NSAIDs; 3%). Dyspepsia was the most common symptom (76%). H. pylori infection was diagnosed using histology (38%), rapid urease test (38%), and 13C‐urea breath test (26%).
TABLE 1.
Baseline demographic and clinical characteristics by group.
| Characteristics | Total (N = 57,798) | Control group (N = 53,394) | Sb group (N = 4404) | p | ||||
|---|---|---|---|---|---|---|---|---|
| Gender | N | 57,709 | 53,308 | 4401 | 0.329 a | |||
| Female | 34,646 | 60.0% | 31,974 | 60.0% | 2673 | 60.7% | ||
| Male | 23,063 | 40.0% | 21,335 | 40.0% | 1728 | 39.3% | ||
| Ethnic group | N | 57,720 | 53,323 | 4397 | 0.000 b | |||
| Caucasian | 50,673 | 87.8% | 47,174 | 88.5% | 3499 | 79.6% | ||
| Black | 378 | 0.7% | 344 | 0.6% | 34 | 0.8% | ||
| Asian | 618 | 1.1% | 541 | 1.0% | 77 | 1.8% | ||
| Other | 4949 | 8.6% | 4243 | 8.0% | 706 | 16.1% | ||
| Unknown | 1102 | 1.9% | 1021 | 1.9% | 81 | 1.8% | ||
| Age (years) | N | 57,589 | 53,193 | 4396 | 0.15 b | |||
| 18–30 | 6395 | 11.1% | 5909 | 11.1% | 486 | 11.1% | ||
| 31–50 | 22,054 | 38.3% | 20,464 | 38.5% | 1590 | 36.2% | ||
| 51–70 | 23,612 | 41.0% | 21,743 | 40.9% | 1869 | 42.5% | ||
| 71+ | 5528 | 9.6% | 5077 | 9.5% | 451 | 10.3% | ||
| Drug allergies | N | 57,724 | 4402 | 53,322 | 0.002 a | |||
| Ooverall | Yes | 2401 | 4.2% | 2180 | 4.1% | 221 | 5.0% | |
| No | 55,323 | 95.8% | 51,142 | 95.9% | 4181 | 95.0% | ||
| Indication | N | 57,708 | 53,306 | 4402 | 0.000 b | |||
| Dyspepsia (normal endoscopy) | 28,411 | 49.2% | 26,761 | 50.2% | 1650 | 37.5% | ||
| Dyspepsia (non‐investigated) | 12,159 | 21.1% | 11,008 | 20.7% | 1151 | 26.1% | ||
| Duodenal ulcer | 5268 | 9.1% | 4861 | 9.1% | 407 | 9.2% | ||
| Gastric ulcer | 4052 | 7.0% | 3646 | 6.8% | 406 | 9.2% | ||
| Preneoplastic lesions | 1669 | 2.9% | 1475 | 2.8% | 194 | 4.4% | ||
| Concomitant | N | 57,677 | 53,276 | 4401 | 0.740 a | |||
| treatments | Yes | 19,662 | 34.1% | 18,172 | 34.1% | 1490 | 33.9% | |
| PPIs | N | 19,599 | 18,112 | 1487 | 0.000 b | |||
| On demand | 4286 | 21.9% | 4050 | 22.4% | 236 | 15.9% | ||
| Daily | 7345 | 37.5% | 6820 | 37.7% | 525 | 35.3% | ||
| No | 7638 | 39.0% | 6918 | 38.2% | 720 | 48.4% | ||
| Aspirin | N | 19,592 | 18,107 | 1485 | 0.000 b | |||
| On demand | 332 | 1.7% | 322 | 1.8% | 10 | 0.7% | ||
| Daily | 2618 | 13.4% | 2368 | 13.1% | 250 | 16.8% | ||
| No | 16,118 | 82.3% | 14,898 | 82.3% | 1220 | 82.2% | ||
| NSAIDs | N | 19,594 | 18,112 | 1482 | 0.000 b | |||
| On demand | 3893 | 19.9% | 3728 | 20.6% | 165 | 11.1% | ||
| Daily | 672 | 3.4% | 643 | 3.6% | 29 | 2.0% | ||
| No | 14,502 | 74.0% | 13,228 | 73.0% | 1274 | 86.0% | ||
| Statins | N | 19,595 | 18,111 | 1484 | 0.000 b | |||
| On demand | 137 | 0.7% | 133 | 0.7% | 4 | 0.3% | ||
| Daily | 5306 | 27.1% | 4922 | 27.2% | 384 | 25.9% | ||
| No | 13,624 | 69.5% | 12,531 | 69.2% | 1093 | 73.7% | ||
| Gastrointestinal | N | 57,747 | 53,343 | 4404 | ||||
| symptoms | No | 4916 | 8.5% | 4259 | 8.0% | 657 | 14.9% | 0.000 a |
| Heartburn | 14,899 | 25.8% | 13,991 | 26.2% | 908 | 20.6% | 0.000 a | |
| Dyspepsia | 44,054 | 76.3% | 41,012 | 76.9% | 3042 | 69.1% | 0.000 a | |
| Other | 7776 | 13.5% | 7192 | 13.3% | 584 | 13.5% | 0.695 a | |
| Diagnosis | N | 57,747 | 53,343 | 4404 | ||||
| 13C‐UBT | 15,045 | 26.1% | 14,320 | 26.8% | 725 | 16.5% | 0.000 a | |
| Serology | 4227 | 7.3% | 3706 | 6.9% | 521 | 11.8% | 0.000 a | |
| Histology | 22,197 | 38.4% | 20,495 | 38.4% | 1702 | 38.6% | 0.772 a | |
| Rapid urease test | 22,177 | 38.4% | 20,606 | 38.6% | 1571 | 35.7% | 0.000 a | |
| Culture | 5407 | 9.4% | 5217 | 9.8% | 190 | 4.3% | 0.000 a | |
| Antibiotic | N | 57,747 | 53,343 | 4404 | ||||
| resistance | No resistance | 2051 | 3.6% | 2008 | 3.8% | 43 | 1.0% | 0.000 a |
| Clarithromycin | 1937 | 3.6% | 1914 | 3.6% | 23 | 0.5% | 0.000 a | |
| Nitroimidazole | 1814 | 3.1% | 1793 | 3.4% | 21 | 0.5% | 0.000 a | |
| Quinolone | 1283 | 2.2% | 1264 | 2.4% | 19 | 0.4% | 0.000 a | |
| Amoxicillin | 50 | 0.1% | 49 | 0.1% | 1 | 0.0% | 0.181 a | |
| Tetracycline | 26 | 0.0% | 26 | 0.0% | 0 | 0.0% | 0.259 a | |
| Not performed | 927 | 1.7% | 907 | 1.7% | 20 | 0.5% | 0.000 a | |
| Geographical | N | 57,747 | 53,343 | 4404 | 0.000 b | |||
| distribution | Eastern | 12,206 | 21.1% | 10,407 | 19.5% | 1799 | 40.8% | |
| European | Central–Eastern | 15,062 | 26.1% | 14,662 | 27.5% | 400 | 9.1% | |
| regions | South‐Western | 21,745 | 37.7% | 20,656 | 38.7% | 1089 | 24.7% | |
| Central‐Western | 5737 | 9.9% | 4777 | 9.0% | 960 | 21.8% | ||
| Northern | 2997 | 5.2% | 2841 | 5.3% | 156 | 3.5% | ||
| Geographical | N | 57,747 | 53,343 | 4404 | 0.000 b | |||
| distribution | Russia | 9450 | 16.4% | 7750 | 14.5% | 1700 | 38.6% | |
| Main countries | Spain | 21,087 | 36.5% | 20,009 | 37.5% | 1078 | 24.5% | |
| Italy | 5320 | 9.2% | 4509 | 8.5% | 811 | 18.4% | ||
| Azerbaijan | 4459 | 7.7% | 4235 | 7.9% | 224 | 5.0% | ||
| Czeck Republic | 477 | 0.8% | 381 | 0.7% | 96 | 2.2% | ||
Abbreviations: NSAIDs, non‐steroidal anti‐inflammatory drugs; PPIs, proton pomp inhibitors; Sb, saccharomyces boulardii CNCM I‐745 single‐strain; UBT, urea breath test.
Pearson Chi2, two‐sided test if p ≥ 0.05 and one‐sided if p < 0.05.
Asymptotic significance (two‐sided).
3.2. First‐Line Empirical Prescriptions and Treatment Compliance
Overall prescription patterns varied across European regions: bismuth quadruple‐CAB was most common in the Eastern region (45%), Triple‐CA in Central‐Eastern (59%), single capsule‐MTcB (38%), and concomitant CAM/T (37%) in the South‐West, and sequential‐CAT/M (50%) and single‐capsule MTcB (23%) in Central‐Western. In contrast, the use of Triple‐AM, Triple‐CM, Triple‐AL, and bismuth quadruple MTcB remained consistently low across all regions (< 10% each) (Table S2).
Use of Sb also varied regionally: Eastern—mainly Triple‐CA (38%) and bismuth quadruple CAB (33%); Central‐Eastern—Sb use remained low (< 13%); South‐Western—single capsule‐MTcB (48.4%) and concomitant‐CAM/T (37.4%); Central‐Western—bismuth quadruple single capsule‐MTcB (42%) and Triple‐CA (28%) (Table S2).
At the country level, Sb prescriptions were highest in Russia (39%), Spain (24%), Italy (18%), Azerbaijan (5%), and the Czech Republic (2%). By regimen, Sb was most frequently combined with triple‐CA (29%), single capsule‐MTcB (19%), bismuth quadruple‐CAB (15%), and concomitant‐CAM/T (13%). (Figure 2).
FIGURE 2.
Distribution of the most frequent first‐line empirical therapies in the S. boulardii CNCM I‐745 and control groups. A, amoxicillin; B, bismuth salts; C, clarithromycin; Conco, concomitant; L, levofloxacin; M, metronidazole; PPI, proton pomp inhibitor; Quad, quadruple; Sb, saccharomyces boulardii CNCM I‐745 (single‐strain); Seq, sequential; T, tinidazole; Tc, tetracycline. Other regimens: PPI + any other antibiotic combination.
Overall compliance was high (97%; Table S3) and roughly similar between groups (Sb 96.5% vs. control 97%; p < 0.05). In Central‐Eastern Europe, compliance was significantly lower in the Sb group, mainly driven by Azerbaijan (control 95% vs. Sb 90%; p < 0.01), whereas in Eastern Europe, a significant difference was observed in favor of Sb users, mainly driven by Russia (control 98% vs. Sb 99%; p < 0.05). By treatment, no significant differences in compliance were observed except for a slightly higher adherence in Sb users for Triple‐CA (97% vs. 98%, respectively; p < 0.05) and the single capsule‐MTcB (97% vs. 95%, respectively; p < 0.01).
3.3. Sb Impact on Effectiveness
First‐line empirical overall effectiveness was 90%, with no significant difference between the Sb and control groups (both 90%; p > 0.05) (Table 2). Multivariate analysis confirmed that adjunctive Sb was not associated with overall effectiveness of first‐line empirical treatment. Across all European regions, mITT overall effectiveness was significantly higher in compliant patients (OR = 10.802; 95% CI: 9.298–12.549), in those receiving standard (OR = 1.453; 1.340–1.576) or high‐dose PPIs (OR = 1.612; 1.474–1.762), and in patients treated for 10 days (OR = 1.544; 1.361–1.752) or 14 days (OR = 1.920; 1.684–2.189) (Table 3). Additionally, female sex, ulcer disease, residence in Eastern or South‐Western Europe, and use of Triple‐AL, concomitant‐CAM/T, or bismuth quadruple single capsule‐MTcB regimens were independently associated with higher eradication success (Table 3a).
TABLE 2.
Success rates of H. pylori eradication therapies with and without S. boulardii CNCM I‐745 supplementation.
| Success rate | Control group | Sb group | Total | p | ||||
|---|---|---|---|---|---|---|---|---|
| All countries, | N (Total) | 38,408 | 2890 | 41,298 | ||||
| all regimens | Success (N, %) | 34,411 | 89.6% | 2590 | 89.6% | 37,001 | 89.6% | 0.495 |
| By eradication regimen | ||||||||
| Triple‐CA | N (Total) | 10,989 | 865 | 11,854 | ||||
| Success (N, %) | 9499 | 86.4% | 751 | 86.8% | 10,250 | 86.5% | 0.396 | |
| Triple‐CM | N (Total) | 1448 | 52 | 1500 | ||||
| Success (N, %) | 1229 | 84.9% | 45 | 86.5% | 1274 | 84.9% | 0.465 | |
| Triple‐AM | N (Total) | 865 | 26 | 891 | ||||
| Success (N, %) | 748 | 86.5% | 20 | 76.9% | 768 | 86.2% | 0.136 | |
| Triple‐AL | N (Total) | 760 | 80 | 840 | ||||
| Success (N, %) | 651 | 85.7% | 74 | 92.5% | 725 | 86.3% | 0.057 | |
| Conco‐ CAM/T | N (Total) | 7064 | 377 | 7441 | ||||
| Success (N, %) | 6366 | 90.1% | 352 | 93.4% | 6718 | 90.3% | 0.020 | |
| Seq‐ CAM/T | N (Total) | 2003 | 23 | 2026 | ||||
| Success (N, %) | 1790 | 89.4% | 20 | 87.0% | 1810 | 89.3% | 0.451 | |
| Quad‐ MTcB | N (Total) | 353 | 58 | 411 | ||||
| Success (N, %) | 307 | 87.0% | 52 | 89.7% | 359 | 87.3% | 0.374 | |
| Quad‐Single cap | N (Total) | 6698 | 593 | 7291 | ||||
| Success (N, %) | 6258 | 93.4% | 549 | 92.6% | 6807 | 93.4% | 0.235 | |
| Quad‐CAB | N (Total) | 5284 | 420 | 5704 | ||||
| Success (N, %) | 4976 | 94.2% | 385 | 91.7% | 5361 | 94.0% | 0.028 | |
| Other regimens | N (Total) | 2944 | 396 | 3340 | ||||
| Success (N, %) | 2587 | 87.9% | 342 | 86.4% | 2929 | 87.7% | 0.217 | |
Abbreviations: A, amoxicillin; B, bismuth salts; C, clarithromycin; Conco, concomitant; L, levofloxacin; M, metronidazole; N, number; PPI, proton pomp inhibitor; Quad, quadruple; Sb, saccharomyces boulardii; CNCM I‐745 (single‐strain); Seq, sequential; T, tinidazole; Tc, tetracycline; Triple‐CA: PPI + C + A; Triple‐CM: PPI + C + M; Triple‐AM: PPI + A + M; Triple‐AL: PPI + A + L; Conco‐ CAM/T: Concomitantly PPI + C + A + T or PPI + C + A + M; Seq‐ CAM/T: Alternatively PPI + C + A + T or PPI + C + A + M; Quad‐MTcB: PPI + M + Tc + Bi; Quad‐Single cap: PPI + M + Tc + Bi in a three‐in‐one single capsule formulation; Quad‐CAB: PPI + C + A + B. Other regimens: PPI + any other antibiotic combination.
TABLE 3.
Multivariate analysis of first‐line empirical overall effectiveness and the impact of S. boulardii CNCM I‐745 in European clinical practice.
| a. Final model: independent factors associated with overall modified intention‐to‐treat eradication success. | |||||
|---|---|---|---|---|---|
| Europe | Reference | OR | 95% CI | p‐value a | |
| Sex [ref. female] | Female | 1.136 | 1.060 | 1.217 | 0.000 |
| Compliance | No (< 90%) | 10.802 | 9.298 | 12.549 | 0.000 |
| Indication | Non‐ulcer | 1.244 | 1.134 | 1.364 | 0.000 |
| PPI* | Low dose | ||||
| Standard dose | 1.453 | 1.340 | 1.576 | 0.000 | |
| High dose | 1.612 | 1.474 | 1.762 | 0.000 | |
| Treatment duration | 7 days | ||||
| 10 days | 1.544 | 1.361 | 1.752 | 0.000 | |
| 14 days | 1.920 | 1.684 | 2.189 | 0.000 | |
| European region | Central‐Western | ||||
| Eastern | 1.812 | 1.618 | 2.029 | 0.000 | |
| Central‐Eastern | 0.941 | 0.848 | 1.045 | 0.255 | |
| South‐Western | 1.829 | 1.573 | 2.126 | 0.000 | |
| Eradication regimen | Other regimens** | ||||
| Triple‐CA/M | 1.111 | 0.896 | 1.377 | 0.337 | |
| Triple‐AL | 1.739 | 1.561 | 1.938 | 0.000 | |
| Conco‐CAM/T | 2.820 | 2.515 | 3.162 | 0.000 | |
| Quad‐Single cap+Quad‐MTcB | 2.159 | 1.896 | 2.459 | 0.000 | |
| Quad‐CAB | 1.093 | 0.981 | 1.218 | 0.106 | |
| b. Final model: independent factors associated with modified intention‐to‐treat eradication success in concomitant CAM/T therapy. b | |||||
|---|---|---|---|---|---|
| Concomitant therapy‐CAM/T | |||||
| Age | 10.009 | 10.003 | 1.016 | 0.005 | |
| Compliance | < 90% | 9.397 | 6.124 | 14.419 | 0.000 |
| PPI dose** | Low dose | ||||
| Standard dose | 1.857 | 1.449 | 2.379 | 0.000 | |
| High dose | 2.427 | 1.859 | 3.169 | 0.000 | |
| Treatment duration | 7 days | ||||
| 10 days | 3.379 | 1.374 | 8.313 | 0.008 | |
| 14 days | 3.840 | 1.579 | 9.337 | 0.003 | |
| Sb use | No | 2.322 | 1.338 | 4.031 | 0.003 |
Abbreviations: A, amoxicillin; B, bismuth salts; C, clarithromycin; Conco, concomitant; CI, confidence interval; L, levofloxacin; M, metronidazole; N, number of patients; OR, odds ratio; PPI, proton pump inhibitor; Quad, quadruple; Sb, saccharomyces boulardii CNCM I‐745 (single‐strain); T, tinidazole.
Statistical significance was set at p < 0.05.
PPI: Proton pump inhibitor; PPI doses: low (4.5–27 mg of omeprazole equivalents given twice a day), standard‐dose (32–40 mg of omeprazole equivalents given twice a day), and high‐dose (54–128 mg of omeprazole equivalents given twice a day).
Other regimens: any regimen including a PPI+ any other antibiotic combinations than those previously described.
All models were run for each of the treatment evaluated; however, no significant association was found between the Sb use and a therapy effectiveness increase (data available in Table S5).
3.4. Regimen‐Specific Analyses
When analyzed by regimen (Table 2), the Sb significantly improved eradication with concomitant CAM/T (93% vs. 90%; p < 0.05; OR = 2.32; 1.34–4.03; p < 0.05) (Table 3b) and showed a trend toward higher effectiveness with Triple‐AL (92.5% vs. 86%; p ≈0.05). Its use slightly reduced effectiveness with bismuth quadruple CAB (92% vs. 94%; p < 0.05), while no significant benefit was observed with bismuth quadruple‐MTcB (90% vs. 87%; p > 0.05) and Triple‐CA (87% vs. 86%; p > 0.05), or single capsule‐MTcB (93% in both groups; p > 0.05); these results were consistent in multivariate analysis (Table 3).
Further information regarding the regimen, regional and country‐specific analyses are reported in File S2, and Tables S4 and S5.
3.5. Sb Impact on Safety
Safety data were available for 44,452 patients (3284 in the Sb group and 41,168 controls). Overall, 22% reported at least one AE. The overall incidence of AEs was similar in the Sb group to that in controls (21% vs. 22%; p > 0.05; Table S6). A total of 47 serious AEs were documented (7 in Sb and 40 in controls), representing 0.16% and 0.07% in each group, respectively (p > 0.05).
Multivariate analysis showed that Sb use was independently associated with a lower risk of experiencing AEs (OR = 0.80; 0.66–0.98; p < 0.05), consistently across European regions.
Adherence to therapy (OR = 0.50; 0.41–0.62) and 10‐day prescriptions (OR = 0.77; 0.61–0.98) were significantly associated with fewer AEs (Table 4); whereas, older age (OR = 1.003; 1.001–1.004), ulcer disease (OR = 1.82; 1.65–2.02), standard‐ (OR = 1.43; 1.28–1.60) or high‐dose PPIs use (OR = 1.92; 1.73–2.15), and certain regimens, notably triple‐AL (OR = 3.22; 2.71–3.82) and concomitant CAM/T (OR = 2.43; 2.04–2.89) increased AE risk. Sb users experienced significantly lower rates of AEs including diarrhea (5% vs. 7.5%), dysgeusia (5% vs. 7%), nausea (4% vs. 7%), dyspepsia (2.5% vs. 3%), abdominal pain (2% vs. 4%), asthenia (2% vs. 4%), heartburn (1% vs. 2%), and anorexia (0.3% vs. 3%). No statistically significant difference in vomiting was observed between Sb users and non‐users (2.5% vs. 3%; p > 0.05).
TABLE 4.
Multivariate analysis of safety in first‐line empirical therapy and the impact of S. boulardii CNCM I‐745 in European clinical practice.
| Dependent variable: incidence of at least one adverse event | Reference category | OR | 95% CI | p‐value a | |
|---|---|---|---|---|---|
| Age | 1.003 | 1.001 | 1.004 | 0.003 | |
| Compliance | No (< 90%) | 0.505 | 0.410 | 0.621 | 0.000 |
| Indication | Non‐ulcer | 1.829 | 1.655 | 2.021 | 0.000 |
| PPI dose* | Low dose | ||||
| Standard dose | 1.430 | 1.282 | 1.594 | 0.000 | |
| High dose | 1.930 | 1.728 | 2.155 | 0.000 | |
| Treatment duration | 7 days | ||||
| 10 days | 0.770 | 0.607 | 0.977 | 0.031 | |
| 14 days | 1.020 | 0.806 | 1.290 | 0.870 | |
| Sb use | No | 0.802 | 0.659 | 0.977 | 0.028 |
| European region | Eastern | ||||
| Central‐Eastern | 0.507 | 0.437 | 0.589 | 0.000 | |
| South‐Western | 0.601 | 0.509 | 0.710 | 0.000 | |
| Central‐Western | 0.361 | 0.286 | 0.454 | 0.000 | |
| Eradication regimen | Other regimens** | ||||
| Triple CA/M | 1.033 | 0.720 | 1.480 | 0.862 | |
| Triple AL | 3.219 | 2.709 | 3.823 | 0.000 | |
| Conco‐CAM/T | 2.424 | 2.037 | 2.885 | 0.000 | |
| Quad‐Single cap+Quad‐MTcB | 0.687 | 0.579 | 0.816 | 0.000 | |
| Quad‐CAB | 1.459 | 1.239 | 1.718 | 0.000 | |
| Dependent variable: diarrhea Incidence | |||||
| Age | 1.003 | 1.001 | 1.004 | 0.003 | |
| Compliance | No (< 90%) | 0.505 | 0.410 | 0.621 | 0.000 |
| Indication | Non‐ulcer | 1.829 | 1.655 | 2.021 | 0.000 |
| PPI dose* | Low dose | ||||
| Standard dose | 1.430 | 1.282 | 1.594 | 0.000 | |
| High dose | 1.930 | 1.728 | 2.155 | 0.000 | |
| Treatment duration | 7 days | ||||
| 10 days | 0.770 | 0.607 | 0.977 | 0.031 | |
| 14 days | 1.020 | 0.806 | 1.290 | 0.870 | |
| Sb use | No | 0.803 | 0.659 | 0.977 | 0.028 |
| European region | Eastern | ||||
| Central‐Eastern | 0.507 | 0.437 | 0.589 | 0.000 | |
| South‐Western | 0.601 | 0.509 | 0.710 | 0.000 | |
| Central‐Western | 0.361 | 0.286 | 0.454 | 0.000 | |
| Eradication regimen | Triple‐CA/M | ||||
| Triple AL | 1.033 | 0.720 | 1.480 | 0.862 | |
| Conco‐CAM/T | 3.219 | 2.709 | 3.823 | 0.000 | |
| Quad‐Single cap+Quad‐MTcB | 2.424 | 2.037 | 2.885 | 0.000 | |
| Quad‐CAB | 0.687 | 0.579 | 0.816 | 0.000 | |
| Other** | 1.459 | 1.239 | 1.718 | 0.000 | |
Abbreviations: A, amoxicillin; B, bismuth salts; C, clarithromycin; Conco, concomitant; CI, confidence interval; L, levofloxacin; M, metronidazole; N, number of patients; OR, odds ratio; PPI, proton pump inhibitor; Quad, quadruple; Sb, saccharomyces boulardii CNCM I‐745 (single‐strain); T, tinidazole.
Statistical significance was set at p < 0.05.
PPI doses: low (4.5–27 mg of omeprazole equivalents given twice a day), standard‐dose (32–40 mg of omeprazole equivalents given twice a day), and high‐dose (54–128 mg of omeprazole equivalents given twice a day).
Other regimens: any regimen including a PPI+ any other antibiotic combinations than those previously described.
Given that diarrhea was among the most frequently reported AEs (3484 cases) and a condition for which Sb is specifically indicated, we examined this outcome in detail. Multivariate analysis showed that Sb use was associated with a reduced risk of diarrhea (OR = 0.80; 0.66–0.98; p < 0.05). Additional factors independently associated with a lower risk of diarrhea included treatment adherence (OR = 0.51; 0.41–0.62), a 7–10‐day treatment duration (OR = 0.77; 0.61–0.98), bismuth quadruple‐CAB (OR = 0.69; 0.58–0.82) and residence in any of the non‐reference European regions. In contrast, increasing age (OR = 1.003; 1.001–1.004), treatment for ulcer disease (OR = 1.83; 1.66–2.02), the use of standard‐ (OR = 1.43; 1.28–1.59) or high‐dose PPIs (OR = 1.93; 1.73–2.16), and several eradication regimens [Conco‐CAM/T (OR = 3.22; 2.71–3.82), single capsule‐MTcB and bismuth quadruple‐MTcB (OR = 2.42; 2.04–2.89), other regimens (OR = 1.46; 1.24–1.72)] were independently associated with a higher risk of diarrhea. The bivariate analysis of safety by region is further specified in File S3 and Table S7.
4. Discussion
This large, multi‐country, real‐world study represents the most comprehensive analysis to date of Sb as an adjunct in H. pylori eradication therapy across Europe. Sb was the most frequently used single‐strain probiotic in first‐line empirical therapy, and when combined with concomitant‐CAM/T significantly improved eradication success and reduced treatment‐related AEs, particularly gastrointestinal symptoms, such as diarrhea, nausea, dysgeusia, abdominal pain, heartburn, and asthenia. Compliance remained very high (> 95%) across all regimens and countries, with only minimal differences between groups (with vs. without Sb), as reported in previous studies [13, 15, 22].
Regimen‐specific analyses highlighted a significant benefit of Sb in the effectiveness of concomitant CAM/T, a recommended first‐line treatment approach in several geographic regions, suggesting a clinically meaningful adjunctive role [2]. However, benefits were not universal; in bismuth‐containing regimens, no improvement was observed, underscoring the complexity of host–microbe–drug interactions and suggesting that Sb may exert the greatest effect when antibiotic‐induced dysbiosis is pronounced, as is typical with exposure to multiple macrolide–β‐lactam–nitroimidazole combinations. Prior evidence also indicates Sb was associated with significantly lower resistance [15].
Marked geographical variability in outcomes reflected differences in regional prescribing patterns, antibiotic resistance and patient characteristics, with Central‐Eastern and South‐Western regions showing higher eradication success among Sb users than Eastern regions. These findings should be interpreted with caution, as regional prescribing biases and unmeasured confounding—particularly local antibiotic resistance patterns—may contribute to variability. Multivariate analysis confirmed that compliance, high‐potency acid suppression, and longer treatment duration remained the strongest predictors of H. pylori eradication success, consistent with international guidelines [1, 23].
Our results confirm that the benefits of probiotic supplementation are regimen‐specific, influenced by regional antibiotic resistance, and support tailored, context‐sensitive clinical recommendations, consistent with prior analyses [24, 25]. Similar reductions in AEs, though smaller effects were observed for eradication outcomes in a recently published Hp‐EuReg study [8], conducting a similar evaluation on the use of different probiotics. Our results also reinforce that eradication success is primarily driven by optimized acid suppression, adequate treatment duration, and high patient compliance, in line with international guidelines [1, 23].
A central finding was the consistent reduction in overall AE incidence among Sb users, particularly diarrhea, supporting its established role in improving tolerability through gut microbiota stabilization, mucosal protection, and inflammation modulation. Maastricht VI (1) specifically mentions Sb as among the strains with the most consistent evidence for reducing therapy‐related AEs. Reduced AEs may further support sustained adherence, particularly in less controlled real‐world settings. Nevertheless, benefits varied by country and regimen, underscoring the influence of antibiotic combinations, PPI dosing, and regional practices.
Strengths of the study include its large sample size, prospective data collection, reflection of European clinical practice, and granular regimen‐ and region‐specific analyses. Limitations include its observational design (and consequent lack of randomization), self‐reported compliance, and relatively small Sb‐treated populations (which subsequently did not allow evaluation of the trends over time).
5. Conclusion
In summary, Sb as an adjunct reduced the incidence of AEs and increased effectiveness in specific H. pylori eradication regimens, particularly concomitant‐CAM/T therapy. These real‐world findings support the incorporation of Sb into H. pylori eradication strategies, reinforcing the value of probiotics in improving tolerability and potentially effectiveness in selected clinical settings.
Author Contributions
Olga P. Nyssen and Javier P. Gisbert planned and coordinated the study; analyzed, summarized, and interpreted the data, wrote, and reviewed the various drafts of the manuscript and are guarantors of the study. lga P Nyssen, Hp‐EuReg and WorldHpReg Scientific Director, performed the data extraction, supervised the monitoring and the quality check, performed the data analysis, interpretation, and synthesis, critically reviewed the various drafts of the manuscript, and approved the final submission. Javier P. Gisbert, Principal investigator of the registry, directed the project, obtained funding, designed the protocol, recruited patients, assisted with the data analysis, critically reviewed the various drafts of the manuscript, and approved the final submission.
Laimas Jonaitis, Ángeles Pérez‐Aísa, Bojan Tepes, Umud Mahmudov, Irina Voynova, Samuel J. Martínez‐Domínguez, Luis Bujanda, Alfredo J. Lucendo, Ludmila Vologzanina, Ana Garre, Frode Lerang, Sayar R. Abdulkhakov, Matteo Pavoni, Maja Denkovski, Emin Mammadov, Mārcis Leja, Javier Tejedor‐Tejada, Jose M. Huguet, Galyna Fadieienko, Ilchishina Tatiana, Manuel Pabón‐Carrasco, Aiman S. Sarsenbaeva, Oleg Zaytsev, Gülüstan Babayeva, Jesús Barrio, Miguel Areia, Monica Perona, Óscar Núñez, Antonietta G. Gravina, Sergey Alekseenko, Blas José Gómez Rodríguez, Quliyev Fərid Vidadi Oğlu, Inmaculada Ortiz‐Polo, Antonio Moreno Loro, György Miklós Buzás, Boris D. Starostin, Juozas Kupcinskas, Dmitry S. Bordin, Antonio Gasbarrini, Oleksiy Gridnyev, Ricardo Marcos‐Pinto, Manuel Jiménez‐Moreno, Mónica Sánchez Alonso, Virginia Flores, Irene Arteagoitia, Anna Cano‐Català, Pablo Parra, Leticia Moreira, Javier P. Gisbert, collected data, critically reviewed the various drafts of the manuscript, and approved the final submission. Anna Cano and Pablo Parra performed the monitoring and quality check of the data. Leticia Moreira, Pablo Parra, Olga P. Nyssen, Francis Mégraud, Colm O'Morain, Javier P. Gisbert are all members of the Hp‐EuReg and WorldHpReg Scientific Committee; they critically reviewed the various drafts of the manuscript and approved the final submission.
Funding
This project was promoted and funded by the European Helicobacter and Microbiota Study Group (EHMSG). The Hp‐EuReg was co‐funded by the European Union programme HORIZON (grant agreement number 101095359) and supported by the UK Research and Innovation (grant agreement number 10058099). However, the views and opinions expressed are those of the author(s) only and do not necessarily reflect those of the European Union or the Health and Digitial Executive Agency (HaDEA). Neither the European Union nor the granting authority can be held responsible for them. The Hp‐EuReg was co‐funded by the European Union programme EU4Health (grant agreement number 101101252). The Hp‐EuReg study was partially co‐funded by Mayoly, Diasorin, Juvisé, Biocodex, and Zambon; however, no clinical data were accessible, and the companies were not involved in any stage of the Hp‐EuReg study (design, data collection, and statistical analysis).
Disclosure
Patient and Public Involvement: Patients and/or the public were not involved in the design, conduct, reporting, or dissemination plans of this research.
Ethics Statement
The Hp‐EuReg protocol was approved by the Ethics Committee Hospital Universitario de la Princesa (Madrid, SPAIN), which acted as a reference Institutional Review Board (20 December 2012) (Ethics approval code: Hp‐EuReg). This research was conducted according to the guidelines of the Declaration of Helsinki, classified by the Spanish Agency for Medicines and Medical Devices, and prospectively registered at Clinical Trials.gov under the code NCT02328131.
Conflicts of Interest
Javier P. Gisbert has served as a speaker, consultant, and advisory member for, or has received research funding from: Mayoly, Diasorin, Juvisé, Biocodex, and Zambon. Olga P. Nyssen has served as a speaker or has received research funding from Mayoly, Diasorin, Juvisé, Biocodex, and Zambon. The other authors declare that they have no competing interests.
Supporting information
File S1: Hp‐EuReg investigators.
File S2: Impact of S. boulardii CNCM I‐745 use on effectiveness at the regimen, regional and country‐levels.
File S3: Safety in the S. boulardii I‐745 group and Control, in each European region.
Table S1: List of countries by European geographic region (A) and list of eradication therapies by category (B).
Table S2: Use of S. boulardii CNCM I‐745 (Sb) Across First‐Line Eradication Regimens in Europe.
Table S3: Compliance by European region, country, and eradication regimen.
Table S4: Eradication Success Rates Across European regions, countries and eradication regimen.
Table S5: Multivariate analysis of factors associated with eradication effectiveness across H. pylori treatment regimens.
Table S6: Overall safety in the Sb and control groups.
Table S7: Safety of each treatment by European region.
Acknowledgments
We thank the Spanish Association of Gastroenterology (AEG) for providing the e‐CRF service free of charge, and Abelia Science (Auxerre, France) for its support in medical writing. This project has received support from the Spanish Association of Gastroenterology (AEG) and the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd).
Contributor Information
Olga P. Nyssen, Email: opn.aegredcap@aegastro.es.
the Hp‐EuReg investigators:
Boris D. Starostin, Sotirios D. Georgopoulos, Doron Boltin, Manuel Domínguez Cajal, Galina N. Tarasova, Fernando Bermejo, Ludmila V. Morkovkina, Cem Simsek, Perminder S. Phull, María Soledad Marcos, Giuseppe Losurdo, Judith Gomez‐Camarero, Emin Verdiyev, Thomas J. Butler, Sinead M. Smith, Pedro Almela, Antonio Mestrovic, Natalya N. Dekhnich, Pilar Mata‐Romero, Daniel Martin‐Holgado, Marinko Marušić, Ian L. P. Beales, Sabir Sagdati, Dmitry N. Andreev, Igor G. Bakulin, Ivan Nagorni, Alla Kononova, Vladimir Milivojevic, Noelia Alcaide, Benito Velayos, Luis Fernández‐Salazar, Georges Kamtoh, Eduardo Iyo, Pablo M. Wolfe García, Natalia V. Bakulina, Ramón Pajares Villarroya, Miguel Fernández‐Bermejo, Jurij Bednarik, Debora Compare, Sabina Hrubá, Marina F. Osipenko, Dan L. Dumitrascu, Alisan Kahraman, Emilija Nikolovska Trpchevska, Montserrat Planella, Consuelo Ramírez, Victor A. Kamburov, Teresa Angueira, Natalia V. Baryshnikova, Ana Beatriz Pozo Blanco, Pedro Delgado, Maria A. Livzan, Melanija Razov Radas, Natalya V. Bakanova, Eva Barreiro Alonso, Michael Doulberis, Rosario Antón Ausejo, Piotr Eder, Natasa Brglez Jurecic, Wojciech Marlicz, Sheyla Montori Pina, Antonio Cuadrado, Jan Kral, Palencia Palencia, Christos Liatsos, Olga A. Kolokolnikova, Manon C. W. Spaander, Piotr Szredzki, María Badía Martínez, Stergios N. Kouvaras, Mila Kovacheva‐Slavova, Regina I. Khlynova, Benito Hermida Pérez, Petra Čavajdová, Sergio Gil Rojas, Luis Hernández, Ekaterina Y. Plotnikova, Xhensila Pemaj, Deirdre McNamara, Guillem Soy, Ioannis Linas, Riccardo Vasapolli, Marko Nikolic, Andreas Blesl, Tamara Matysiak‐Budnik, Diego Burgos‐Santamaría, Rashad A. Hasanov, Lumir Kunovsky, Carlos Maroto‐Martín, Pilar Bernal Checa, Paola Chaudarcas, Pilar Pazo Mejide, Giulia Fiorini, Ramiro Carreño Macián, Rosa Rosania, Anna‐Maria Tiefenthaller, Teresa Valdés‐Lacasa, Amir Mari, Anna L. Pakhomova, Jan Bornschein, Suzanne Cauchi, Jesus M. Gonzalez‐Santiago, Petra Koňaříková, Isabel Pérez‐Martínez, David Přidal, Jorge Yebra, Miguel Suárez Matías, Natalie Friedova, Diego Ledro Cano, Mirjana Kalauz, Jose Xavier Segarra Ortega, Adam Vasura, Senador Moran Sanchez, Petr Bauer, Katarina Jankovic, Sara Hoxha, Marjan Stankovic, Hagai Schweistein, Alma Keco‐Huerga, Ismar Hasukić, Thomas Balanis, Jakub Langner, Patrick Dinkhauser, Patricia Sanz‐Segura, Melek Balamir, Theodore Rokkas, Mikel Ganuza, Milica Bjelakovic, Antonia Perelló, Marta Pascual‐Mato, Alexander Link, Marino Venerito, Jan Krivinka, Cristina Maria Sabo, Lyudmila Boyanova, Eduardo Albéniz, Skerdi Prifti, Pierre Ellul, Katja Repitsch, Ramazan Erdem Er, and Skender Telaku
Data Availability Statement
Raw data were generated at AEG#x02010; REDCap. All data relevant to the study are included in the article or uploaded as supporting information. De#x02010; identified raw data referring to the current study are available from the WorldHpReg and Hp#x02010; EuReg Scientific director and the principal investigator (PI) of the project (OPN and JPG respectively) upon request. Individual participant data will not be shared.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
File S1: Hp‐EuReg investigators.
File S2: Impact of S. boulardii CNCM I‐745 use on effectiveness at the regimen, regional and country‐levels.
File S3: Safety in the S. boulardii I‐745 group and Control, in each European region.
Table S1: List of countries by European geographic region (A) and list of eradication therapies by category (B).
Table S2: Use of S. boulardii CNCM I‐745 (Sb) Across First‐Line Eradication Regimens in Europe.
Table S3: Compliance by European region, country, and eradication regimen.
Table S4: Eradication Success Rates Across European regions, countries and eradication regimen.
Table S5: Multivariate analysis of factors associated with eradication effectiveness across H. pylori treatment regimens.
Table S6: Overall safety in the Sb and control groups.
Table S7: Safety of each treatment by European region.
Data Availability Statement
Raw data were generated at AEG#x02010; REDCap. All data relevant to the study are included in the article or uploaded as supporting information. De#x02010; identified raw data referring to the current study are available from the WorldHpReg and Hp#x02010; EuReg Scientific director and the principal investigator (PI) of the project (OPN and JPG respectively) upon request. Individual participant data will not be shared.