Role of Probiotics in Helicobacter pylori Eradication: Lessons from a Study of Lactobacillus reuteri Strains DSM 17938 and ATCC PTA 6475 (Gastrus®) and a Proton-Pump Inhibitor

Abstract

Background: Meta-analyses involving >4000 subjects with probiotics added to antimicrobial Helicobacter pylori eradication therapy have reported a mean increase in the eradication rate of 12 to 14%. It is unclear how to translate that result into clinical practice.

Aim: To evaluate whether administration of Lactobacillus reuteri plus a PPI without antibiotics would eradicate H. pylori infections.

Methods: This was a double-blind placebo-controlled randomized 2-site study of L. reuteri (Gastrus®) at a dose of 2 × 108 CFU, 7 times per day, or matching placebo plus 20 mg pantoprazole b.i.d. for 4 weeks. Cure was defined by negative 13C-UBT, 4 weeks after therapy. Sample size required ≥50% cure rates for using probiotics as a clinically useful monotherapy.

Results: Recruitment was halted after 56 subjects because of the low cure rate; there were 8 dropouts; 48 subjects completed therapy (71% women, average age 49 years). The cure rates per protocol were 3/24 (12.5%; 95% CI 2.6-32%) with L. reuteri vs. 1/24 (4.1%) with placebo. Side effects (most often diarrhea) occurred infrequently (in 5/28 vs. 3/28; active vs. placebo therapy) (P=0.53).

Conclusion: L. reuteri plus a PPI therapy was unable to provide a clinically important rate of H. pylori eradication. The cure rate albeit low (12.5%) was essentially identical to that achieved when probiotics were added to antibiotic therapy. The incremental improvement was additive and independent of antimicrobial resistance or antibiotics use. Probiotics can reliably increase the cure rate to ≥90% only in regimens achieving cure rates of ∼80%. This trial is registered with NCT03404440.

Figures

Figure 1

(a) Hp-nomogram [9] showing theoretical cure rates with 7-day triple therapy in the absence and presence of resistance plotted based on a cure rate of 95% with susceptible infections and 20% with resistant infections consistent results in western populations. Using the data from the meta-analysis [4], the overall cure rate PP was 74.1% (circle) which would be equivalent to a proportion with resistance of approximately 28%. The results with probiotics are plotted (square) as the same resistance rate as they came from the same population. (b) Hp-treatment nomogram showing the results plotted as an additive effect (i.e., the cure rate of the overall population plus 9.1% which is the absolute delta that achieved a 12.1% increase from 74.1 to 83.5% as shown in Figure 1(a) based on [4]). The formula would be ((cure rate with susceptible infections) × (proportion with susceptible infections) + (cure rate with resistant infections) times (proportion with resistant infections)) + (absolute percent increase with probiotic). (c) Hp-treatment nomogram showing the alternate ways the outcomes could be plotted if the increase with the probiotic had been entirely dependent on the increased effect among those with susceptible infections (dotted line) or among those with resistant infections (dashed line). The experiment described above showed that the best representation is the one shown in Figure 2.

Figure 2

Disposition of study patients. PP = per protocol; ITT = intention to treat.

Figure 3

Hp-treatment nomogram showing theoretical cure rates with 14-day triple therapy with standard dose PPI (e.g., 40 mg of omeprazole b.i.d.) in the absence and presence of resistance. This would increase the population cure rate in the “all clarithromycin resistant” subgroup (PPI + amoxicillin) from 20 to 40%. Based on an increase in the cure rate of 12% with probiotic, the addition of probiotic adjuvant therapy would increase the point where the cure rates fell below 90% from approximately 13% (solid line) to 33% (dotted line).

Figure 4

Hp nomogram showing theoretical cure rates with 7 day vonoprazan 20 mg b.i.d. plus amoxicillin 1 g b.i.d. in the absence and presence of resistance [19]. Based on an increase in the cure rate of 12% with probiotic, the addition of probiotic adjuvant therapy would increase the point where the cure rates fell below 90% from approximately 42% (solid line) to 100% (dotted line) such that dual vonoprazan-amoxicillin therapy would be sufficient and clarithromycin would become unnecessary.