Research in context
Systematic review
We searched PubMed using the terms “H. pylori”, “eradication”, “long-term”, and “microbiota”, for papers published from Jan 1, 2000, to Nov 10, 2018, without language restrictions. We found no randomised trials that compared the long-term (≥1 year) changes of gut microbiota after triple therapy, concomitant therapy, and bismuth quadruple therapy for Helicobacter pylori eradication. We identified three studies that reported the long-term changes in the gut microbiota after H pylori eradication. Jakobsson and colleagues showed that the diversity of the microbiota recovered to resemble the pretreatment states, with some notable changes at the genus levels at 1 year and 4 year after triple therapy, but formal statistical analysis was not done owing to small sample size (six patients). Yap and colleagues also showed no significant differences in richness and evenness of bacterial species, but they found some notable changes at the phylum and genus levels after triple therapy (17 patients). Hsu and colleagues reported that the relative abundances of all phyla restored to the amounts at baseline at 48 weeks after bismuth quadruple therapy (11 patients). We identified another four studies that only reported the short-term changes in the gut microbiota after H pylori eradication (20–70 patients each). These studies showed significant changes in diversity shortly after H pylori eradication.
We did a further PubMed search using the terms “H. pylori”, “eradication”, “long-term”, and “resistance”, for papers published up to Nov 10, 2018, without language restrictions. We identified one brief communication that compared clarithromycin resistance of enterococci in five patients before and 1 year after triple therapy with five controls who did not receive antibiotics. In that study, numerically higher clarithromycin resistance prevalence was observed in patients who received triple therapy (two [50%] of four), compared with none of the controls. We searched the Web of Science to identify articles that cited this study and identified another study that compared clarithromycin resistance rates of Staphylococcus spp, Streptococcus spp, Enterococcus spp, and Bacteroides spp in 85 patients who received triple therapy and 12 controls who did not. They reported numerically higher resistance rates of staphylococcus against clarithromycin in patients who received triple therapy at 1 year (20 [34%] of 58), compared with the control group (two [20%] of ten). However, the difference was not significant.
Finally, we searched PubMed using the terms “H. pylori”, “eradication”, and “insulin resistance” for papers published up to Nov 10, 2018, without language restrictions. We identified six prospective and retrospective studies that reported the short-term changes (6–12 weeks) of insulin resistance after H pylori eradication. These studies showed contradictory results. None of them assessed the long-term changes of insulin resistance after H pylori eradication.
Added value of this trial
To our knowledge, this is the first large-scale randomised trial to show the distinct short-term and long-term effects of triple therapy, concomitant therapy, and bismuth quadruple therapy on the gut microbiota, antibiotic resistance, and metabolic parameters. We found that short-term perturbation of gut microbiota and short-term increase of antibiotic resistance of E coli were restored at 1 year after H pylori eradication. However, the speed and extent of restoration of gut microbiota varied with regimens. Whereas the gut microbiota was less perturbed by triple therapy, bismuth quadruple therapy induced minimal increase in the antibiotic resistance of E coli. Although there were trivial increases in body-mass index and bodyweight, insulin resistance and triglyceride concentrations decreased, indicating potential beneficial metabolic effects after H pylori eradication.
Interpretation of all the available evidence
Eradication of H pylori infection has minimal disruption of the microbiota, no effect on antibiotic resistance of E coli, and some positive effects on metabolic parameters. These findings collectively lend support to the long-term safety of H pylori eradication therapy. Taken together with our previous study, bismuth quadruple therapy is recommended in regions with clarithromycin resistance of greater than 15% because it is more effective than triple therapy, its efficacy is less affected by clarithromycin resistance, and it exerts minimal effects on the antibiotic resistance of E coli and Klebsiella pneumoniae. Triple therapy for 14 days exerts minimal perturbation of gut microbiota and might be an alternative therapy in regions with clarithromycin resistance of less than 10–15%.