The Unfinished Agenda in Helicobacter pylori Treatment: Resistance, Microbiome Effects, and Future Directions

Helicobacter pylori infection is the principal cause of peptic ulcer disease, mucosa-associated lymphoid tissue lymphoma, and noncardia gastric cancer. The major advances in diagnostics and treatment and eradication success are threatened by rising antimicrobial resistance and concerns about disruption of the normal microbiome. This review summarizes current unresolved issues in H pylori treatment, with a focus on resistance, optimal regimens, ecological impact, and emerging therapies.

Extensive review of randomized controlled trials, meta-analyses, international consensus guidelines, molecular epidemiology studies, microbiome analyses, and translational research related to H pylori eradication, resistance, microbiome effects, and novel therapies.

Global resistance to clarithromycin, metronidazole, and fluoroquinolones significantly undermines the performance of traditionally effective antimicrobial therapies. The corner stone of successful antimicrobial therapy is susceptibility-guided therapy but remains of limited use with H pylori because of lack of infrastructure. Eradication regimens potentially induce substantial alterations in gut and gastric microbiota and expand the antimicrobial resistome. Probiotics and N-acetylcysteine offer at best very modest improvements in eradication and tolerability. Novel and still experimental platforms, including engineered phage therapy, antimicrobial peptides, nanoparticle-delivered urease inhibitors, biofilm-targeting agents, and vaccines show promise. Implementation gaps, persistent use of suboptimal regimens, and global inequities constrain the impact of available therapies.

Optimizing H pylori treatment requires evidence-based regimen selection, precision-guided strategies, antimicrobial stewardship, and equitable access to essential medications. Advances in molecular diagnostics, antimicrobial development, and implementation science are all critical to reducing the global burden of H pylori-associated disease and gastric cancer.