Bile acid metabolism dysregulation following Helicobacter pylori eradication promotes plasmid-mediated antimicrobial resistance in the gut microbiome.

Abstract

Antimicrobial resistance (AMR) transmission within the gut microbiome poses a major health risk during antibiotic exposure, primarily via horizontal gene transfer (HGT). However, how antibiotic-induced metabolic remodeling of the intestinal environment modulates plasmid-mediated AMR dissemination remains unclear. Herein, integrating metagenomics, metabolomics, in vitro conjugation assays, and in vivo mouse models, we show that Helicobacter pylori eradication therapy reshapes gut metabolism in ways that enhance transfer of antibiotic resistance genes (ARGs). Metagenomic analysis revealed the expansion of Escherichia populations and the enrichment of plasmid-borne ARGs after H. pylori eradication. Fecal filtrates from treated individuals significantly increased conjugation frequencies of the broad-host-range plasmid RP4 in E. coli. Metabolomic profiling identified a pronounced accumulation of primary bile acids, including glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, and taurochenodeoxycholic acids, which could increase bacterial membrane permeability, induce the SOS response, and upregulate conjugation and pilus assembly genes, thereby accelerating ARG transfer. Molecular docking further suggested these bile acids may likely participates in interacting with global plasmid repressors KorA/KorB, derepressing conjugation operons. In mice, H. pylori eradication therapy elevated fecal primary bile acid levels and significantly promoted in vivo plasmid transfer, with the critical role of bile acids further confirmed through interventions using the bile acid sequestrant cholestyramine or glycocholic acid. Together, these findings demonstrate that dysregulation of bile acid metabolism due to H. pylori eradication creates a permissive gut niche for plasmid-mediated ARG dissemination, providing mechanistic insight into how clinical antibiotic regimens can unintentionally promote microbiome-associated AMR risk.