Dual RNA sequencing of and host cell transcriptomes reveals ontologically distinct host-pathogen interaction.

Unlabelled: is a highly successful pathogen that poses a substantial threat to human health. However, the dynamic interaction between and the human gastric epithelium has not been fully investigated. In this study, using dual RNA sequencing technology, we characterized a cytotoxin-associated gene A ()-modulated bacterial adaption strategy by enhancing the expression of ATP-binding cassette transporter-related genes, and , upon coculturing with human gastric epithelial cells. We observed a general repression of electron transport-associated genes by , leading to the activation of oxidative phosphorylation. Temporal profiling of host mRNA signatures revealed the downregulation of multiple splicing regulators due to bacterial infection, resulting in aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to infection. Moreover, we demonstrated a protective effect of gastric colonization against chronic dextran sulfate sodium (DSS)-induced colitis. Mechanistically, we identified a cluster of propionic and butyric acid-producing bacteria, , selectively enriched in the colons of -pre-colonized mice, which may contribute to the restoration of intestinal barrier function damaged by DSS treatment. Collectively, this study presents the first dual-transcriptome analysis of during its dynamic interaction with gastric epithelial cells and provides new insights into strategies through which promotes infection and pathogenesis in the human gastric epithelium.

Importance: Simultaneous profiling of the dynamic interaction between and the human gastric epithelium represents a novel strategy for identifying regulatory responses that drive pathogenesis. This study presents the first dual-transcriptome analysis of when cocultured with gastric epithelial cells, revealing a bacterial adaptation strategy and a general repression of electron transportation-associated genes, both of which were modulated by cytotoxin-associated gene A (). Temporal profiling of host mRNA signatures dissected the aberrant pre-mRNA splicing of functional genes involved in the cell cycle process in response to infection. We demonstrated a protective effect of gastric colonization against chronic DSS-induced colitis through both and experiments. These findings significantly enhance our understanding of how promotes infection and pathogenesis in the human gastric epithelium and provide evidence to identify targets for antimicrobial therapies.