AbstractHelicobacter pylori (H. pylori) infection remains a cause of significant morbidity and mortality worldwide. Comprehensive understanding of the pathogenic mechanism of H. pylori and its interaction with host will contribute to developing novel prophylactical and therapeutical strategies. Here, we first determined microRNA (miRNA) levels in H. pylori-infected patients with gastritis, duodenal ulcer, gastric cancer or mucosa-associated lymphoid tissue lymphoma using miRNA data sets. Thirty-four differentially expressed miRNAs were identified and functional enrichment analysis of those miRNA target genes revealed that H. pylori infection were strongly associated with pathway in cancer and regulation of mRNA synthesis. Using disease connectivity analysis of 28 hub genes, we found that H. pylori may increase the risk of many extragastric diseases (e.g. cardiovascular disease, hemic and lymphatic diseases and nervous system disease). Altogether, our integrated analysis provided a new method to predict pathogen–human disease connectivity based on miRNA-mRNA interaction network and indicated anti-H. pylori therapy as an effective means of human diseases prevention.