We proposed a systematic method to understand H. pylori's genetic diversity, phylogenetic clustering, and regulatory relations. This study provides a pangenome analysis of over 1,300 complete H. pylori strains, which is over ten times higher than previous studies, significantly expanding the scope of genetic exploration. We identified 1,015 core genes, 986 accessory genes, and 38,357 rare genes. Non-negative matrix factorization (NMF) was used for phylogenetic clustering, allowing us to decompose the accessory gene matrix for a better mathematical representation. We applied a Random Forest Classifier to characterize the genetic basis of these phylogroups, highlighting the genes that contribute most significantly to phylon differentiation. Finally, by integrating genome data with RNA-seq analysis, we created a multi-strain dataset with enhanced statistical power and comparability to better understand gene functionality and discover new regulatory networks and to address the challenge of limited availability of single-strain transcriptomic data in many bacterial species. This approach creates a comprehensive framework for H. pylori studies using public genomic and transcriptomic data, offering a scalable model for similar studies in other bacterial species.