Genomic Diversity, Virulence, and Antimicrobial Resistance of Helicobacter suis Isolated from Human Stomachs

Background: Helicobacter suis, a bacterial species naturally hosted by pigs, can colonize the human stomach in the context of gastric diseases, such as gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Because H. suis has been successfully isolated from pigs, but not from humans, evidence linking human H. suis infection to gastric diseases has remained incomplete. The aim of this study is to elucidate the pathogenicity of H. suis by genetic characterization and through animals infected with H. suis isolated from human stomachs. Methods: H. suis from human gastric biopsies was isolated as previously described in pigs, with modifications. Mice were orally infected with H. suis for 4 months, and then pathogenesis was analyzed. Whole-genome analysis of H. suis isolates was performed by short-read and long-read sequencing, and their genomes were subjected to comparative analysis. Findings: H. suis was successfully isolated from three patients with gastric diseases, including gastric MALT lymphoma. Successful eradication of H. suis yielded significant improvements in endoscopic and histopathological findings in all patients. H. suis infection in mice using clinical isolates elicited gastric and systemic inflammatory responses, and H. suis could be isolated from the stomachs of infected mice. Therefore, according to Koch’s postulates, these findings demonstrate that H. suis is a human gastric pathogen. Genomic analysis revealed high similarity between isolates from humans and pigs, suggesting possible horizonal transmission of H. suis. Interpretation: This is the first study to directly demonstrate virulence-associated features of H. suis infection using isolates obtained from human stomachs. Since H. suis would have been missed by routine diagnostic tests for Helicobacter pylori, large-scale epidemiological research on H. suis is needed to identify causal relationships with gastric diseases and develop novel diagnostic methods. Funding: MEXT/JSPS KAKENHI Grant numbers JP19H03474 for (HM) and JP20K08365 for (KT), and AMED Grant Numbers JP20fk0108148 (ER) and JP20fk0108133 (MS). Conflict of Interest: ER has received research funding from GlaxoSmithKline, outside the submitted work. All other authors declare no competing interests. Ethical Approval: Ethical approvals were obtained from all participating hospitals and the National Institute of Infectious Diseases (NIID). Written informed consent was obtained from all participants.