Non-Helicobacter pylori Gastric Microbiome Modulates Prooncogenic Responses and Is Associated With Gastric Cancer Risk

Ryota Niikura; Yoku Hayakawa; Naoyoshi Nagata; Tohru Miyoshi-Akiayama; Koji Miyabayashi; Mayo Tsuboi; Nobumi Suzuki; Masahiro Hata; Junya Arai; Ken Kurokawa; Sohei Abe; Chie Uekura; Kotaro Miyoshi; Sozaburo Ihara; Yoshihiro Hirata; Atsuo Yamada; Hiroaki Fujiwara; Tetsuo Ushiku; Susan L. Woods; Daniel L. Worthley; Masanori Hatakeyama; Yiping W. Han; Timothy C. Wang; Takashi Kawai; Mitsuhiro Fujishiro

Gastro Hep Advances (Jan 2023)

Non-Helicobacter pylori Gastric Microbiome Modulates Prooncogenic Responses and Is Associated With Gastric Cancer Risk

Ryota Niikura,
Yoku Hayakawa,
Naoyoshi Nagata,
Tohru Miyoshi-Akiayama,
Koji Miyabayashi,
Mayo Tsuboi,
Nobumi Suzuki,
Masahiro Hata,
Junya Arai,
Ken Kurokawa,
Sohei Abe,
Chie Uekura,
Kotaro Miyoshi,
Sozaburo Ihara,
Yoshihiro Hirata,
Atsuo Yamada,
Hiroaki Fujiwara,
Tetsuo Ushiku,
Susan L. Woods,
Daniel L. Worthley,
Masanori Hatakeyama,
Yiping W. Han,
Timothy C. Wang,
Takashi Kawai,
Mitsuhiro Fujishiro

Affiliations

Ryota Niikura: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan; Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
Yoku Hayakawa: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan; Correspondence: Address correspondence to: Yoku Hayakawa, MD, PhD, Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Naoyoshi Nagata: Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Naoyoshi Nagata, MD, PhD, Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan.
Tohru Miyoshi-Akiayama: Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
Koji Miyabayashi: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Mayo Tsuboi: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Nobumi Suzuki: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Masahiro Hata: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Junya Arai: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Ken Kurokawa: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Sohei Abe: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Chie Uekura: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Kotaro Miyoshi: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Sozaburo Ihara: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Yoshihiro Hirata: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Atsuo Yamada: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Hiroaki Fujiwara: Department of Gastroenterology, The Institute for Medical Science, Asahi-life Foundation, Tokyo, Japan
Tetsuo Ushiku: Department of Pathology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan
Susan L. Woods: Cancer Theme, SAHMRI, Adelaide, South Australia, Australia; Medical Specialties, Medical School, The University of Adelaide, Adelaide, South Australia, Australia
Daniel L. Worthley: Cancer Theme, SAHMRI, Adelaide, South Australia, Australia
Masanori Hatakeyama: Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
Yiping W. Han: Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York; Department of Microbiology and Immunology, Vagelos College of Physicians & Surgeons, Columbia University, New York, New York; Section of Oral, Diagnostic and Rehabilitation Sciences, College of Dental Medicine, Columbia University, New York, New York
Timothy C. Wang: Division of Digestive and Liver Disease, Department of Medicine, Columbia University, New York, New York
Takashi Kawai: Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
Mitsuhiro Fujishiro: Department of Gastroenterology, Graduate school of medicine, The University of Tokyo, Tokyo, Japan

Journal volume & issue: Vol. 2, no. 5
pp. 684 – 700

Abstract

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Background and Aims: Although Helicobacter pylori is the most important bacterial carcinogen in gastric cancer (GC), GC can emerge even after H. pylori eradication. Studies suggest that various constituents of the gastric microbiome may influence GC development, but the role of individual pathogens is unclear. Methods: Human gastric mucosal samples were analyzed by 16SrRNA sequencing to investigate microbiome composition and its association with clinical parameters, including GC risk. Identified bacteria in the stomach were cocultured with gastric epithelial cells or inoculated into mice, and transcriptomic changes, DNA damage, and inflammation were analyzed. Bacterial reads in GC tissues were examined together with transcriptomic and genetic sequencing data in the cancer genome atlas dataset. Results: Patients after Helicobacter pylori eradication formed 3 subgroups based on the microbial composition revealed by 16SrRNA sequencing. One dysbiotic group enriched with Fusobacterium and Neisseria species was associated with a significantly higher GC incidence. These species activated prooncogenic pathways in gastric epithelial cells and promoted inflammation in mouse stomachs. Sugar chains that constitute gastric mucin attenuate host-bacteria interactions. Metabolites from Fusobacterium species were genotoxic, and the presence of the bacteria was associated with an inflammatory signature and a higher tumor mutation burden. Conclusion: Gastric microbiota in the dysbiotic stomach is associated with GC development after H. pylori eradication and plays a pathogenic role through direct host-bacteria interaction.

Published in Gastro Hep Advances

ISSN: 2772-5723 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Diseases of the digestive system. Gastroenterology
Website: https://www.sciencedirect.com/journal/gastro-hep-advances

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