Metagenome Data on Intestinal Phage-Bacteria Associations Aids the Development of Phage Therapy against Pathobionts

Kosuke Fujimoto; Yasumasa Kimura; Masaki Shimohigoshi; Takeshi Satoh; Shintaro Sato; Georg Tremmel; Miho Uematsu; Yunosuke Kawaguchi; Yuki Usui; Yoshiko Nakano; Tetsuya Hayashi; Koji Kashima; Yoshikazu Yuki; Kiyoshi Yamaguchi; Yoichi Furukawa; Masanori Kakuta; Yutaka Akiyama; Rui Yamaguchi; Sheila E Crowe; Peter B Ernst; Satoru Miyano; Hiroshi Kiyono; Seiya Imoto; Satoshi Uematsu

doi:10.1016/j.chom.2020.06.005

Metagenome Data on Intestinal Phage-Bacteria Associations Aids the Development of Phage Therapy against Pathobionts

Cell Host Microbe. 2020 Sep 9;28(3):380-389.e9. doi: 10.1016/j.chom.2020.06.005. Epub 2020 Jul 10.

Authors

Kosuke Fujimoto¹, Yasumasa Kimura², Masaki Shimohigoshi³, Takeshi Satoh², Shintaro Sato⁴, Georg Tremmel⁵, Miho Uematsu³, Yunosuke Kawaguchi³, Yuki Usui², Yoshiko Nakano³, Tetsuya Hayashi³, Koji Kashima⁶, Yoshikazu Yuki⁶, Kiyoshi Yamaguchi⁷, Yoichi Furukawa⁷, Masanori Kakuta⁵, Yutaka Akiyama⁸, Rui Yamaguchi⁵, Sheila E Crowe⁹, Peter B Ernst¹⁰, Satoru Miyano⁵, Hiroshi Kiyono¹¹, Seiya Imoto¹², Satoshi Uematsu¹³

Affiliations

¹ Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; Division of Metagenome Medicine, Human Genome Center, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
² Division of Systems Immunology, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
³ Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.
⁴ Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; Mucosal Vaccine Project, BIKEN Innovative Vaccine Research Alliance Laboratories, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
⁵ Laboratory of DNA Information Analysis, Human Genome Center, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
⁶ Division of Mucosal Immunology, Department of Microbiology and Immunology, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
⁷ Division of Clinical Genome Research, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
⁸ Department of Computer Science, Tokyo Institute of Technology, Tokyo 152-8550, Japan.
⁹ Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹⁰ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, La Jolla, CA 92093, USA; Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
¹¹ Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California, San Diego, La Jolla, CA 92093, USA; Division of Comparative Pathology and Medicine, Department of Pathology, University of California, San Diego, La Jolla, CA 92093, USA; Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Sciences, The University of Tokyo, Tokyo 108-8639, Japan; International Research and Development Center for Mucosal Vaccines, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan.
¹² Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo 113-8657, Japan. Electronic address: imoto@ims.u-tokyo.ac.jp.
¹³ Department of Immunology and Genomics, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan; Division of Metagenome Medicine, Human Genome Center, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, the Institute of Medical Sciences, the University of Tokyo, Tokyo 108-8639, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Tokyo 113-8657, Japan. Electronic address: uematsu.satoshi@med.osaka-cu.ac.jp.

PMID: 32652061
DOI: 10.1016/j.chom.2020.06.005

Abstract

The application of bacteriophages (phages) is proposed as a highly specific therapy for intestinal pathobiont elimination. However, the infectious associations between phages and bacteria in the human intestine, which is essential information for the development of phage therapies, have yet to be fully elucidated. Here, we report the intestinal viral microbiomes (viromes), together with bacterial microbiomes (bacteriomes), in 101 healthy Japanese individuals. Based on the genomic sequences of bacteriomes and viromes from the same fecal samples, the host bacteria-phage associations are illustrated for both temperate and virulent phages. To verify the usefulness of the comprehensive host bacteria-phage information, we screened Clostridioides difficile-specific phages and identified antibacterial enzymes whose activity is confirmed both in vitro and in vivo. These comprehensive metagenome analyses reveal not only host bacteria-phage associations in the human intestine but also provide vital information for the development of phage therapies against intestinal pathobionts.

Keywords: CRISPR; Clostridioides difficile infection; bacteriome; bacteriophage; host bacteria-phage association; metagenome analysis; prophage; virome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Bacterial Agents / pharmacology
Bacteriophages / genetics*
Bacteriophages / isolation & purification
Clostridioides difficile / virology*
Clostridium Infections / therapy
Disease Models, Animal
Endopeptidases / genetics*
Endopeptidases / pharmacology
Feces / microbiology
Female
Gastrointestinal Microbiome / genetics*
Genome, Bacterial
Genome, Viral
Humans
Metagenome
Mice
Mice, Inbred C57BL
Phage Therapy / methods*
Prophages / genetics*
Sequence Analysis, DNA
Specific Pathogen-Free Organisms
Viral Proteins / genetics
Viral Proteins / pharmacology

Substances

Anti-Bacterial Agents
Viral Proteins
Endopeptidases
endolysin

Grants and funding

R01 AI079145/AI/NIAID NIH HHS/United States