Functional Restoration of Bacteriomes and Viromes by Fecal Microbiota Transplantation.

Affiliation

Fujimoto K(1), Kimura Y(2), Allegretti JR(3), Yamamoto M(4), Zhang YZ(4), Katayama K(4), Tremmel G(5), Kawaguchi Y(6), Shimohigoshi M(6), Hayashi T(6), Uematsu M(6), Yamaguchi K(7), Furukawa Y(7), Akiyama Y(8), Yamaguchi R(5), Crowe SE(9), Ernst PB(10), Miyano S(5), Kiyono H(11), Imoto S(12), Uematsu S(13).
Author information:
(1)Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan; Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(2)Division of Systems Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(3)Division of Gastroenterology, Hepatology, and Endoscopy, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
(4)Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(5)Laboratory of DNA Information Analysis, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(6)Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan.
(7)Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(8)Department of Computer Science, Tokyo Institute of Technology, Meguro-ku, Tokyo, Japan.
(9)Department of Medicine, University of California, San Diego, La Jolla, California.
(10)Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California San Diego, San Diego, La Jolla, California; Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, La Jolla, California; Center for Veterinary Sciences and Comparative Medicine, University of California, San Diego, La Jolla, California.
(11)Division of Gastroenterology, Department of Medicine, CU-UCSD Center for Mucosal Immunology, Allergy and Vaccines, University of California San Diego, San Diego, La Jolla, California; Division of Comparative Pathology and Medicine, Department of Pathology, University of California San Diego, San Diego, La Jolla, California; Department of Mucosal Immunology, IMSUT Distinguished Professor Unit, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
(12)Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: [Email]
(13)Department of Immunology and Genomics, Osaka City University, Graduate School of Medicine, Abeno-ku, Osaka, Japan; Division of Metagenome Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Division of Innate Immune Regulation, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan; Collaborative Research Institute for Innovative Microbiology, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. Electronic address: [Email]

Abstract

BACKGROUND & AIMS: Fecal microbiota transplantation (FMT) is an effective therapy for recurrent Clostridioides difficile infection (rCDI). However, the overall mechanisms underlying FMT success await comprehensive elucidation, and the safety of FMT has recently become a serious concern because of the occurrence of drug-resistant bacteremia transmitted by FMT. We investigated whether functional restoration of the bacteriomes and viromes by FMT could be an indicator of successful FMT. METHODS: The human intestinal bacteriomes and viromes from 9 patients with rCDI who had undergone successful FMT and their donors were analyzed. Prophage-based and CRISPR spacer-based host bacteria-phage associations in samples from recipients before and after FMT and in donor samples were examined. The gene functions of intestinal microorganisms affected by FMT were evaluated. RESULTS: Metagenomic sequencing of both the viromes and bacteriomes revealed that FMT does change the characteristics of intestinal bacteriomes and viromes in recipients after FMT compared with those before FMT. In particular, many Proteobacteria, the fecal abundance of which was high before FMT, were eliminated, and the proportion of Microviridae increased in recipients. Most temperate phages also behaved in parallel with the host bacteria that were altered by FMT. Furthermore, the identification of bacterial and viral gene functions before and after FMT revealed that some distinctive pathways, including fluorobenzoate degradation and secondary bile acid biosynthesis, were significantly represented. CONCLUSIONS: The coordinated action of phages and their host bacteria restored the recipients' intestinal flora. These findings show that the restoration of intestinal microflora functions reflects the success of FMT.