Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation

Sara Federici, Sharon Kredo-Russo, Rafael Valdés-Mas, Denise Kviatcovsky, Eyal Weinstock, Yulia Matiuhin, Yael Silberberg, Koji Atarashi, Munehiro Furuichi, Akihiko Oka, Bo Liu, Morine Fibelman, Iddo Nadav Weiner, Efrat Khabra, Nyssa Cullin, Noa Ben-Yishai, Dana Inbar, Hava Ben-David, Julian Nicenboim, Noga KowalsmanWolfgang Lieb, Edith Kario, Tal Cohen, Yael Friedman Geffen, Lior Zelcbuch, Ariel Cohen, Urania Rappo, Inbar Gahali-Sass, Myriam Golembo, Vered Lev, Mally Dori-Bachash, Hagit Shapiro, Claudia Moresi, Amanda Cuevas-Sierra, Gayatree Mohapatra, Lara Kern, Danping Zheng, Samuel Philip Nobs, Jotham Suez, Noa Stettner, Alon Harmelin, Naomi Zak, Sailaja Puttagunta, Merav Bassan, Kenya Honda, Harry Sokol, Corinna Bang, Andre Franke, Christoph Schramm, Nitsan Maharshak, Ryan Balfour Sartor, Rotem Sorek, Eran Elinav*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

258 Scopus citations

Abstract

Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflammatory bowel diseases (IBD), yet their targeted suppression remains a daunting unmet challenge. In four geographically distinct IBD cohorts (n = 537), we identify a clade of Klebsiella pneumoniae (Kp) strains, featuring a unique antibiotics resistance and mobilome signature, to be strongly associated with disease exacerbation and severity. Transfer of clinical IBD-associated Kp strains into colitis-prone, germ-free, and colonized mice enhances intestinal inflammation. Stepwise generation of a lytic five-phage combination, targeting sensitive and resistant IBD-associated Kp clade members through distinct mechanisms, enables effective Kp suppression in colitis-prone mice, driving an attenuated inflammation and disease severity. Proof-of-concept assessment of Kp-targeting phages in an artificial human gut and in healthy volunteers demonstrates gastric acid-dependent phage resilience, safety, and viability in the lower gut. Collectively, we demonstrate the feasibility of orally administered combination phage therapy in avoiding resistance, while effectively inhibiting non-communicable disease-contributing pathobionts.

Original languageEnglish
Pages (from-to)2879-2898.e24
JournalCell
Volume185
Issue number16
DOIs
StatePublished - 4 Aug 2022

Funding

FundersFunder number
Weizmann Institute of Science and BiomX
Deutsch-Israelische Projektkooperation
Helmholtz Association
Israel Ministry of Science and Technology, Israel Ministry of Health
Hanna and Dr. Ludwik Wallach Cancer Research Fund
Pearl Welinsky Merlo Scientific Progress Research Fund
Else Kröner-Fresenius-Stiftung
IDSA Foundation
Israel Ministry of Science and Technology , Israel Ministry of Health
Park Avenue Charitable Fund
Crohn's and Colitis Foundation of America
Israel Innovation Authority
AbbVie
Takeda Pharmaceutical Company
European Research Council , Israel Science Foundation
Wellcome Trust
Abbott Laboratories
Weizmann Institute of Science
Wolfson Foundation
Leona M. and Harry B. Helmsley Charitable Trust
Wolfson Family Charitable Trust
Janssen Pharmaceuticals
Ben B. and Joyce E. Eisenberg Foundation
Sun Yat-sen University
Exeliom Bioscience
Jeanne and Joseph Nissim Center for Life Sciences Research
Daniel Morris Trust
Bristol-Myers Squibb
BiomX
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Ke Lin Program of the First Affiliated Hospital
Bill and Melinda Gates Foundation
Canadian Institute for Advanced Research
European Research Council, Israel Science Foundation
Pfizer
Abney Foundation
European Crohn's and Colitis Organisation
Garvan Institute of Medical Research
Howard Hughes Medical Institute
National Institutes of HealthP30DK007737, P40OD010995, P01DK094779
Japan Society for the Promotion of Science20H05627
European Molecular Biology OrganizationALTF767-201
Not added819439
Deutsche Forschungsgemeinschaft447836288

    Keywords

    • Crohn's disease
    • Klebsiella pneumoniae
    • inflammatory bowel diseases
    • microbiome
    • microbiota
    • phage therapy
    • resistome
    • ulcerative colitis

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