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

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
Ben B. and Joyce E. Eisenberg Foundation
BiomX
Daniel Morris Trust
Deutsch-Israelische Projektkooperation
European Research Council , Israel Science Foundation
European Research Council, Israel Science Foundation
Exeliom Bioscience
Hanna and Dr. Ludwik Wallach Cancer Research Fund
IDSA Foundation
Israel Innovation Authority
Israel Ministry of Science and Technology , Israel Ministry of Health
Israel Ministry of Science and Technology, Israel Ministry of Health
Jeanne and Joseph Nissim Center for Life Sciences Research
Ke Lin Program of the First Affiliated Hospital
Park Avenue Charitable Fund
Pearl Welinsky Merlo Scientific Progress Research Fund
Weizmann Institute of Science and BiomX
National Institutes of HealthP30DK007737, P40OD010995, P01DK094779
National Institutes of Health
Howard Hughes Medical Institute
Bill and Melinda Gates Foundation
Crohn's and Colitis Foundation of America
Abbott Laboratories
Abney Foundation
Bristol-Myers Squibb
Pfizer
European Molecular Biology OrganizationALTF767-201
European Molecular Biology Organization
AbbVie
Leona M. and Harry B. Helmsley Charitable Trust
Canadian Institute for Advanced Research
Takeda Pharmaceutical Company
Janssen Pharmaceuticals
Wellcome Trust
European Crohn's and Colitis Organisation
IDSA Foundation
Wolfson Foundation
Deutsche Forschungsgemeinschaft447836288
Deutsche Forschungsgemeinschaft
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Weizmann Institute of Science
Sun Yat-sen University
Else Kröner-Fresenius-Stiftung
Garvan Institute of Medical Research
Wolfson Family Charitable Trust
Helmholtz Association

    Keywords

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

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