Journal
CELL
Volume 185, Issue 16, Pages 2879-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2022.07.003
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Funding
- Leona M. and Harry B. Helmsley Charitable Trust
- Israel Innovation Authority
- Sergio Lombroso Foundation fellowship
- Weizmann Institute La Caixa Foundation Postdoctoral Fellowship
- Walter Benjamin postdoctoral fellowship from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [447836288]
- European Crohns and Colitis Organization (ECCO) Fellowship
- Ke Lin Program of the First Affiliated Hospital, Sun Yat-sen University
- SNSF Early Postdoc Mobility Fellowship
- EMBO Long-term Fellowship [ALTF767- 201]
- SNSF Postdoc Mobility Fellowship
- National Institutes of Health [P40OD010995, P30DK007737, P01DK094779]
- Crohns and Colitis Foundation of America
- Abney Foundation
- Pearl Welinsky Merlo Scientific Progress Research Fund
- Park Avenue Charitable Fund
- Hanna and Dr. Ludwik Wallach Cancer Research Fund
- Daniel Morris Trust
- Wolfson Family Charitable Trust
- Wolfson Foundation
- Ben B. and Joyce E. Eisenberg Foundation
- White Rose International Foundation
- Estate of Bernard Bishin for the WIS-Clalit Program
- Else Krener-Fresenius Foundation
- Jeanne and Joseph Nissim Center for Life Sciences Research
- European Research Council
- Israel Science Foundation
- Israel Ministry of Science and Technology
- Israel Ministry of Health
- Helmholtz Foundation
- Garvan Institute of Medical Research
- European Crohns and Colitis Organization
- Deutsch-Israelische Projektkooperation
- IDSA Foundation
- Wellcome Trust
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A clade of Klebsiella pneumoniae strains has been found to be strongly associated with exacerbation and severity of inflammatory bowel diseases. By generating a lytic five-phage combination targeting these strains, effective suppression of the bacteria and attenuation of inflammation can be achieved.
Human gut commensals are increasingly suggested to impact non-communicable diseases, such as inflam-matory 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, tar-geting 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.
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