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 language | English |
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Pages (from-to) | 2879-2898.e24 |
Journal | Cell |
Volume | 185 |
Issue number | 16 |
DOIs | |
State | Published - 4 Aug 2022 |
Funding
Funders | Funder number |
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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 Health | P30DK007737, P40OD010995, P01DK094779 |
Japan Society for the Promotion of Science | 20H05627 |
European Molecular Biology Organization | ALTF767-201 |
Not added | 819439 |
Deutsche Forschungsgemeinschaft | 447836288 |
Keywords
- Crohn's disease
- Klebsiella pneumoniae
- inflammatory bowel diseases
- microbiome
- microbiota
- phage therapy
- resistome
- ulcerative colitis