Cited by 546Bacteriophages and microbial interactionsGut microbiota and healthInflammatory Bowel Disease

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

Open access
Federici, Sara, Kredo-Russo, Sharon, Valdés-Mas, Rafael, Kviatcovsky, Denise, Weinstock, Eyal, Matiuhin, Yulia, Silberberg, Yael, Atarashi, Koji +45 more·2022·Cell

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.

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Crossref · 10.1016/j.cell.2022.07.003

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Authors
Federici, S., Kredo-Russo, S., Valdés-Mas, R., Kviatcovsky, D., Weinstock, E., Matiuhin, Y., Silberberg, Y., Atarashi, K., Furuichi, M., Oka, A., Liu, B., Fibelman, M., Weiner, I. N., Khabra, E., Cullin, N., Ben-Yishai, N., Inbar, D., Ben-David, H., Nicenboim, J., Kowalsman, N., Lieb, W., Kario, E., Cohen, T., Geffen, Y. F., Zelcbuch, L., Cohen, A., Rappo, U., Gahali-Sass, I., Golembo, M., Lev, V., Dori-Bachash, M., Shapiro, H., Moresi, C., Cuevas-Sierra, A., Mohapatra, G., Kern, L., Zheng, D., Nobs, S. P., Suez, J., Stettner, N., Harmelin, A., Zak, N., Puttagunta, S., Bassan, M., Honda, K., Sokol, H., Bang, C., Franke, A., Schramm, C., Maharshak, N., Sartor, R. B., Sorek, R., & Elinav, E.
Affiliations
  • Weizmann Institute of Science (IL)
  • Keio University (JP)
  • University of North Carolina at Chapel Hill (US)
  • Tel Aviv University (IL)
  • German Cancer Research Center (DE)
  • Christian-Albrechts-Universität zu Kiel (DE)
  • Inserm (FR)
  • University Medical Center Hamburg-Eppendorf (DE)
Corresponding author
Elinav, Eran
Venue
Cell
Publisher
Elsevier BV
Published
2022-08
Volume
185
Issue
16
Pages
2879-2898.e24
ISSN
0092-8674 (ISSN-L)
OpenAlex
W4289780574
Cited by
542
References
121
Citations by year
2026: 124 · 2025: 152 · 2024: 130 · 2023: 108 · 2022: 27
FWCI
56.34
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Research Explorer (The University of Manchester) (publishedVersion, other-oa)
  • HAL (submittedVersion)
Funders
Japan Society for the Promotion of Science (20H05627)
Topics
  • Physical Sciences › Environmental Science › Ecology › Bacteriophages and microbial interactions
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Inflammatory Bowel Disease
Keywords
inflammatory bowel disease, Klebsiella pneumoniae, phage therapy, bacteriophages, gut commensals, intestinal inflammation, antibiotic resistance, mobilome, colitis, germ-free mice, gastric acid, pathobionts, disease severity
MeSH terms
Gastrointestinal Microbiome, Animals, Bacteriophages, Colitis, Humans, Inflammation, Klebsiella pneumoniae, Inflammatory Bowel Diseases, Mice

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