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

作者：Sara Federici, S. Kredo-Russo, R. Valdés-Mas, Denise Kviatcovsky, E. Weinstock, Yulia Matiuhin, Yael Silberberg, K. Atarashi, Munehiro Furuichi, A. Oka, Bo Liu, M. Fibelman, I. Weiner, E. Khabra, N. Cullin, Noa Ben-Yishai, D. Inbar, H. Ben-David, J. Nicenboim, Noga Kowalsman, W. Lieb, Edith Kario, T. Cohen, Yael Friedman Geffen, L. Zelcbuch, Ariel Cohen, U. Rappo, I. Gahali-Sass, M. Golembo, V. Lev, Mally Dori-Bachash, H. Shapiro, C. Moresi, Amanda Cuevas-Sierra, Gayatree Mohapatra, Lara Kern, D. Zheng, S. Nobs, Jotham Suez, Noa Stettner, A. Harmelin, N. Zak, S. Puttagunta, M. Bassan, K. Honda, H. Sokol, C. Bang, A. Franke, C. Schramm, N. Maharshak, R. Sartor, R. Sorek, E. Elinav · 发表于：Cell · 年份：2022 · DOI：10.1016/j.cell.2022.07.003 · 被引用次数：476 · 研究领域：Medicine

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.