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

被引:329
作者
Federici, Sara [1 ]
Kredo-Russo, Sharon [2 ,3 ]
Valdes-Mas, Rafael [1 ]
Kviatcovsky, Denise [1 ]
Weinstock, Eyal [2 ,3 ,4 ]
Matiuhin, Yulia [2 ,3 ]
Silberberg, Yael [2 ,3 ]
Atarashi, Koji [5 ,6 ]
Furuichi, Munehiro [5 ,6 ]
Oka, Akihiko [7 ,8 ]
Liu, Bo [8 ]
Fibelman, Morine [9 ,10 ]
Weiner, Iddo Nadav [2 ,3 ]
Khabra, Efrat [2 ,3 ]
Cullin, Nyssa [11 ]
Ben-Yishai, Noa [2 ,3 ]
Inbar, Dana [2 ,3 ]
Ben-David, Hava [2 ,3 ]
Nicenboim, Julian [2 ,3 ]
Kowalsman, Noga [2 ,3 ]
Lieb, Wolfgang [12 ]
Kario, Edith [2 ,3 ]
Cohen, Tal [2 ,3 ]
Geffen, Yael Friedman [2 ,3 ]
Zelcbuch, Lior [2 ,3 ]
Cohen, Ariel [2 ,3 ]
Rappo, Urania [2 ,3 ]
Gahali-Sass, Inbar [2 ,3 ]
Golembo, Myriam [2 ,3 ]
Lev, Vered [2 ,3 ]
Dori-Bachash, Mally [1 ]
Shapiro, Hagit [1 ]
Moresi, Claudia [1 ]
Cuevas-Sierra, Amanda [1 ]
Mohapatra, Gayatree [1 ]
Kern, Lara [1 ]
Zheng, Danping [1 ]
Nobs, Samuel Philip [1 ]
Suez, Jotham [1 ]
Stettner, Noa [13 ]
Harmelin, Alon [13 ]
Zak, Naomi [2 ,3 ]
Puttagunta, Sailaja [2 ,3 ]
Bassan, Merav [2 ,3 ]
Honda, Kenya [5 ,6 ]
Sokol, Harry [14 ,15 ,16 ,17 ]
Bang, Corinna [18 ]
Franke, Andre [18 ,19 ]
Schramm, Christoph [20 ,21 ,22 ]
Maharshak, Nitsan [9 ,23 ]
机构
[1] Weizmann Inst Sci, Syst Immunol Dept, Rehovot, Israel
[2] BiomX Ltd, 22 Einstein St, IL-7414001 Ness Ziona, Israel
[3] BiomX Inc, 36 E Ind Rd, Branford, CT 06405 USA
[4] Weizmann Inst Sci, Mol Genet Dept, Rehovot, Israel
[5] RIKEN, Ctr Integrat Med Sci IMS, Tsurumi Ku, Yokohama, Kanagawa 2300045, Japan
[6] Keio Univ, Dept Microbiol & Immunol, Sch Med, Shinjuku Ku, Tokyo 1608582, Japan
[7] Shimane Univ, Dept Internal Med 2, Matsue, Shimane, Japan
[8] Univ N Carolina, Ctr Gastrointestinal Biol & Dis, Div Gastroenterol & Hepatol, Chapel Hill, NC 27515 USA
[9] Tel Aviv Univ, Sackler Fac Med, Tel Aviv, Israel
[10] Tel Aviv Sourasky Med Ctr, Dept Internal Med A, Tel Aviv, Israel
[11] DKFZ, Div Microbiome & Canc, Heidelberg, Germany
[12] Christian Albrechts Univ Kiel, Inst Epidemiol, Kiel, Germany
[13] Weizmann Inst Sci, Dept Vet Resources, Rehovot, Israel
[14] Sorbonne Univ, AP HP, CRSA, INSERM,UMRS 938,Ctr Rech St Antoine, Paris, France
[15] Federat Hosp Univ, Paris Ctr Microbiome Med, Paris, France
[16] INRAE, UMR1319, Micalis, Jouy En Josas, France
[17] AgroParisTech, Jouy En Josas, France
[18] Christian Albrechts Univ Kiel, Inst Clin Mol Biol, Kiel, Germany
[19] Univ Hosp Schleswig Holstein UKSH, Kiel Campus, Kiel, Germany
[20] Univ Med Ctr Hamburg Eppendorf, Dept Internal Med, Hamburg, Germany
[21] Univ Med Ctr Hamburg Eppendorf, Martin Zeitz Ctr Rare Dis, Hamburg, Germany
[22] Univ Med Ctr Hamburg Eppendorf, Hamburg Ctr Translat Immunol HCTI, Hamburg, Germany
[23] Tel Aviv Sourasky Med Ctr, Dept Gastroenterol & Hepatol, Tel Aviv, Israel
基金
欧洲研究理事会; 美国国家卫生研究院; 以色列科学基金会; 英国惠康基金;
关键词
ULCERATIVE-COLITIS; BOWEL-DISEASE; BACTERIOPHAGE THERAPY; CROHNS-DISEASE; T-CELLS; TRANSPLANTATION; RESISTANCE; ANTIBIOTICS; INDUCTION; ALIGNMENT;
D O I
10.1016/j.cell.2022.07.003
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:2879 / +
页数:45
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