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

来源：

CELL | 2022年 / 185卷 / 16期

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

页码：2879 / +

页数：45

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