Targeted suppression of human IBD-associated gut microbiota commensals by phage consortia for treatment of intestinal inflammation
Sara Federici, Sharon Kredo-Russo, Rafael Valdés-Mas, Denise Kviatcovsky, Eyal Weinstock, Yulia Matiuhin, Yael Silberberg, Koji Atarashi, Munehiro Furuichi, Akihiko Oka, Bo Liu, Morine Fibelman, Iddo Weiner, Efrat Khabra, Nyssa Cullin, Noa Ben-Yishai, Dana Inbar, Hava Ben-David, Julian Nicenboim, Noga Kowalsman, Wolfgang Lieb, Edith Kario, Tal Cohen, Yael Geffen, Lior Zelcbuch, Ariel Cohen, Urania Rappo, Inbar Gahali-Sass, Myriam Golembo, Vered Lev, Mally Dori-Bachash, Hagit Shapiro, Claudia Moresi, Amanda Cuevas-Sierra, Gayatree Mohapatra, Lara Kern, Danping Zheng, Samuel Nobs, Jotham Suez, Noa Stettner, Alon Harmelin, Naomi Zak, Sailaja Puttagunta, Merav Bassan, Kenya Honda, Harry Sokol, Corinna Bang, Andre Franke, Christoph Schramm, Nitsan Maharshak, Ryan Sartor, Rotem Sorek, Eran Elinav
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.