Bacteriophage therapy against pathological Klebsiella pneumoniae ameliorates the course of primary sclerosing cholangitis

• Published in: Nature communications Vol. 14; no. 1; p. 3261
• Main Authors: Ichikawa, Masataka, Nakamoto, Nobuhiro, Kredo-Russo, Sharon, Weinstock, Eyal, Weiner, Iddo Nadav, Khabra, Efrat, Ben-Ishai, Noa, Inbar, Dana, Kowalsman, Noga, Mordoch, Ron, Nicenboim, Julian, Golembo, Myriam, Zak, Naomi, Jablonska, Jagoda, Sberro-Livnat, Hila, Navok, Sharon, Buchshtab, Nufar, Suzuki, Takahiro, Miyamoto, Kentaro, Teratani, Toshiaki, Fujimori, Sota, Aoto, Yoshimasa, Konda, Mikiko, Hayashi, Naoki, Chu, Po-Sung, Taniki, Nobuhito, Morikawa, Rei, Kasuga, Ryosuke, Tabuchi, Takaya, Sugimoto, Shinya, Mikami, Yohei, Shiota, Atsushi, Bassan, Merav, Kanai, Takanori
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.06.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 13/31; 13/51; 45/77; 692/4020/4021/1607/2744; 692/699/1503/2745; Animal models; Animals; Cholangitis; Cholangitis, Sclerosing - therapy; Clinical outcomes; Commensals; Dysbacteriosis; Feces; Fibrosis; Germfree; Helper cells; Hepatocytes; Humanities and Social Sciences; Inflammation; Inflammation - pathology; Injury prevention; Klebsiella; Klebsiella pneumoniae; Liver; Liver - pathology; Liver diseases; Lymph nodes; Lymphocytes T; Mice; multidisciplinary; Oral administration; Pathogens; Phage Therapy; Phages; Science; Science (multidisciplinary); Specific pathogen free; Translocation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-39029-9

Primary sclerosing cholangitis (PSC) is characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. Here we detect abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in fecal samples from 45 PSC patients, regardless of intestinal complications. Carriers of both pathogens exhibit high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen-free (SPF) hepatobiliary injury-prone mice enhances hepatic Th17 cell responses and exacerbates liver injury through bacterial translocation to mesenteric lymph nodes. We developed a lytic phage cocktail that targets PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowers Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Furthermore, we demonstrate that oral and intravenous phage administration successfully suppresses Kp levels and attenuates liver inflammation and disease severity in hepatobiliary injury-prone SPF mice. These results collectively suggest that using a lytic phage cocktail shows promise for targeting Kp in PSC. Patients with primary sclerosing cholangitis (PSC) harboring Klebsiella pneumoniae (Kp) exhibit poor clinical outcomes. Here, the authors show that administration of a phage cocktail targeting PSC-derived Kp reduces bacterial burden in Kp-colonized mice and alleviates liver injury.