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

Masataka Ichikawa, Nobuhiro Nakamoto (), Sharon Kredo-Russo, Eyal Weinstock, Iddo Nadav Weiner, Efrat Khabra, Noa Ben-Ishai, Dana Inbar, Noga Kowalsman, Ron Mordoch, Julian Nicenboim, Myriam Golembo, Naomi Zak, Jagoda Jablonska, Hila Sberro-Livnat, Sharon Navok, Nufar Buchshtab, Takahiro Suzuki, Kentaro Miyamoto, Toshiaki Teratani, Sota Fujimori, Yoshimasa Aoto, Mikiko Konda, Naoki Hayashi, Po-Sung Chu, Nobuhito Taniki, Rei Morikawa, Ryosuke Kasuga, Takaya Tabuchi, Shinya Sugimoto, Yohei Mikami, Atsushi Shiota, Merav Bassan and Takanori Kanai ()
Additional contact information
Masataka Ichikawa: Keio University
Nobuhiro Nakamoto: Keio University
Sharon Kredo-Russo: BiomX Ltd.
Eyal Weinstock: BiomX Ltd.
Iddo Nadav Weiner: BiomX Ltd.
Efrat Khabra: BiomX Ltd.
Noa Ben-Ishai: BiomX Ltd.
Dana Inbar: BiomX Ltd.
Noga Kowalsman: BiomX Ltd.
Ron Mordoch: BiomX Ltd.
Julian Nicenboim: BiomX Ltd.
Myriam Golembo: BiomX Ltd.
Naomi Zak: BiomX Ltd.
Jagoda Jablonska: BiomX Ltd.
Hila Sberro-Livnat: BiomX Ltd.
Sharon Navok: BiomX Ltd.
Nufar Buchshtab: BiomX Ltd.
Takahiro Suzuki: Keio University
Kentaro Miyamoto: Keio University
Toshiaki Teratani: Keio University
Sota Fujimori: Keio University
Yoshimasa Aoto: JSR-Keio University Medical and Chemical Innovation Center (JKiC), JSR Corp.
Mikiko Konda: JSR-Keio University Medical and Chemical Innovation Center (JKiC), JSR Corp.
Naoki Hayashi: JSR-Keio University Medical and Chemical Innovation Center (JKiC), JSR Corp.
Po-Sung Chu: Keio University
Nobuhito Taniki: Keio University
Rei Morikawa: Keio University
Ryosuke Kasuga: Keio University
Takaya Tabuchi: Keio University
Shinya Sugimoto: Keio University
Yohei Mikami: Keio University
Atsushi Shiota: Keio University
Merav Bassan: BiomX Ltd.
Takanori Kanai: Keio University

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: Abstract 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.

Date: 2023
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DOI: 10.1038/s41467-023-39029-9

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