Bacteriophage therapy against pathological Klebsiella pneumoniae that determine the clinical course of primary sclerosing cholangitis

Primary sclerosing cholangitis (PSC) is a cholestatic liver disease characterized by progressive biliary inflammation and fibrosis. Although gut commensals are associated with PSC, their causative roles and therapeutic strategies remain elusive. We detected abundant Klebsiella pneumoniae (Kp) and Enterococcus gallinarum in faecal samples from 45 patients with PSC regardless of intestinal complications. Carriers of both pathogens exhibited high disease activity and poor clinical outcomes. Colonization of PSC-derived Kp in specific pathogen free (SPF) hepatobiliary injury-prone mice enhanced hepatic Th17 cell responses and exacerbated liver injury through bacterial translocation to mesenteric lymph nodes. We developed a cocktail of lytic phage that targeted PSC-derived Kp with a sustained suppressive effect in vitro. Oral administration of the phage cocktail lowered Kp levels in Kp-colonized germ-free mice and SPF mice, without off-target dysbiosis. Oral and intravenous phage administration suppressed Kp in hepatobiliary injury-prone SPF mice, thereby attenuating liver inflammation and disease severity. Using a lytic phage cocktail shows promise for targeting Kp in PSC.