Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and its frequent complication with ulcerative colitis highlights the pathogenic role of epithelial barrier dysfunction. Intestinal barrier dysfunction has been implicated in the pathogenesis of PSC, yet its underlying mechanism remains unknown. Here, we identify Klebsiella pneumonia in the microbiota of patients with PSC and demonstrate that K. pneumoniae disrupts the epithelial barrier to initiate bacterial translocation and liver inflammatory responses. Gnotobiotic mice inoculated with PSC-derived microbiota exhibited T helper 17 (TH17) cell responses in the liver and increased susceptibility to hepatobiliary injuries. Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis and Enterococcus gallinarum, which were prevalently detected in patients with PSC. A bacterial-organoid co-culture system visualized the epithelial-damaging effect of PSC-derived K. pneumoniae that was associated with bacterial translocation and susceptibility to TH17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the TH17 immune response induced by PSC-derived microbiota. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.
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The data supporting the findings of this study are available from the corresponding authors upon request. 16S rRNA sequencing and whole-genome sequencing data have been deposited in the DNA Data Bank of Japan (DDBJ) database with the accession numbers DRA007475 and DRA007476 for 16S rRNA sequencing and PRJDB7545 for whole-genome sequencing. RNA sequencing data have been deposited in the European Genome-phenome Archive (EGA) database with the accession number EGAS00001003332.
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We thank S. Chiba, S. Shiba, R. Morikawa, T. Katayama, A. Ikura, Y. Mikami and T. Sujino (Division of Gastroenterology and Hepatology, Keio University) for technical assistance and critical reading of this manuscript. This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI Grant-in-Aid (C) 16K09374 and (A) 15H02534, the Advanced Research and Development Programs for Medical Innovation (AMED-CREST; 16gm1010003h0001), the TAKEDA Science Fund, Ezaki Glico Co. Ltd and Keio University Medical Fund. K.H. was funded through AMED LEAP under grant number JP17gm0010003. A. Yoshimura was supported by the JSPS KAKENHI Grant-in-Aid (S) JP17H06175, Challenging Research (P) JP18H05376 and AMED-CREST JP18gm0510019 and JP18gm1110009.
The authors declare no competing interests.
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Supplementary Figures 1–8.
Demographic characteristics of study subjects.
Fpkm values in RNA-seq analysis.
Phylogenetic relationship among K. pneumoniae strains used in this study.
Genes positively correlated with the epithelial pore-forming capacity.
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Nakamoto, N., Sasaki, N., Aoki, R. et al. Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. Nat Microbiol 4, 492–503 (2019). https://doi.org/10.1038/s41564-018-0333-1
Seminars in Immunopathology (2022)
Seminars in Immunopathology (2022)
Seminars in Immunopathology (2022)
Seminars in Immunopathology (2022)