April 21, 2020  |  

Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis.

Authors: Nakamoto, Nobuhiro and Sasaki, Nobuo and Aoki, Ryo and Miyamoto, Kentaro and Suda, Wataru and Teratani, Toshiaki and Suzuki, Takahiro and Koda, Yuzo and Chu, Po-Sung and Taniki, Nobuhito and Yamaguchi, Akihiro and Kanamori, Mitsuhiro and Kamada, Nobuhiko and Hattori, Masahira and Ashida, Hiroshi and Sakamoto, Michiie and Atarashi, Koji and Narushima, Seiko and Yoshimura, Akihiko and Honda, Kenya and Sato, Toshiro and Kanai, Takanori

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.

Journal: Nature microbiology
DOI: 10.1038/s41564-018-0333-1
Year: 2019

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