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

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

  • Nat Microbiol. 2019 Mar;4(3):492-503. doi: 10.1038/s41564-018-0333-1.
Nobuhiro Nakamoto 1,  Nobuo Sasaki 1 2,  Ryo Aoki 1 3,  Kentaro Miyamoto 1 4,  Wataru Suda 5 6,  Toshiaki Teratani 1,  Takahiro Suzuki 1 4,  Yuzo Koda 1 7,  Po-Sung Chu 1,  Nobuhito Taniki 1,  Akihiro Yamaguchi 1,  Mitsuhiro Kanamori 5,  Nobuhiko Kamada 8,  Masahira Hattori 6 9,  Hiroshi Ashida 10,  Michiie Sakamoto 11,  Koji Atarashi 5 12,  Seiko Narushima 5 12,  Akihiko Yoshimura 5,  Kenya Honda 5 12,  Toshiro Sato 13,  Takanori Kanai 14 15
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, Japan.
  • 2 AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan.
  • 3 Institute of Health Science, Ezaki Glico Co., Ltd, Osaka, Japan.
  • 4 Miyarisan Pharmaceutical Co., Ltd, Tokyo, Japan.
  • 5 Department of Microbiology and Immunology, Keio University School of Medicine, Shinanomachi, Tokyo, Japan.
  • 6 Laboratory of Metagenomics, Department of Computational Biology and Medical Sciences, The University of Tokyo, Chiba, Japan.
  • 7 Research Unit/Immunology & Inflammation, Sohyaku Innovative Research Division, Mitsubishi Tanabe Pharma Corporation, Kanagawa, Japan.
  • 8 Division of Gastroenterology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
  • 9 Cooperative Major in Advanced Health Science, Graduate School of Advanced Science and Engineering, Faculty of Science and Engineering, Waseda University, Tokyo, Japan.
  • 10 Department of Bacterial Infection and Host Response, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
  • 11 Department of Pathology, Keio University School of Medicine, Shinanomachi, Tokyo, Japan.
  • 12 RIKEN Center for Integrative Medical Sciences, Laboratory for Gut Homeostasis, Kanagawa, Japan.
  • 13 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, Japan. [email protected].
  • 14 Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, Shinanomachi, Tokyo, Japan. [email protected].
  • 15 AMED-CREST, Japan Agency for Medical Research and Development, Tokyo, Japan. [email protected].
PMID: 30643240 DOI: 10.1038/s41564-018-0333-1
Abstract

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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