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

Nobuhiro Nakamoto, Nobuo Sasaki, Ryo Aoki, Kentaro Miyamoto, Wataru Suda, Toshiaki Teratani, Takahiro Suzuki, Yuzo Koda, Hakusyo Cho, Nobuhito Taniki, Akihiro Yamaguchi, Mitsuhiro Kanamori, Nobuhiko Kamada, Masahira Hattori, Hiroshi Ashida, Michiie Sakamoto, Koji Atarashi, Seiko Narushima, Akihiko Yoshimura, Kenya HondaToshiro Sato, Takanori Kanai

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish
JournalNature Microbiology
DOIs
Publication statusAccepted/In press - 2019 Jan 1

Fingerprint

Th17 Cells
Sclerosing Cholangitis
Liver Diseases
Microbiota
Bacterial Translocation
Pneumonia
Organoids
Germ-Free Life
Proteus mirabilis
Liver
Enterococcus
Wounds and Injuries
Klebsiella pneumoniae
Coculture Techniques
Ulcerative Colitis
Lymph Nodes
Anti-Bacterial Agents
Inflammation
Therapeutics

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Applied Microbiology and Biotechnology
  • Genetics
  • Microbiology (medical)
  • Cell Biology

Cite this

Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. / Nakamoto, Nobuhiro; Sasaki, Nobuo; Aoki, Ryo; Miyamoto, Kentaro; Suda, Wataru; Teratani, Toshiaki; Suzuki, Takahiro; Koda, Yuzo; Cho, Hakusyo; Taniki, Nobuhito; Yamaguchi, Akihiro; Kanamori, Mitsuhiro; Kamada, Nobuhiko; Hattori, Masahira; Ashida, Hiroshi; Sakamoto, Michiie; Atarashi, Koji; Narushima, Seiko; Yoshimura, Akihiko; Honda, Kenya; Sato, Toshiro; Kanai, Takanori.

In: Nature Microbiology, 01.01.2019.

Research output: Contribution to journalArticle

Nakamoto, Nobuhiro ; Sasaki, Nobuo ; Aoki, Ryo ; Miyamoto, Kentaro ; Suda, Wataru ; Teratani, Toshiaki ; Suzuki, Takahiro ; Koda, Yuzo ; Cho, Hakusyo ; Taniki, Nobuhito ; Yamaguchi, Akihiro ; Kanamori, Mitsuhiro ; Kamada, Nobuhiko ; Hattori, Masahira ; Ashida, Hiroshi ; Sakamoto, Michiie ; Atarashi, Koji ; Narushima, Seiko ; Yoshimura, Akihiko ; Honda, Kenya ; Sato, Toshiro ; Kanai, Takanori. / Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis. In: Nature Microbiology. 2019.
@article{de2e450dc849474f9220a45f89c9af9c,
title = "Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis",
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.",
author = "Nobuhiro Nakamoto and Nobuo Sasaki and Ryo Aoki and Kentaro Miyamoto and Wataru Suda and Toshiaki Teratani and Takahiro Suzuki and Yuzo Koda and Hakusyo Cho and Nobuhito Taniki and Akihiro Yamaguchi and Mitsuhiro Kanamori and Nobuhiko Kamada and Masahira Hattori and Hiroshi Ashida and Michiie Sakamoto and Koji Atarashi and Seiko Narushima and Akihiko Yoshimura and Kenya Honda and Toshiro Sato and Takanori Kanai",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41564-018-0333-1",
language = "English",
journal = "Nature Microbiology",
issn = "2058-5276",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

AU - Nakamoto, Nobuhiro

AU - Sasaki, Nobuo

AU - Aoki, Ryo

AU - Miyamoto, Kentaro

AU - Suda, Wataru

AU - Teratani, Toshiaki

AU - Suzuki, Takahiro

AU - Koda, Yuzo

AU - Cho, Hakusyo

AU - Taniki, Nobuhito

AU - Yamaguchi, Akihiro

AU - Kanamori, Mitsuhiro

AU - Kamada, Nobuhiko

AU - Hattori, Masahira

AU - Ashida, Hiroshi

AU - Sakamoto, Michiie

AU - Atarashi, Koji

AU - Narushima, Seiko

AU - Yoshimura, Akihiko

AU - Honda, Kenya

AU - Sato, Toshiro

AU - Kanai, Takanori

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85059947736&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85059947736&partnerID=8YFLogxK

U2 - 10.1038/s41564-018-0333-1

DO - 10.1038/s41564-018-0333-1

M3 - Article

C2 - 30643240

AN - SCOPUS:85059947736

JO - Nature Microbiology

JF - Nature Microbiology

SN - 2058-5276

ER -