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

被引：337

作者：

Nakamoto, Nobuhiro ^{[1
]}

Sasaki, Nobuo ^{[1
,2
]}

Aoki, Ryo ^{[1
,3
]}

Miyamoto, Kentaro ^{[1
,4
]}

Suda, Wataru ^{[5
,6
]}

Teratani, Toshiaki ^{[1
]}

Suzuki, Takahiro ^{[1
,4
]}

Koda, Yuzo ^{[1
,7
]}

Chu, Po-Sung ^{[1
]}

Taniki, Nobuhito ^{[1
]}

Yamaguchi, Akihiro ^{[1
]}

Kanamori, Mitsuhiro ^{[5
]}

Kamada, Nobuhiko ^{[8
]}

Hattori, Masahira ^{[6
,9
]}

Ashida, Hiroshi ^{[10
]}

Sakamoto, Michiie ^{[11
]}

Atarashi, Koji ^{[5
,12
]}

Narushima, Seiko ^{[5
,12
]}

Yoshimura, Akihiko ^{[5
]}

Honda, Kenya ^{[5
,12
]}

Sato, Toshiro ^{[1
]}

Kanai, Takanori ^{[1
,2
]}

机构：

[1] Keio Univ, Sch Med, Dept Internal Med, Div Gastroenterol & Hepatol, Shinanomachi, Tokyo, Japan

[2] Japan Agcy Med Res & Dev, AMED CREST, Tokyo, Japan

[3] Ezaki Glico Co Ltd, Inst Hlth Sci, Osaka, Japan

[4] Miyarisan Pharmaceut Co Ltd, Tokyo, Japan

[5] Keio Univ, Sch Med, Dept Microbiol & Immunol, Shinanomachi, Tokyo, Japan

[6] Univ Tokyo, Dept Computat Biol & Med Sci, Lab Metagen, Chiba, Japan

[7] Mitsubishi Tanabe Pharma Corp, Sohyaku Innovat Res Div, Res Unit Immunol & Inflammat, Yokohama, Kanagawa, Japan

[8] Univ Michigan, Dept Internal Med, Div Gastroenterol, Ann Arbor, MI 48109 USA

[9] Waseda Univ, Grad Sch Adv Sci & Engn, Fac Sci & Engn, Adv Hlth Sci, Tokyo, Japan

[10] Tokyo Med & Dent Univ, Grad Sch Med & Dent Sci, Dept Bacterial Infect & Host Response, Tokyo, Japan

[11] Keio Univ, Sch Med, Dept Pathol, Shinanomachi, Tokyo, Japan

[12] RIKEN Ctr Integrat Med Sci, Lab Gut Homeostasis, Yokohama, Kanagawa, Japan

来源：

NATURE MICROBIOLOGY | 2019年 / 4卷 / 03期

基金：

日本学术振兴会;

关键词：

DISEASE; TRANSLOCATION; MICROBIOTA; INDUCTION; BACTERIA; MODEL; PSC; IBD;

D O I：

10.1038/s41564-018-0333-1

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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(T(H)17) 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 T(H)17-mediated hepatobiliary injuries. We also show that antibiotic treatment ameliorated the T(H)17 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.

引用

页码：492 / 503

页数：12

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