Nature子刊:肠道中的致病共生菌如何促进原发性硬化性胆管炎?
  • 定植原发性硬化性胆管炎(PSC)伴溃疡性结肠炎患者的粪便菌群,可促进小鼠肝脏内的Th17应答和炎症,以及DDC诱导的肝胆管损伤;
  • 从小鼠肠系膜淋巴结中分离出肺炎克雷伯菌、奇异变形杆菌和鹑鸡肠球菌,在PSC患者中也普遍存在;
  • 这3种菌在小鼠中足以入侵肠粘膜、促进细菌移位和Th17介导的肝胆管疾病进展,这需要特定肺炎克雷伯菌株在肠上皮“造孔”的能力;
  • 抗生素治疗可缓解PSC菌群诱导的小鼠肝脏Th17免疫应答。
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mildbreeze
原发性硬化性胆管炎(PSC)是一种慢性炎性肝病,常伴随溃疡性结肠炎,肠上皮屏障紊乱可能是共同致病因素。Nature Microbiology本周发表的最新研究发现,PSC患者肠道菌群中的肺炎克雷伯菌可在肠上皮“打洞”,之后的致病共生菌移位可引起肝脏中的Th17应答,从而促进PSC疾病进展。这些发现提示,靶向肺炎克雷伯菌等菌群中的危险分子,恢复肠道屏障功能,或减少Th17免疫应答,是防治PSC的潜在策略。
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Gut pathobionts underlie intestinal barrier dysfunction and liver T helper 17 cell immune response in primary sclerosing cholangitis

原发性硬化性胆管炎中,肠道致病共生菌是肠道屏障紊乱和肝辅助性T细胞17免疫应答的基础

10.1038/s41564-018-0333-1

2019-01-14, Article

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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.

First Authors:
Nobuhiro Nakamoto

Correspondence Authors:
Toshiro Sato,Takanori Kanai

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

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