PSC患者由来糞便微生物を無菌マウスに移入したヒトフローラ化マウス (PSCUCマウス) において肝臓内TH17細胞の増加を認め、同マウスの腸間膜リンパ節からKlebsiella pneumonia (KP)、Proteus mirabilis (PM)、Enterococcus gallinarum (EG) のbacterial translocation (BT) 誘導菌3菌を分離した。定量PCRの結果、上記BT誘導菌はPSC患者の糞便中に高率に検出され (PSC/UC患者18名中17名で検出)、腸管病変を有するPSCの診断マーカー、および治療標的として有用である可能性が示唆された。
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 PSC patients 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 (Th) 17 cell responses in the live . Bacterial culture of mesenteric lymph nodes in these mice isolated K. pneumoniae, Proteus mirabilis, and Enterococcus gallinarum, which were prevalently detected in PSC patients. These results highlight the role of pathobionts in intestinal barrier dysfunction and liver inflammation, providing insights into therapeutic strategies for PSC.

研究種目 : 基盤研究 (C) (一般)
研究期間 : 2016～2018
課題番号 : 16K09374
研究分野 : 消化器内科