Department of Oral and Maxillofacial Pathobiology, Basic Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
J Gastroenterol. 2013 Nov;48(11):1259-70. doi: 10.1007/s00535-012-0738-1. Epub 2013 Jan 11.
We investigated the effects of dental infection with Porphyromonas gingivalis (P.g.), an important periodontal pathogen, on NASH progression, by feeding mice a high fat diet (HFD)and examining P.g. infection in the liver of NASH patients.
C57BL/6J mice were fed either chow-diet (CD) or HFD for 12 weeks, and then half of the mice in each group were infected with P.g. from the pulp chamber (HFD-P.g.(-), HFD-P.g.(+), CD-P.g.(-) and CD-P.g.(+)). Histological and immunohistochemical examinations, measurement of serum lipopolysaccharide (LPS) levels and ELISA for cytokines in the liver were performed. We then studied the effects of LPS from P.g. (P.g.-LPS) on palmitate-induced steatotic hepatocytes in vitro, and performed immunohistochemical detection of P.g. in liver biopsy specimens of NASH patients.
Serum levels of LPS are upregulated in P.g.(+) groups. Steatosis of the liver developed in HFD groups, and foci of Mac2-positive macrophages were prominent in HFD-P.g.(+). P.g. was detected in Kupffer cells and hepatocytes. Interestingly, areas of fibrosis with proliferation of hepatic stellate cells and collagen formation were only observed in HFD-P.g.(+). In steatotic hepatocytes, expression of TLR2, one of the P.g.-LPS receptors, was upregulated. P.g.-LPS further increased mRNA levels of palmitate-induced inflammasome and proinflammatory cytokines in steatotic hepatocytes. We demonstrated for the first time that P.g. existed in the liver of NASH patients with advanced fibrosis.
Dental infection of P.g. may play an important role in NASH progression through upregulation of the P.g.-LPS-TLR2 pathway and activation of inflammasomes. Therefore, preventing and/or eliminating P.g. infection by dental therapy may have a beneficial impact on management of NASH.
我们通过高脂肪饮食（HFD）喂养小鼠并检查 NASH 患者肝脏中的 P. gingivalis（P.g.）感染，研究了重要牙周病原体 P.g. 感染对 NASH 进展的影响。
C57BL/6J 小鼠分别用标准饮食（CD）或 HFD 喂养 12 周，然后每组一半的小鼠从牙髓腔感染 P.g.（HFD-P.g.(-), HFD-P.g.(+), CD-P.g.(-), 和 CD-P.g.(+)）。进行组织学和免疫组织化学检查、血清脂多糖（LPS）水平测量和肝内细胞因子的 ELISA 检测。然后，我们研究了 P.g. LPS（P.g.-LPS）对体外棕榈酸诱导的脂肪变性肝细胞的影响，并对 NASH 患者肝活检标本中的 P.g. 进行免疫组织化学检测。
P.g.(+) 组血清 LPS 水平上调。HFD 组肝脏出现脂肪变性，HFD-P.g.(+) 组 Mac2 阳性巨噬细胞灶明显。P.g. 在库普弗细胞和肝细胞中均有检测到。有趣的是，仅在 HFD-P.g.(+) 中观察到伴有肝星状细胞增殖和胶原形成的纤维性区域。在脂肪变性的肝细胞中，P.g.-LPS 的一种受体 TLR2 的表达上调。P.g.-LPS 进一步增加了棕榈酸诱导的炎症小体和促炎细胞因子在脂肪变性肝细胞中的 mRNA 水平。我们首次证明 P.g. 存在于具有晚期纤维化的 NASH 患者的肝脏中。
P.g. 的口腔感染可能通过上调 P.g.-LPS-TLR2 途径和激活炎症小体在 NASH 进展中起重要作用。因此，通过口腔治疗预防和/或消除 P.g. 感染可能对 NASH 的管理有有益的影响。
