Fusobacterium nucleatum Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation.
Fusobacterium nucleatum Secretes Outer Membrane Vesicles and Promotes Intestinal Inflammation.
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DOI：
10.1128/mbio.02706-20
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发表时间：
2021-03-02
期刊：
影响因子：
6.4
通讯作者：
Versalovic J
中科院分区：
文献类型：
--
作者：
Engevik MA;Danhof HA;Ruan W;Engevik AC;Chang-Graham AL;Engevik KA;Shi Z;Zhao Y;Brand CK;Krystofiak ES;Venable S;Liu X;Hirschi KD;Hyser JM;Spinler JK;Britton RA;Versalovic J
几项研究已经确定了在结肠癌、肝硬化、原发性硬化性胆管炎、胃食管反流病、HIV感染和酒精中毒患者的肠道中梭杆菌属的丰度增加。然而，梭杆菌对胃肠道内病理生理的直接作用机制尚不清楚。多项研究表明微生物参与了炎症的发展，但其机制仍不清楚。已在消化系统疾病患者的肠粘膜中鉴定出梭杆菌属的细菌;因此，我们假设具核梭杆菌促进肠道炎症。添加>50 kDa F.含有外膜囊泡（OMV）的有核细胞条件培养基刺激结肠上皮细胞分泌促炎细胞因子白细胞介素-8（IL-8）和肿瘤坏死因子（TNF）。此外，纯化的F.核质OMV，而不是<50 kDa的化合物，刺激IL-8和TNF产生;其通过Toll样受体4（TLR 4）的药理学抑制而降低。这些效应与下游效应物p-ERK、p-CREB和NF-κB相关。F.核仁>50-kDa的化合物也刺激人结肠样单层中的TNF分泌、p-ERK、p-CREB和NF-κB活化。在携带人类微生物群的小鼠中，用抗生素预处理和单次口服灌胃F。nucleatum导致炎症。与接受载体对照的小鼠相比，用F. nucleatum显示结肠结构破坏，免疫细胞浸润增加，粘液层减少。粘膜基因表达分析显示，在第3天和第5天，F.与对照组相比，nucleatum处理的小鼠。这些促炎作用在接受F. nucleatum没有用抗生素预处理，表明完整的微生物组对F.核介导的免疫反应。这些数据为F.在耗尽的肠道微生物组的背景下，具核质促进促炎信号级联。
Several studies have identified an increased abundance of Fusobacterium in the intestinal tracts of patients with colon cancer, liver cirrhosis, primary sclerosing cholangitis, gastroesophageal reflux disease, HIV infection, and alcoholism. However, the direct mechanism(s) of action of Fusobacterium on pathophysiological within the gastrointestinal tract is unclear. Multiple studies have implicated microbes in the development of inflammation, but the mechanisms remain unknown. Bacteria in the genus Fusobacterium have been identified in the intestinal mucosa of patients with digestive diseases; thus, we hypothesized that Fusobacterium nucleatum promotes intestinal inflammation. The addition of >50 kDa F. nucleatum conditioned media, which contain outer membrane vesicles (OMVs), to colonic epithelial cells stimulated secretion of the proinflammatory cytokines interleukin-8 (IL-8) and tumor necrosis factor (TNF). In addition, purified F. nucleatum OMVs, but not compounds <50 kDa, stimulated IL-8 and TNF production; which was decreased by pharmacological inhibition of Toll-like receptor 4 (TLR4). These effects were linked to downstream effectors p-ERK, p-CREB, and NF-κB. F. nucleatum >50-kDa compounds also stimulated TNF secretion, p-ERK, p-CREB, and NF-κB activation in human colonoid monolayers. In mice harboring a human microbiota, pretreatment with antibiotics and a single oral gavage of F. nucleatum resulted in inflammation. Compared to mice receiving vehicle control, mice treated with F. nucleatum showed disruption of the colonic architecture, with increased immune cell infiltration and depleted mucus layers. Analysis of mucosal gene expression revealed increased levels of proinflammatory cytokines (KC, TNF, IL-6, IFN-γ, and MCP-1) at day 3 and day 5 in F. nucleatum-treated mice compared to controls. These proinflammatory effects were absent in mice who received F. nucleatum without pretreatment with antibiotics, suggesting that an intact microbiome is protective against F. nucleatum-mediated immune responses. These data provide evidence that F. nucleatum promotes proinflammatory signaling cascades in the context of a depleted intestinal microbiome.