High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway.
High fat diet-induced gut microbiota exacerbates inflammation and obesity in mice via the TLR4 signaling pathway.
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DOI：
10.1371/journal.pone.0047713
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Kim DH
中科院分区：
文献类型：
--
作者：
Kim KA;Gu W;Lee IA;Joh EH;Kim DH
虽然人们普遍认为肥胖与轻度全身炎症有关，但炎症的分子起源仍不清楚。在这里，我们研究了高脂饮食通过全身和肠道水平的TLR 4信号通路对内毒素诱导的炎症的影响。C57 BL/6 J和TLR 4缺陷型C57 BL/10 ScNJ小鼠维持低脂（10 kcal %脂肪）饮食（LFD）或高脂（60 kcal %脂肪）饮食（HFD）8周。HFD诱导脂肪组织中的巨噬细胞浸润和炎症，以及循环促炎细胞因子的增加。HFD增加了血浆和粪便内毒素水平，并通过增加厚壁菌门与拟杆菌门的比例导致肠道微生物群失调。HFD在体外诱导肠杆菌科细菌生长和内毒素产生。此外，HFD还可诱导结肠炎症反应，包括促炎细胞因子表达增加，Toll样受体4（TLR 4）、iNOS、考克斯-2的表达增加，NF-κB B的活化。HFD降低了结肠中紧密连接相关蛋白claudin-1和occludin的表达。与LFD小鼠相比，HFD小鼠在结肠中表现出更高水平的Akt和FOXO 3磷酸化。虽然HFD喂养的小鼠的体重在TLR 4缺陷型和野生型小鼠中均显著增加，但HFD喂养的TLR 4缺陷型小鼠的附睾脂肪重量和血浆内毒素水平分别为HFD喂养的野生型小鼠的69%和18%。此外，HFD没有增加TLR 4缺陷小鼠的促炎细胞因子水平。HFD通过增加肠腔中的内毒素水平以及通过改变肠道微生物群组成和通过诱导TLR 4增加其肠道渗透性来增加血浆中的内毒素水平来诱导炎症，从而加速肥胖。
While it is widely accepted that obesity is associated with low-grade systemic inflammation, the molecular origin of the inflammation remains unknown. Here, we investigated the effect of endotoxin-induced inflammation via TLR4 signaling pathway at both systemic and intestinal levels in response to a high-fat diet. C57BL/6J and TLR4-deficient C57BL/10ScNJ mice were maintained on a low-fat (10 kcal % fat) diet (LFD) or a high–fat (60 kcal % fat) diet (HFD) for 8 weeks. HFD induced macrophage infiltration and inflammation in the adipose tissue, as well as an increase in the circulating proinflammatory cytokines. HFD increased both plasma and fecal endotoxin levels and resulted in dysregulation of the gut microbiota by increasing the Firmicutes to Bacteriodetes ratio. HFD induced the growth of Enterobecteriaceae and the production of endotoxin in vitro. Furthermore, HFD induced colonic inflammation, including the increased expression of proinflammatory cytokines, the induction of Toll-like receptor 4 (TLR4), iNOS, COX-2, and the activation of NF-κB in the colon. HFD reduced the expression of tight junction-associated proteins claudin-1 and occludin in the colon. HFD mice demonstrated higher levels of Akt and FOXO3 phosphorylation in the colon compared to the LFD mice. While the body weight of HFD-fed mice was significantly increased in both TLR4-deficient and wild type mice, the epididymal fat weight and plasma endotoxin level of HFD-fed TLR4-deficient mice were 69% and 18% of HFD-fed wild type mice, respectively. Furthermore, HFD did not increase the proinflammatory cytokine levels in TLR4-deficient mice. HFD induces inflammation by increasing endotoxin levels in the intestinal lumen as well as in the plasma by altering the gut microbiota composition and increasing its intestinal permeability through the induction of TLR4, thereby accelerating obesity.
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影响因子：
16.2
作者：
Ghanim H;Abuaysheh S;Sia CL;Korzeniewski K;Chaudhuri A;Fernandez-Real JM;Dandona P
通讯作者：
Dandona P
影响因子：
7.7
作者：
Cani, Patrice D.;Amar, Jacques;Burcelin, Remy
通讯作者：
Burcelin, Remy
DOI：
10.1152/ajpgi.00098.2010
发表时间：
2010-08-01
影响因子：
4.5
作者：
de La Serre, Claire Barbier;Ellis, Collin L.;Raybould, Helen E.
通讯作者：
Raybould, Helen E.
影响因子：
9.8
作者：
Li, Hong;Lelliott, Christopher;Michaelsson, Erik
通讯作者：
Michaelsson, Erik
DOI：
10.1073/pnas.0504978102
发表时间：
2005-08-02
影响因子：
11.1
作者：
Ley, RE;Bäckhed, F;Gordon, JI
通讯作者：
Gordon, JI