Lipopolysaccharides transport during fat absorption in rodent small intestine
Lipopolysaccharides transport during fat absorption in rodent small intestine
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DOI：
10.1152/ajpgi.00079.2020
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发表时间：
2020-06-01
影响因子：
4.5
通讯作者：
Kaunitz, Jonathan D.
中科院分区：
文献类型：
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作者：
Akiba, Yasutada;Maruta, Koji;Kaunitz, Jonathan D.
脂多糖（LPS）是一种强效的促炎分子，通过不确定的机制从肠腔进入体循环。我们研究了这些机制以及外源性胰高血糖素样肽-2 （GLP-2）对LPS在啮齿动物小肠内转运的影响。测定了大鼠空肠粘膜脂多糖的跨黏膜转运。在麻醉大鼠十二指肠内灌注油酸和牛磺胆酸（OA/TCA）后，同时监测异硫代氰酸荧光素(FITC)-LPS进入门静脉（PV）和肠系膜淋巴的情况。在体外，光施LPS仅在有OA/TCA存在的浆膜溶液中迅速出现，被脂质筏抑制剂甲基- p -环糊精（M13CD）和CD36抑制剂磺基琥珀酰酰油酸酯（SSO）或浆膜GLP-2抑制。在体内，OA/TCA灌注FITC-LPS可迅速增加FITC-LPS进入PV的外观，随后进入淋巴的FITC-LPS逐渐增加。添加M13CD或SSO可抑制PV的快速转运，而乳糜蛋白合成抑制可抑制PV进入淋巴的转运。静脉注射稳定的GLP-2类似物特度葡肽可急剧抑制FITC-LPS向PV的转运，但通过nw -硝基-L-精氨酸甲酯（L -名）和pg97 -269敏感机制加速FITC-LPS向淋巴的转运。小鼠空肠的体内共聚焦显微镜证实了细胞内FITC-LPS摄取，没有细胞外局部化的证据。这是第一次在体内直接证明，在脂肪吸收过程中，内源性LPS可以通过脂质筏和cd36介导的机制生理地穿过小肠屏障，然后主要转运到PV中，并且teduglutide在体内抑制LPS摄取到PV中。新的和值得注意的是，我们报告了直接在体内证实的跨细胞脂多糖（LPS）从肠道摄取到门静脉（PV），涉及CD36和脂筏，少量通过典型乳糜微粒途径摄取。肠道激素胰高血糖素样肽-2 （GLP-2）抑制摄取到PV。这些数据表明，大部分脂多糖的吸收是通过PV到肝脏的，这有助于阐明脂多糖作为“肠-肝”轴的一部分转运到PV的机制。这些数据不支持脂多糖的细胞旁转运，这与“漏肠”综合征的发病机制有关。
Lipopolysaccharides (LPS) are po-tent pro-inflammatory molecules that enter the systemic circulation from the intestinal lumen by uncertain mechanisms. We investigated these mechanisms and the effect of exogenous glucagon-like pep-tide-2 (GLP-2) on LPS transport in the rodent small intestine. Trans-mucosal LPS transport was measured in Ussing-chambered rat jejunal mucosa. In anesthetized rats, the appearance of fluorescein isothio-cyanate (FITC)-LPS into the portal vein (PV) and the mesenteric lymph was simultaneously monitored after intraduodenal perfusion of FITC-LPS with oleic acid and taurocholate (OA/TCA). In vitro, luminally applied LPS rapidly appeared in the serosal solution only with luminal OA/TCA present, inhibited by the lipid raft inhibitor methyl-P-cyclodextrin (M13CD) and the CD36 inhibitor sulfosuccin-imidyl oleate (SSO), or by serosal GLP-2. In vivo, perfusion of FITC-LPS with OA/TCA rapidly increased FITC-LPS appearance into the PV, followed by a gradual increase of FITC-LPS into the lymph. Rapid PV transport was inhibited by the addition of M13CD or by SSO, whereas transport into the lymph was inhibited by chylomi-cron synthesis inhibition. Intraveous injection of the stable GLP-2 analog teduglutide acutely inhibited FITC-LPS transport into the PV, yet accelerated FITC-LPS transport into the lymph via Nw-nitro-L- arginine methyl ester (L -NAME)-and PG97-269-sensitive mecha-nisms. In vivo confocal microscopy in mouse jejunum confirmed intracellular FITC-LPS uptake with no evidence of paracellular local-ization. This is the first direct demonstration in vivo that luminal LPS may cross the small intestinal barrier physiologically during fat absorption via lipid raft-and CD36-mediated mechanisms, followed by predominant transport into the PV, and that teduglutide inhibits LPS uptake into the PV in vivo.NEW & NOTEWORTHY We report direct in vivo confirmation of transcellular lipopolysaccharides (LPS) uptake from the intestine into the portal vein (PV) involving CD36 and lipid rafts, with minor uptake via the canonical chylomicron pathway. The gut hormone glucagon-like peptide-2 (GLP-2) inhibited uptake into the PV. These data suggest that the bulk of LPS absorption is via the PV to the liver, helping clarify the mechanism of LPS transport into the PV as part of the"gut-liver" axis. These data do not support the paracellular transport of LPS, which has been implicated in the pathogenesis of the "leaky gut" syndrome.