Chronic intestinal inflammation suppresses brain activity by inducing neuroinflammation in mice.
Chronic intestinal inflammation suppresses brain activity by inducing neuroinflammation in mice.
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DOI：
10.1016/j.ajpath.2021.09.006
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发表时间：
2021-10
期刊：
影响因子：
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通讯作者：
Jonathon Mitchell;S. Kim;Cody S. Howe;Seulah Lee;J. Her;M. Patel;Gayoung Kim;Jaewon Lee;E. Im;S. Rhee
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文献类型：
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作者：
Jonathon Mitchell;S. Kim;Cody S. Howe;Seulah Lee;J. Her;M. Patel;Gayoung Kim;Jaewon Lee;E. Im;S. Rhee
慢性肠道炎症如炎症性肠病被认为与人类神经退行性疾病有关。然而，这种脑-肠相互作用的直接证据和潜在机制仍然难以捉摸。在这项研究中，锰增强磁共振成像被用来评估清醒和自由活动的慢性结肠炎小鼠的功能性大脑活动。与对照小鼠相比，慢性结肠炎小鼠海马中锰离子摄取（指示Ca 2+流入神经元细胞）和蓄积减少。长期记忆下降，神经炎症信号，包括IL-1β的产生和caspase-1，caspase-11和gasdermin的激活，被诱导。高迁移率族蛋白1（HMGB 1）水平升高，在血清和海马，然而，脂多糖（LPS）水平保持在低水平，在这些样品中没有显着的变化。慢性结肠炎小鼠血脑屏障通透性增加。在LPS存在下，HMGB 1处理诱导小鼠小胶质细胞系SIM-A9中caspase-11和gasdermin的活化。这些发现表明，从发炎的肠道释放的HMGB 1可能通过血液循环系统移动到大脑;与低水平的内源性LPS结合，升高的HMGB 1随后可以激活脑中的半胱天冬酶介导的炎症反应。
Chronic gut inflammation such as inflammatory bowel disease is believed to be associated with neurodegenerative diseases in humans. However, the direct evidence for and the underlying mechanism of this brain–gut interaction remain elusive. In this study, manganese-enhanced magnetic resonance imaging was used to assess functional brain activity from awake and freely moving mice with chronic colitis. Manganese ion uptake (indicative of Ca2+influx into neuronal cells) and accumulation were reduced in the hippocampus of chronic colitis mice compared with control mice. Long-term memory declined and neuroinflammatory signals, including IL-1β production and activation of caspase-1, caspase-11, and gasdermin, were induced. High-mobility group box 1 (HMGB1) levels were elevated both in the serum and in the hippocampus; however, lipopolysaccharide (LPS) levels remained at low levels without significant changes in these samples. The blood–brain barrier permeability was increased in chronic colitis mice. In the presence of LPS, HMGB1 treatment induced the activation of caspase-11 and gasdermin in the mouse microglial cell line SIM-A9. These findings suggest that HMGB1 released from the inflamed intestine may move to the brain through the blood circulatory system; in conjunction with a low level of endogenous LPS, elevated HMGB1 can subsequently activate caspase-mediated inflammatory responses in the brain.