Studying the Gut-Brain inflammatory interaction

项目摘要 新的证据表明，帕金森病(PD)和神经退行性疾病的风险 阿尔茨海默病(AD)在没有性别的炎症性肠病(IBD)患者中显著增加 不同之处。因此，人们认为慢性肠炎可能会改变脑生理。然而，在那里 没有直接证据表明肠道炎症会引起大脑的病理状况；其潜在的分子 机制仍然难以捉摸。因此，本应用程序的目标是(1)演示慢性肠道 炎症改变大脑功能使用“锰增强磁共振成像”(MEMRI)在 以及(2)揭示其潜在的机制。 使用MEMRI技术这一优秀的非侵入性活体生物成像技术测量大脑 在活体动物中，我们发现C57BL/6小鼠患有多周期DSS诱导的慢性结肠炎 与健康小鼠相比，小鼠海马区的大脑活动减少。因此，从长远来看 慢性结肠炎小鼠的记忆力下降。神经炎性反应，包括IL-1水平和 与慢性结肠炎小鼠相比，慢性结肠炎小鼠海马区caspase-1和caspase-11的活性升高 控制的那些。HMGB1水平在血清和海马区均显著升高 慢性结肠炎小鼠，而内毒素水平保持在低水平，这些组织没有明显变化。这个 慢性结肠炎小鼠血脑屏障通透性显著增加。 鉴于HMGB1将胞外内毒素转运到胞浆内以触发caspase-11介导的事实 巨噬细胞的下垂，因此我们的中心假设是，在慢性肠炎条件下， HMGB1被释放并进入大脑。然后，HMGB1水平升高，与低水平的 本土内毒素，能够激活caspase-11介导的小胶质细胞炎症反应； 从而导致脑部发炎。为了研究这一假设，我们提出了目标：(目标1)检验 HMGB1是否介导慢性结肠炎小鼠脑内炎症反应，并(目的2)检测 慢性结肠炎IL-10-KO小鼠是否表现出脑活动改变。

Project Summary Emerging evidence indicates that the risk of neurodegenerative disease such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) is substantially increased in inflammatory bowel diseases (IBD) patients without sex differences. Therefore, it is believed that chronic gut inflammation may change brain physiology. However, there is no direct evidence that gut inflammation elicits a pathological condition in the brain; its underlying molecular mechanism remains elusive. Accordingly, the goal of this application is (1) to demonstrate that chronic gut inflammation alters the brain function using “manganese-enhanced magnetic resonance imaging” (MEMRI) in mice and (2) to uncover its underlying mechanism. Using the MEMRI technique that is an excellent non-invasive, in vivo bio-imaging technique to measure the brain activity in living animals, we discovered that C57BL/6 mice suffering from multicycle DSS-induced chronic colitis exhibit reduced brain activity in the hippocampus compared to that of healthy mice. Accordingly, long-term memory is declined in chronic colitis mice. Neuroinflammatory responses, including IL-1 levels and the activation of caspase-1 and caspase-11, are elevated in the hippocampus of chronic colitis mice compared to those of controls. HMGB1 levels are substantially increased both in the blood serum and in the hippocampus of chronic colitis mice, while LPS levels remain at low levels without significant changes in these tissues. The permeability of the blood brain barrier is markedly increased in chronic colitis mice. Given the fact that HMGB1 transports extracellular LPS into the cytosol to trigger caspase-11-medaited pyroptosis in macrophages, our central hypothesis is, therefore, that in chronic gut inflammatory conditions, HMGB1 is released and travels to the brain. Then, elevated levels of HMGB1, in conjunction with a low level of indigenous LPS, are capable of activating caspase-11-mediated inflammatory responses in microglial cells; thereby, causing the inflammation in the brain. To study this hypothesis, we propose the aims: (Aim 1) examine whether HMGB1 mediates the inflammatory response in the brain of chronic colitis mice, and (Aim 2) examine whether IL-10-ko mice with chronic colitis exhibit altered brain activity.