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Detrimental effects of age-related gut dysbiosis on stroke outcomes are mediated via the aryl hydrocarbon receptor

与年龄相关的肠道菌群失调对中风结果的有害影响是通过芳基烃受体介导的

基本信息

批准号：
10217060
负责人：
Pedram Honarpisheh
金额：
$ 3.27万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-06-16 至 2022-05-15
项目状态：
已结题

项目摘要

Stroke is a leading cause of morbidity and mortality. The gut microbiota-immune-brain axis is a key regulator of the immune response to stroke. Immune cells constantly adapt to the gut environment using specialized receptors such as the ligand-activated transcription factor, aryl hydrocarbon receptor (AHR). AHR integrates environmental, dietary, microbial, and metabolic cues to control the immune system. Moreover, accumulating evidence implicates AHR in the inflammatory response to stroke. For example, elevated plasma levels of endogenous AHR activators are positively correlated with infarct volume and mortality in stroke patients. Recent data suggests that post-stroke inhibition of AHR can be neuroprotective. However, these data were obtained from young male animal models. This distinction is important because stroke prevalence increases with age and it disproportionately affects women. In this project, I will investigate whether age and sex affect the neuroprotective effect of AHR inhibitors (AHRI). Further, age-related changes in the microbiota are associated with shifts in the metabolic pathways that regulate AHR ligands. I hypothesize that the benefits of post-stroke AHRI therapy are due to a reduction in the detrimental effects of gut dysbiosis. Using a reversible middle-cerebral artery occlusion model (MCAO), I will examine whether post-stroke AHRI treatment of aged mice of both sexes improves neurological outcomes. Additionally, I will determine whether AHRI reduces the deleterious effects of experimentally-induced dysiosis after MCAO. Lastly, I will examine whether a combination therapy with AHRI and fecal microbiota transplant (FMT) from youthful donors act synergistically to improve stroke outcomes. Our preliminary data shows that AHR expression on flow-sorted immune cells decreases with aging in the brain but increases with aging in the lamina propria of distal ileum and cecum. Our results show that AHR expression is increased in gut immune cells of young mice after FMT from aged donors (i.e. reflects the age of the donors). The results from this proposal can identify a molecular mechanism of the gut-immune-brain axis dysfunction after stroke. Future management of stroke patients may involve acute AHRI therapy with sub-acute manipulation of the gut microbiota via FMT from healthy donors.

中风是发病率和死亡率的主要原因。肠道微生物区系-免疫-脑轴是对中风的免疫反应。免疫细胞不断地适应肠道环境，使用专门的受体，如配体激活的转录因子，芳香烃受体(AHR)。AHR集成控制免疫系统的环境、饮食、微生物和代谢线索。此外，积累有证据表明，AHR与中风的炎症反应有关。例如，血浆中高水平的内源性AHR激活物与卒中患者的脑梗塞体积和死亡率呈正相关。最近的数据表明，卒中后抑制AHR可以起到神经保护作用。然而，这些数据是从年轻的雄性动物模型中获得。这一区别很重要，因为中风患病率增加随着年龄的增长，这对女性的影响不成比例。在这个项目中，我将调查年龄和性别是否会影响 AHR抑制剂(AHRI)的神经保护作用。此外，微生物区系中与年龄相关的变化是与调节AHR配体的代谢途径的变化有关。我假设这样做的好处卒中后的AHRI治疗是由于减少了肠道生物失调的有害影响。使用可逆的建立大脑中动脉闭塞模型(MCAO)，观察老年卒中后AHRI的治疗效果无论性别的小鼠都能改善神经功能。此外，我将确定AHRI是否会降低大脑中动脉阻塞后人工诱导的吞咽困难的有害影响。最后，我将研究一个 AHRI与年轻供者粪便微生物区系移植(FMT)联合治疗具有协同作用以改善中风的结果。我们的初步数据显示，AHR在流动分类的免疫细胞上的表达在大脑中随着年龄的增长而减少，但在回肠远端和盲肠的固有层中随着年龄的增长而增加。我们的结果表明，老年供者FMT后幼鼠肠道免疫细胞中AHR的表达增加 (即反映捐赠者的年龄)。这一建议的结果可以确定一种分子机制中风后肠道免疫脑轴功能障碍。未来对中风患者的治疗可能涉及急性AHRI 通过健康供者的FMT对肠道微生物区系进行亚急性操作的治疗。