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

中风是发病率和死亡率的主要原因。肠道微生物群-免疫-脑轴是一个关键的调节器， 对中风的免疫反应免疫细胞不断适应肠道环境， 受体，如配体激活的转录因子、芳烃受体（AHR）。AHR集成 环境、饮食、微生物和代谢线索来控制免疫系统。此外，积累 有证据表明AHR参与了中风的炎症反应。例如，升高的血浆 内源性AHR激活物与卒中患者的梗死体积和死亡率呈正相关。 最近的数据表明，中风后抑制AHR可以是神经保护性的。然而，这些数据是 从年轻的雄性动物模型中获得。这种区别很重要，因为中风患病率增加 随着年龄的增长，它不成比例地影响妇女。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，微生物群中与年龄相关的变化是 与调节AHR配体的代谢途径的变化相关。我假设 中风后AHRI治疗的主要原因是肠道生态失调的有害影响减少。使用可逆 大脑中动脉闭塞模型（MCAO），我将检查是否中风后AHRI治疗老年人 两种性别的小鼠都改善了神经学结果。此外，我将确定AHRI是否减少了 MCAO后实验诱导的发育不良的有害影响。最后，我将研究是否有一个 AHRI和来自年轻供体的粪便微生物群移植（FMT）的联合治疗具有协同作用 来改善中风的预后我们的初步数据表明，流式分选免疫细胞上的AHR表达 随着大脑的老化而减少，但随着回肠末端和盲肠的固有层的老化而增加。我们 结果表明，老年供体FMT后，年轻小鼠肠道免疫细胞中AHR表达增加 (i.e.（1）捐赠者的年龄。从这个建议的结果可以确定的分子机制， 中风后肠-免疫-脑轴功能障碍卒中患者的未来管理可能涉及急性AHRI 通过来自健康供体的FMT对肠道微生物群进行亚急性操作的治疗。

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.