Understanding the regulation of the intestinal epithelium in Alzheimer’s disease by commensal bacteria and the role it plays in preventing neurocognitive decline

摘要 阿尔茨海默病(AD)是一种以淀粉样β斑块为特征的进行性神经退行性疾病 神经原纤维缠绕在大脑中，并伴随着大脑和全身的炎症。这导致了 关于微生物群落或感染是神经炎症发展的原因的理论， 免疫衰老和炎症老化在AD中可见。我们自己的研究已经证明了肠道的减少 AD患者具有抗炎特性的微生物区系和较高数量的促炎肠道微生物区系 长辈们。然而，目前尚不清楚AD微生物群如何对中枢神经系统产生影响。致信地址 这一知识缺口我们已经进行了肠道微生物组图谱，血液中免疫细胞群体的分析， 每隔90天对AD老年人进行血清细胞因子谱分析和认知评估。这一分析确定了 B细胞群体中类转换丰度增加和亚群丰度降低的变化 幼稚的B细胞处于更大的认知障碍水平。为了更好地了解微生物群如何控制 AD进展，我们建议研究AD微生物组和获得性免疫之间的联系 该系统的重点是通过共生肠道细菌来调节肠道上皮。具体地说，我们打算 使用从我们的AD队列中收集的粪便和血浆样本来测量肠道通透性和 确定AD肠道微生物群分泌的代谢物是否会导致肠道上皮的破坏。 我们将通过将粪便上清液应用于肠上皮细胞来直接研究AD粪便的干扰作用， 使用已建立的检测方法来量化上皮通透性的变化，并确定特定的分类群 在AD中被耗尽足以导致上皮破裂。在我们之前公布的数据中，我们观察到 植物雌激素代谢细菌Adlercreutzia equolifaciens(AE)在AD微生物组中的丢失 长辈们。我的初步研究表明，AE的代谢产物(S)-QUOL可以防止小鼠皮肤上皮损伤 炎症的环境。因此，我们的目标是确定AE或其代谢产物是否保护 肠上皮细胞。为了理清AD微生物组在我们观察到的班级切换和变化中的作用 幼稚的B细胞，我收集了初步的数据，证明了小鼠与微生物群的定植 与认知障碍老年人的定植相比，AD老年人的B细胞类转换更容易 没有AD。这个应用程序建议扩展这一发现，并表征适应性 由AD微生物群引起的免疫系统。这项持续的工作将进一步建立联系 阿尔茨海默病相关的神经认知衰退、微生物群和免疫系统之间的关系。

ABSTRACT Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by amyloid beta plaques and neurofibrillary tangles in the brain along with inflammation both in the brain and systemically. This has led to the theory of microbial communities or infections as causative in the development of neuroinflammation, immunosenescence, and inflamm-aging seen in AD. Our own research has demonstrated a decrease in gut microbiota with anti-inflammatory properties and higher abundances of pro-inflammatory gut microbiota in AD elders. However, it is unclear how the AD microbiome exerts effects on the central nervous system. To address this gap in knowledge we have performed gut microbiome profiling, analysis of immune cell populations in blood, serum cytokine profiling, and cognitive assessments of AD elders at 90-day intervals. This analysis identified changes in B cell populations with an increased abundance of class-switched and decreased abundance of naïve B cells at levels of greater cognitive impairment. To better understand how the microbiome may control AD progression, we propose to investigate the connection between the AD microbiome and the adaptive immune system with a focus on regulation of the intestinal epithelium by commensal gut bacteria. Specifically, we intend to use stool and plasma samples collected from our AD cohort to measure makers of intestinal permeability and determine whether metabolites secreted by the AD gut microbiome cause disruptions in the intestinal epithelium. We will directly study the disruptive effects of AD stool by applying stool supernatants to intestinal epithelial cells, quantifying changes in epithelial permeability using established assays, and determining whether specific taxa depleted in AD are sufficient to cause epithelial disruption. In our previously published data, we have observed the loss of the phytoestrogen-metabolizing bacteria, Adlercreutzia equolifaciens (AE), in the microbiome of AD elders. My preliminary studies reveal that a metabolic product of AE, (S)-equol, prevents epithelial damage in the setting of inflammation. Therefore, we aim to determine whether AE or its metabolic products protect the intestinal epithelium. To untangle the role of the AD microbiome on our observed changes in class switched and naïve B cells, I have collected preliminary data which demonstrates that colonization of mice with the microbiome of AD elders promotes B cell class switching when compared with colonization of cognitively impaired elders without AD. This application proposes to expand this finding and characterize the changes in the adaptive immune system caused by the AD microbiome. This continuing work will further establish the connection between AD related neurocognitive decline, the microbiome, and immune system.