Protection from Mucosal Pathology by Gut Microbiota during Experimental Colitis

项目摘要/摘要 阿尔茨海默病(AD)是一种破坏性的神经退行性疾病，其特征是进行性 认知和功能障碍，最终导致记忆力丧失。大多数阿尔茨海默病患者起病晚， 零星的，没有孟德尔遗传模式的证据，这表明 环境对疾病发生和/或发展的贡献。没有有效的治疗方法可以减缓， 阻止或逆转AD的症状，目前批准的药物疗法只提供温和和 短暂的利益。此外，最近的许多药物试验都未能达到其可消除标志的终点。 阿尔茨海默病大脑中的斑块或改善记忆。导致AD的病理后果被认为是 涉及淀粉样蛋白-β肽(A-β)在神经元中的积聚，随后是神经纤维的沉积 缠结，导致特定脑区突触和神经元功能障碍以及神经元死亡 地区。AD病理的特点是循环免疫细胞和 大脑的常驻免疫细胞，称为小胶质细胞。有趣的是，最近的研究表明，微生物群 AD患者与匹配的健康对照组不同，在小鼠模型中使用抗生素治疗 影响Aβ的病理和免疫反应。值得注意的是，微生物群调节着多种免疫细胞类型。 遍及全身。我们的实验室已经发现了防止炎症的特定细菌分子， 识别免疫细胞中介导抗炎作用的受体和信号通路，以及 揭示了宿主-微生物相互作用如何在几个小鼠模型中改善炎症条件。 这些重大进展是由NIDDK的母公司R01资助的。本行政副刊 建议利用我们对特定肠道微生物分子的开创性研究，具有强大的抗 炎症特性，以测试AD的新治疗方法。特异性目标1将描述粘膜免疫 在两个成熟的阿尔茨海默病小鼠模型中，以前所未有的详细程度进行了反应。此外，我们将确定是否 实验性肠炎会加速或加重小鼠的AD样病理和症状。特定的 目标2将专注于通过抑制肠道细菌分子的炎症来测试治疗AD的新疗法 预防和治疗肠道炎症。正在测试的创新假设是粘膜炎症 有助于小鼠模型中AD样的病理和行为，以及抗炎免疫的激活 肠道细菌产生的细胞可以改善学习和记忆缺陷。对这一概念的验证，以及对 根据作用机制，将降低对阿尔茨海默病肠道-大脑联系的进一步研究的风险，并推动 利用肠道微生物群可能导致安全和有效的治疗选择的令人兴奋的可能性 对于阿尔茨海默氏症，这是当代和未来几代人最关心的医学问题之一。

PROJECT SUMMARY/ABSTRACT Alzheimer’s disease (AD) is a devastating neurodegenerative disorder that is characterized by progressive cognitive and functional impairment, and ultimately memory loss. Most cases of AD are late-onset and sporadic, with no evidence for a Mendelian pattern of inheritance, suggesting a significant role for environmental contributions to disease onset and/or progression. There are no validated treatments that slow, halt or reverse the symptoms of AD, and currently approved pharmacotherapies provide only modest and transient benefits. Further, many recent drug trials have failed to meet their endpoints of dissolving hallmark plaques in the AD brain or improving memory. The pathological consequences leading to AD are believed to involve accumulation of the amyloid-β peptide (Aβ) in neurons followed by the deposition of neurofibrillary tangles, which result in the onset of synaptic and neuronal dysfunction and neuronal death in specific brain regions. AD pathology is characterized by an inflammatory response in circulating immune cells and in the brain's resident immune cells, known as microglia. Intriguingly, it has recently been shown that the microbiome of AD patients differs from that of matched healthy controls, and that antibiotic treatment in mouse models impacts Aβ pathology and immune responses. Notably, the microbiome regulates numerous immune cell types throughout the body. Our laboratory has discovered specific bacterial molecules that prevent inflammation, identified receptors and signaling pathways in immune cells that mediate anti-inflammatory effects, and revealed how host-microbial interactions can ameliorate inflammatory conditions in several mouse models. These major advances have been funded by the parent R01 from NIDDK. This Administrative Supplement proposes to leverage our ground-breaking studies of specific gut microbial molecules with potent anti- inflammatory properties to test novel treatments for AD. Specific Aim 1 will profile the mucosal immune response, in unprecedented detail, in two well-established mouse models of AD. Further, we will determine if experimental gut inflammation accelerates or exacerbates AD-like pathologies and symptoms in mice. Specific aim 2 will focus on testing novel therapies for AD by suppressing inflammation with gut bacterial molecules that prevent and treat intestinal inflammation. The innovative hypothesis being tested is that mucosal inflammation contributes to AD-like pathologies and behaviors in mouse models, and activation of anti-inflammatory immune cells by gut bacteria ameliorates learning and memory deficits. Validation of this concept, and discovery of underling mechanisms of action, will de-risk further research into the gut-brain connection in AD, and advance the exciting possibility that harnessing the gut microbiome may lead to safe and effective therapeutic options for Alzheimer’s disease, one of the greatest medical concerns of current and future generations.