Protection from Mucosal Pathology by Gut Microbiota during Experimental Colitis

实验性结肠炎期间肠道微生物群对粘膜病理的保护作用

基本信息

批准号：
10121503
负责人：
Sarkis K Mazmanian
金额：
$ 41.6万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
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：
2020-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10121503
关键词：
3xTg-AD mouse Administrative Supplement Affect Alzheimer like pathology Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos s disease therapy Amyloid beta-Protein Anti-Inflammatory Agents Antibiotic Therapy Antiinflammatory Effect Anxiety Bacteroides fragilis Behavior Brain Brain Pathology Brain region CD4 Positive T Lymphocytes Caregivers Cells Chemicals Cognition Disorders Cognitive Cognitive deficits Colitis Colon Coupled Data Dendritic Cells Deposition Development Economic Burden Environment Etiology FOXP3 gene Family Functional disorder Funding Future Generations Gastrointestinal tract structure Germ-Free Goals Human Immune Immune response Immune system Immunity Immunology Impaired cognition In Vitro Inflammation Inflammatory Inflammatory Response Inheritance Patterns Interleukin-10 Intervention Intestines Investigation Knowledge Laboratories Late Onset Alzheimer Disease Lead Learning Link Mediating Medical Medical Economics Membrane Memory Memory Loss Memory impairment Mental Depression Metabolic Metabolic Diseases Microbe Microbiology Microglia Mucosal Immune Responses Mucosal Immunity Mucositis Mucous Membrane Mus Names National Institute of Diabetes and Digestive and Kidney Diseases Neuraxis Neurodegenerative Disorders Neurofibrillary Tangles Neuroimmune Neuronal Dysfunction Neurons Neurosciences Nociception Onset of illness Oral Outcome Parents Parkinson Disease Pathologic Pathology Pathway interactions Patients Peripheral Pharmaceutical Preparations Pharmacotherapy Play Polysaccharides Prevention Probiotics Production Property Publishing Receptor Signaling Regulatory T-Lymphocyte Reporting Research Risk Rodent Model Role Seminal Signal Pathway Signal Transduction Site Societies Study models Surface Symptoms Synapses System T-Lymphocyte TLR2 gene Technology Testing Therapeutic Time Treatment Efficacy United States Validation Vesicle abeta accumulation autism spectrum disorder body system cell type effective therapy efficacy testing functional disability gut bacteria gut microbes gut microbiome gut microbiota host-microbe interactions immunoregulation improved in vivo inflammatory disease of the intestine innovation insight microbial microbiome mouse model nervous system disorder neuroinflammation neuron loss novel novel therapeutics particle prevent

项目摘要

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.

项目概要/摘要阿尔茨海默病 (AD) 是一种破坏性的神经退行性疾病，其特征是进行性进展认知和功能障碍，最终导致记忆丧失，大多数 AD 病例都是迟发性的。零星的，没有证据表明孟德尔遗传模式，这表明环境对疾病发生和/或进展的影响尚无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能提供适度和有效的治疗此外，最近的许多药物试验未能达到消除标志的终点。 AD 大脑中的斑块或改善记忆力被认为是导致 AD 的病理后果。涉及淀粉样β肽（Aβ）在神经元中的积累，随后神经原纤维的沉积缠结，导致特定大脑中突触和神经元功能障碍以及神经元死亡 AD 病理学的特点是循环免疫细胞和免疫细胞中的炎症反应有趣的是，最近的研究表明，微生物组是大脑中常驻的免疫细胞。 AD 患者的差异与匹配的健康对照不同，并且小鼠模型中的抗生素治疗影响 Aβ 病理学和免疫反应值得注意的是，微生物组调节多种免疫细胞类型。我们的实验室发现了可以预防炎症的特定细菌分子，确定了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改善几种小鼠模型的炎症状况。这些重大进展由 NIDDK 的母公司 R01 资助。提议利用我们对特定肠道微生物分子的突破性研究，具有有效的抗测试 AD 新疗法的炎症特性。具体目标 1 将分析粘膜免疫。在两个成熟的 AD 小鼠模型中，我们将确定是否存在前所未有的详细反应。实验性肠道炎症会加速或恶化小鼠的 AD 样病理和症状。目标 2 将重点通过肠道细菌分子抑制炎症来测试 AD 的新疗法，正在测试的创新假设是粘膜炎症。有助于小鼠模型中出现类似 AD 的病理和行为，并激活抗炎免疫肠道细菌的细胞改善了学习和记忆缺陷。验证了这一概念并发现了这一点。作用机制的基础，将降低对 AD 肠脑连接的进一步研究的风险，并推进利用肠道微生物群可能带来安全有效的治疗选择，这一可能性令人兴奋阿尔茨海默病是当代和未来几代人最关心的医学问题之一。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Protective Role of Bacteroides fragilis in a Murine Model of Colitis-Associated Colorectal Cancer.

脆弱拟杆菌在结肠炎相关结直肠癌小鼠模型中的保护作用。

DOI：
发表时间：
2018
期刊：
影响因子：
4.8
作者：
Lee, Yun Kyung;Mehrabian, Parpi;Boyajian, Silva;Wu, Wei;Selicha, Jane;Vonderfecht, Steven;Mazmanian, Sarkis K
通讯作者：
Mazmanian, Sarkis K

Finding the missing links among metabolites, microbes, and the host.

DOI：
10.1016/j.immuni.2014.05.015
发表时间：
2014-06-19
期刊：
Immunity
影响因子：
32.4
作者：
Dorrestein PC;Mazmanian SK;Knight R
通讯作者：
Knight R

The Enteric Network: Interactions between the Immune and Nervous Systems of the Gut.

肠道网络：肠道免疫系统和神经系统之间的相互作用。

DOI：
10.1016/j.immuni.2017.05.011
发表时间：
2017-06-20
期刊：
Immunity
影响因子：
32.4
作者：
Yoo BB;Mazmanian SK
通讯作者：
Mazmanian SK

Bacterial colonization factors control specificity and stability of the gut microbiota.

细菌定植因子控制肠道微生物群的特异性和稳定性。

DOI：
发表时间：
2013-09-19
期刊：
影响因子：
64.8
作者：
Lee, S Melanie;Donaldson, Gregory P;Mikulski, Zbigniew;Boyajian, Silva;Ley, Klaus;Mazmanian, Sarkis K
通讯作者：
Mazmanian, Sarkis K

Disruption of the gut microbiome as a risk factor for microbial infections.

肠道微生物组的破坏是微生物感染的危险因素。