The microbiota-gut-brain axis in Alzheimers disease

阿尔茨海默病中的微生物群-肠-脑轴

基本信息

批准号：
10283496
负责人：
Melanie G Gareau
金额：
$ 32.74万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-12-01 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10283496
关键词：
Address Adult Aging Alzheimer&apos s Disease Anti-Anxiety Agents Antibiotics Behavior Behavioral Brain Brain Pathology Butyrates Butyric Acids Cecum Cells Child Cognition Disorders Cognitive deficits Colon Coupled Defect Development Disease Disease model Elderly Epithelial Cells Esters Functional disorder Gastrointestinal tract structure Genetic Germ-Free Goals Human Immune Impaired cognition Impairment Individual Infection Inflammation Intestines Knowledge Lactobacillus Lead Learning Life Mediating Memory Modeling Mucous Membrane Mus Neonatal Nerve Degeneration Neurodegenerative Disorders Neurons Onset of illness Pathology Pathway interactions Physiology Predisposition Prefrontal Cortex Probiotics Process Rattus Role Severities Signal Transduction Stress Testing Time Volatile Fatty Acids Weaning anxiety-like behavior brain behavior commensal microbes critical developmental period dysbiosis gastrointestinal gut colonization gut dysbiosis gut microbiota gut-brain axis host-microbe interactions ileum microbiota microbiota-gut-brain axis motor deficit motor disorder myelination neonatal period neonate neurodevelopment neurogenesis neuroinflammation new therapeutic target pathogenic bacteria prevent receptor restoration symptomatic improvement trauma exposure tributyrin

项目摘要

ABSTRACT Host-microbe interactions are paramount for maintaining normal physiology of the human host, including the brain and behavior. Bacterial colonization of the gastrointestinal (GI) tract, formation of GI mucosal barrier function, neurogenesis, and myelination of neurons all occur during a critical developmental window in early life. Thus, exposure to trauma such as stress, infection or inflammation during neonatal life could detrimentally impact the developing microbiota, gut and brain (MGB) axis. Disrupted MGB axis signaling, including dysbiosis, mucosal barrier defects and/or changes in behavior, occur in multiple diseases, including Alzheimer’s disease. Antibiotics (Abx) are administered to children more frequently than adults, due to increased susceptibility to bacterial pathogens. Since the MGB axis is developing during this critical time, Abx administration may have long-lasting effects. Beneficial bacterial metabolites, including short chain fatty acids (SCFAs) can ameliorate numerous pathologies, including dysbiosis, mucosal barrier dysfunction, inflammation and behavioral defects. We have demonstrated that modifying the gut microbiota, for example using Lactobacillus-containing probiotics, can prevent stress-induced MGB axis deficits following infection with a bacterial pathogen. We hypothesize that administration of specific SCFAs can prevent neonatal Abx-induced deficits in the adult MGB axis. Therefore, our primary objective is to address the effects of neonatal dysbiosis on the development of the MGB axis using a model of neonatal Abx administration. Our overall goal is to determine whether intestinal dysbiosis disrupts the gut-brain axis, and whether administration of SCFAs beneficially modulates the MGB axis. This goal will be accomplished by the following Specific Aims: (1) Neonatal dysbiosis disrupts myelination leading to neurodegeneration and (2) SCFAs regulate the MBG axis via myelination Taken together, these proposed studies will demonstrate whether neonatal dysbiosis disrupts the developing MGB axis, impacting the microbiota composition, altering myelination in the brain, and causing behavioral deficits in late adulthood. Furthermore, we will determine whether administering select SCFAs ameliorates these effects, in part restoration of impaired myelination in the brain. Finally, our results may promote use of SCFAs to prevent development MGB axis deficits, particularly in older adults.

抽象的宿主与微生物的相互作用对于维持人类宿主的正常生理机能至关重要，包括胃肠道（GI）的细菌定植，胃肠道粘膜屏障的形成。神经元的功能、神经发生和髓鞘形成都发生在早期的关键发育窗口期。因此，新生儿生活期间遭受压力、感染或炎症等创伤可能会造成痛苦。影响微生物群、肠道和大脑 (MGB) 轴的发育，包括 MGB 轴信号传导中断。生态失调、粘膜屏障缺陷和/或行为改变发生在多种疾病中，包括阿尔茨海默病。由于对抗生素的敏感性增加，儿童比成人更频繁地使用抗生素 (Abx) 由于 MGB 轴在此关键时期正在发育，因此 Abx 给药可能会抑制细菌病原体。有益的细菌代谢物，包括短链脂肪酸 (SCFA) 可以改善效果。许多病理学，包括生态失调、粘膜屏障功能障碍、炎症和行为缺陷。我们已经证明，改变肠道微生物群，例如使用含有乳酸菌的益生菌可以预防细菌病原体感染后应激引起的 MGB 轴缺陷。促进特定 SCFA 的施用可以预防新生儿 Abx 引起的成人 MGB 缺陷因此，我们的主要目标是解决新生儿生态失调对发育的影响。 MGB 轴使用新生儿 Abx 给药模型，我们的总体目标是确定肠道是否正常。生态失调会破坏肠脑轴，以及 SCFA 的施用是否有益地调节 MGB 轴将通过以下具体目标来实现：(1) 新生儿生态失调破坏。髓鞘形成导致神经变性，(2) SCFA 通过髓鞘形成调节 MBG 轴总而言之，这些拟议的研究将证明新生儿生态失调是否会破坏 MGB 轴的发育，影响微生物群的组成，改变大脑中的髓鞘形成，并导致此外，我们将确定是否使用特定的短链脂肪酸 (SCFA)。改善这些影响，部分恢复大脑中受损的髓鞘形成。最后，我们的结果可能是这样的。促进使用 SCFA 来预防 MGB 轴发育缺陷，特别是老年人。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Shaping the future of physiology.

塑造生理学的未来。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Ferdek, Pawel;Gareau, Melanie G;Gonzalez, Javier;Wilson, Calum
通讯作者：
Wilson, Calum

Sexually Dimorphic Influence of Neonatal Antibiotics on Bone.

新生儿抗生素对骨的性别二态性影响。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Pusceddu, Matteo M;Stokes, Patricia J;Wong, Alice;Gareau, Melanie G;Genetos, Damian C
通讯作者：
Genetos, Damian C

Myelin as a regulator of development of the microbiota-gut-brain axis.

髓磷脂作为微生物群-肠-脑轴发育的调节剂。

DOI：
发表时间：
2021
期刊：
影响因子：
0
作者：
Keogh, Ciara E;Kim, Danielle H J;Pusceddu, Matteo M;Knotts, Trina A;Rabasa, Gonzalo;Sladek, Jessica A;Hsieh, Michael T;Honeycutt, Mackenzie;Brust;Barboza, Mariana;Gareau, Mélanie G
通讯作者：
Gareau, Mélanie G

Intestinal Lactobacillus in health and disease, a driver or just along for the ride?

肠道乳酸菌在健康与疾病中，是驱动者还是只是搭便车？

DOI：
10.1016/j.copbio.2017.08.004
发表时间：
2018-03
期刊：
Current opinion in biotechnology
影响因子：
7.7
作者：
Heeney DD;Gareau MG;Marco ML
通讯作者：
Marco ML

Neonatal Enteropathogenic Escherichia coli Infection Disrupts Microbiota-Gut-Brain Axis Signaling.

新生儿肠病性大肠杆菌感染会破坏微生物群-肠-脑轴信号传导。

DOI：
发表时间：
2021
期刊：
影响因子：
3.1
作者：
Hennessey, Carly;Keogh, Ciara E;Barboza, Mariana;Brust;Knotts, Trina A;Sladek, Jessica A;Pusceddu, Matteo M;Stokes, Patricia;Rabasa, Gonzalo;Honeycutt, Mackenzie;Walsh, Olivia;Nichols, Rene;Reardon, Colin;Gareau, Mélanie G
通讯作者：
Gareau, Mélanie G