Strengthening gut barrier integrity with beneficial microbes to increase lifespan and healthspan

利用有益微生物加强肠道屏障完整性，延长寿命和健康寿命

• 批准号: 10295986
• 负责人: Jimmy W Crott
• 金额: $ 71.46万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2022-02-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295986
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease related dementia; Anti-Inflammatory Agents; Attention; Bacteria; Bacterial Antigens; Bacterial Toxins; Bacteroides; Blood Circulation; Cardiovascular Diseases; Cell Culture Techniques; Chronic Disease; Cloning; Co-Immunoprecipitations; Cognitive; Colon; Colorectal Cancer; Deterioration; Development; Diet; Diffusion; Disease; Drosophila genus; Ecosystem; Elderly; Encephalitis; Escherichia coli; Extravasation; Functional disorder; Genes; Goals; Health; Health Promotion; Human; Impaired cognition; In Vitro; Inflammation; Inflammatory; Intestinal Mucosa; Intestinal permeability; Intestines; Knowledge; Link; Longevity; Maintenance; Malignant Neoplasms; Measures; Memory; Metabolic syndrome; Microbe; Mus; Mutate; Outcome; Pathology; Penetration; Play; Population; Process; Property; Proteins; Recombinants; Role; TLR4 gene; Testing; Tight Junctions; Transgenes; Translations; Up-Regulation; Vertebrates; Work; age related; anti aging; beneficial microorganism; cognitive function; commensal bacteria; comparative genomics; dietary control; experimental study; frailty; gastrointestinal epithelium; genetic manipulation; gut bacteria; gut microbes; gut microbiota; healthspan; human old age (65+); in vivo; inflammatory disease of the intestine; inflammatory marker; innovation; intestinal barrier; microbial; monolayer; mutant; novel; preservation; prevent; sensor; success

Many age-related diseases (ARD) like colorectal cancer and Alzheimer’s disease, as well as the process of aging itself, have been linked to changes in the composition of microbes in our gut. Moreover, the ability of our gut to exclude toxic microbial components from our bloodstream (so-called gut barrier function) deteriorates with increasing age and results in inflammation which, in-turn, can accelerate aging and promote various ARDs. Our long-term goal is to identify bacteria with anti-inflammatory properties, and could therefore promote health, and to understand their mechanism of action. We have discovered that Parabacteroides distasonis (Pd), a normal gut bacterium, lowers inflammation and strengthens gut barrier function in mice. Furthermore, Pd increased lifespan and slowed age-related loss of vigor in fruit flies. The objectives of this application are to determine whether Pd can extend lifespan, preserve vigor and slow cognitive decline relevant to Alzheimer’s disease and/or Alzheimer’s-related dementias (AD/ADRD) during aging in mice and to understand the mechanisms involved. Furthermore, to understand the importance of gut barrier function in the loss of vigor and development of AD/ADRD-related pathologies during aging. We hypothesize that gut barrier function deteriorates during aging due to diminished ZO-1 expression, resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of vigor and development of AD/ADRD-related pathologies. Furthermore, specific gut bacteria, such as Pd, can prevent or slow age-related gut barrier dysfunction, thereby reducing inflammation, preserving health and preventing AD/ADRD-related pathologies. The specific aims of the study are to: 1) determine if Pd can increase lifespan, preserve vigor and prevent AD/ADRD-related markers in mice; 1a) understand how proteins involved in gut barrier maintenance are altered by aging and Pd exposure; 2) determine whether altering ZO-1 expression in the intestine affects lifespan, vigor and AD/ADRD-related markers in mice; 3) identify the active factor of Pd; 3a) test whether the ZO-1 upregulating factor of Pd promotes longevity and healthspan and 3b) identify the mouse target of Pd. The aims of this study will be addressed by conducting several inter-related experiments in cell culture, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier function, inflammation and measures of frailty and cognitive health, including several measures of memory and brain inflammation directly relevant to AD/ADRD, between mice fed diet with or without with added Pd. Next, we will compare the same readouts between mice with normal, deleted and high ZO-1 expression in the intestine. To identify the active factor of Pd, we will identify additional species of bacteria that are able to up-regulate ZO-1 and find the genes they have in common with Pd. These will then be mutated or transferred to other bacteria one by one. Determining whether Pd can extend lifespan, preserve vigor and prevent AD/ADRD related pathologies in mice, as well as identifying its active factor, will pave the way for this bacterium, or its active factor, to be utilized in therapies to extend the healthy lifespan and establish ZO-1 as a target for such therapies.

许多与年龄相关的疾病（ARD），如结直肠癌和阿尔茨海默病，以及衰老过程 它本身与我们肠道微生物组成的变化有关。此外，我们的肠道 从我们的血液中排除有毒微生物成分（所谓的肠道屏障功能）恶化， 增加年龄并导致炎症，这反过来又会加速衰老并促进各种ARDs。我们 长期目标是识别具有抗炎特性的细菌，因此可以促进健康， 了解它们的作用机制。我们已经发现，Parabacteroides distasonis（Pd），一种正常的 肠道细菌，降低炎症，增强肠道屏障功能。此外，Pd增加 寿命并减缓果蝇与年龄相关的活力丧失。本申请的目的是确定 Pd是否可以延长寿命，保持活力和减缓与阿尔茨海默病相关的认知衰退，和/或 阿尔茨海默氏症相关痴呆症（AD/ADRD）在小鼠衰老过程中的作用，并了解其机制。 此外，为了了解肠道屏障功能在丧失活力和发展中的重要性， 衰老过程中AD/ADRD相关病理。我们推测，随着年龄的增长， 由于ZO-1表达减少，导致细菌毒素渗漏到血流中， 以及丧失活力和发展AD/ADRD相关的病理。此外，特定的肠道细菌，如 Pd，可以预防或减缓与年龄相关的肠道屏障功能障碍，从而减轻炎症，维护健康 和预防AD/ADRD相关的病理。本研究的具体目的是：1）确定Pd是否可以 增加小鼠寿命，保持活力并预防AD/ADRD相关标志物; 1a）了解蛋白质如何 参与肠道屏障维持的细胞因子通过老化和Pd暴露而改变; 2）确定改变ZO-1是否 肠中的表达影响小鼠的寿命、活力和AD/ADRD相关标志物; 3）鉴定活性 3a）测试Pd的ZO-1上调因子是否促进长寿和健康寿命，以及3b） 确定Pd的小鼠靶点。本研究的目的将通过进行几个相互关联的 在细胞培养、小鼠和果蝇中进行的实验。首先，我们将比较寿命，肠道屏障功能， 炎症和脆弱和认知健康的措施，包括记忆和大脑的几个措施， 与AD/ADRD直接相关的炎症，在喂食有或没有添加Pd的饮食的小鼠之间。接下来我们就 比较在肠中具有正常、缺失和高ZO-1表达的小鼠之间的相同读数。到 确定Pd的活性因子，我们将确定能够上调ZO-1的其他细菌种类 并找出他们与帕金森病的共同基因然后这些细菌会发生突变或转移到其他细菌中 一个接一个。确定Pd是否可以延长寿命，保持活力和预防AD/ADRD相关 小鼠的病理学，以及鉴定其活性因子，将为这种细菌，或其活性因子， 用于治疗以延长健康寿命并将ZO-1确立为这种治疗的靶点。