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: 10659262
• 负责人: Jimmy W Crott
• 金额: $ 59.24万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 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 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659262
• 关键词: Ablation; Acceleration; Address; Adherent Culture; Affect; Age; Aging; Alzheimer' s Disease; Anti-Inflammatory Agents; Attention; Bacteria; Bacterial Antigens; Bacterial Toxins; Bacteroides; Blood Circulation; Cardiovascular Diseases; Cells; Chronic Disease; Cloning; Co-Immunoprecipitations; Cognitive; Colon; Colorectal Cancer; Dementia; Deterioration; Diet; Diffusion; Disease; Drosophila genus; Ecosystem; Elderly; Encephalitis; Exclusion; Extravasation; Functional disorder; Genes; Goals; Health; Homologous Gene; Human; In Vitro; Inflammation; Inflammatory; Intestinal Mucosa; Intestinal permeability; Intestines; Knowledge; Life; Link; Longevity; Maintenance; Malignant Neoplasms; Measures; Memory; Metabolic syndrome; Microbe; Mus; Mutate; Outcome; Penetration; Persons; Physical Function; Play; Population; Process; Proteins; Recombinants; Role; TLR4 gene; Testing; Tight Junctions; Translations; Up-Regulation; Vertebrates; Work; age related; anti aging; beneficial microorganism; cognitive function; commensal bacteria; comparative genomics; experimental study; fly; frailty; gastrointestinal epithelium; genetic manipulation; gut bacteria; gut inflammation; gut microbes; gut microbiota; healthspan; human old age (65+); in vivo; innovation; intestinal barrier; loss of function; microbial; novel; preservation; prevent; sensor; success

Many diseases of old age 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 chronic diseases. Our long-term goal is to identify bacteria with anti-aging, anti-inflammatory or other beneficial effects on human health and to understand their mechanism of action. So far, 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-relator loss of vigor when fed to fruit flies. The objectives of this application are to determine whether Pd can extend lifespan and healthspan in mice, understand the importance of a protein involved in maintaining gut barrier function called ZO-1, and finally to identify the active factor of Pd and its target molecule. We hypothesize that gut barrier function deteriorates during aging due to loss of ZO-1 expression, resulting in leakage of bacterial toxins into the bloodstream, inflammation and loss of function. Furthermore, specific gut bacteria, such as Pd, can be exploited to prevent or slow age-related gut barrier dysfunction, thereby reducing inflammation and preserving health. The specific aims of the study are to: 1) determine if Pd can increase lifespan and healthspan 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 colon affects lifespan and healthspan in mice; 3) identify the active factor of Pd; 3a) identify the mouse target of Pd and 4) determine the mechanism of fruit fly lifespan extension by Pd. The aims of this study will be addressed by conducting several inter-related experiments in cells, mice and fruit flies. Firstly, we will compare the lifespan, gut barrier function, inflammation and various measures of health throughout life, of 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. Importantly, mice will be subjected to a battery of tests to assess their frailty and cognitive health – including several measures of memory and brain inflammation that have direct relevance to Alzheimer’s disease and its Related Dementias (ADRD). To identify the active factor of Pd, we will identify additional species of bacteria that are able to increase gut barrier function (via 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. Finally, we will delete the pyd gene, the fly version of ZO-1, and compare the lifespan and age-related loss of vigor to normal flies in the presence of absence of Pd. Determining whether Pd can extend lifespan and healthspan 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.

许多老年疾病，如结肠直肠癌和阿尔茨海默病，以及衰老本身的过程， 与我们肠道微生物组成的变化有关。此外，我们的肠道排除 我们血液中的有毒微生物成分（所谓的肠道屏障功能）随着时间的推移而恶化。 老化和炎症的结果，反过来，可以加速老化和促进各种慢性疾病。我们 长期目标是鉴定具有抗衰老、抗炎或其他对人体健康有益作用的细菌 并了解它们的作用机制。迄今为止，我们已经发现Parabacteroides distasonis（Pd）， 一种正常的肠道细菌，降低炎症并增强小鼠的肠道屏障功能。此外，Pd 增加寿命和减缓与年龄相关的活力丧失。本申请的目的 是为了确定Pd是否可以延长小鼠的寿命和健康寿命，了解蛋白质的重要性， 参与维持肠道屏障功能的ZO-1，并最终确定Pd的活性因子及其靶点 分子。我们推测，由于ZO-1表达的丧失， 导致细菌毒素泄漏到血液中、炎症和功能丧失。此外，委员会认为， 可以利用特定的肠道细菌，例如Pd，来预防或减缓与年龄相关的肠道屏障功能障碍，从而 消炎、保健。本研究的具体目的是：1）确定Pd是否可以 增加小鼠的寿命和健康寿命; 1a）了解参与肠道屏障维持的蛋白质是如何 2）确定改变结肠中ZO-1表达是否影响寿命 和healthspan; 3）鉴定Pd的活性因子; 3a）鉴定Pd的小鼠靶点和4）确定 Pd延长果蝇寿命的机制。本研究的目的将通过开展 在细胞、小鼠和果蝇中进行的几个相互关联的实验。首先，我们将比较寿命，肠道屏障 功能，炎症和各种健康措施，在整个生命周期中，喂养的饮食有或没有添加 警局接下来，我们将比较ZO-1表达正常、缺失和高表达的小鼠之间的相同读数。 肠子重要的是，小鼠将接受一系列测试，以评估它们的脆弱性和认知能力。 健康-包括记忆和大脑炎症的几项措施，这些措施与 阿尔茨海默病及其相关痴呆症（ADRD）。为了确定Pd的活性因子，我们将确定 能够增加肠道屏障功能（通过ZO-1）的其他细菌种类，并找到它们的基因。 与Pd相同。然后它们会被突变或一个接一个地转移到其他细菌中。最后我们将 删除pyd基因，ZO-1的苍蝇版本，并将寿命和与年龄相关的活力损失与正常人进行比较 在不存在Pd的情况下飞行。确定Pd是否可以延长小鼠的寿命和健康寿命， 以及鉴定其活性因子，将为该细菌或其活性因子用于 因此，研究人员正在研究延长健康寿命的治疗方法，并将ZO-1确立为此类治疗的靶点。