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，例如结直肠癌和阿尔茨海默氏病，以及衰老的过程， 与肠道中微生物组成的变化有关。而且，我们的肠道排除能力 来自我们的血液（所谓肠道屏障功能）的有毒微生物成分随着增加而决定 年龄和炎症会导致炎症，这可以加速衰老并促进各种慢性疾病。我们的 长期目标是鉴定具有抗衰老，抗炎或其他有益影响人类健康的细菌 并了解他们的行动机制。到目前为止，我们已经发现副细胞动物（PD）， 一种正常的肠道细菌，降低了小鼠的注射和强度肠道屏障功能。此外，PD 喂入水果苍蝇时，寿命增加并减慢了年龄较大的活力丧失。此应用程序的目标 要确定PD是否可以延长小鼠的寿命和健康状态，了解蛋白质的重要​​性 参与维持称为ZO-1的肠道屏障功能，最后确定PD的活性因子及其目标 分子。我们假设由于ZO-1表达丧失，肠道屏障功能在衰老期间确定， 导致细菌毒素渗入血液，感染和功能丧失。此外， 可以探索特定的肠道细菌，例如PD，以预防或缓慢与年龄有关的肠道屏障功能障碍 减少炎症并保留健康。该研究的具体目的是：1）确定PD是否可以 增加小鼠的寿命和健康范围； 1A）了解肠道屏障维护中涉及的蛋白质如何 通过衰老和PD暴露改变； 2）确定在结肠中改变ZO-1表达是否会影响寿命 和小鼠的健康范围； 3）确定PD的活性因子； 3A）确定PD的鼠标目标，4）确定 PD果蝇寿命扩展的机制。这项研究的目的将通过进行 在细胞，小鼠和果蝇中进行了几个相互关联的实验。首先，我们将比较寿命，肠道障碍 在整个生命中的功能，炎症和各种健康措施，喂养饮食的小鼠以有或不添加 PD。接下来，我们将比较具有正常，删除和高ZO-1表达的小鼠之间的相同读数 肠。重要的是，小鼠将经过一系列测试以评估其脆弱和认知 健康 - 包括与与大脑感染有关的几种措施，与 阿尔茨海默氏病及其相关痴呆症（ADRD）。要识别PD的活性因素，我们将确定 能够提高肠道屏障功能（通过ZO-1）并找到基因的其他细菌种类 与PD有共同点。然后将它们突变或转移到其他细菌中。最后，我们会的 删除PYD基因，ZO-1的飞行版本，并将与年龄相关的活力丧失与正常的寿命和年龄相关的丧失 在不存在PD的情况下苍蝇。确定PD是否可以延长小鼠的寿命和HealthSpan，因为 以及确定其活性因子，将为该细菌或其活性因子铺平道路 延长健康寿命并确定ZO-1作为此类疗法的靶标。