Investigating the influence of gut microbial metabolism on normal age-related cognitive decline

认知是一种获取知识和理解我们周围世界的心理过程，它通常会随着年龄的增长而恶化。这种恶化往往与大脑的结构和功能变化同时发生。虽然健康的生活方式可以降低与年龄相关的认知能力下降的速度，但肥胖与此有关。这一点很重要，因为英国的肥胖率持续上升，在45-54岁的成年人中达到顶峰（36%肥胖），在55-74岁的老年人中仍然很高（33.5%）。人类肠道中存在着大量的微生物，统称为肠道菌群。我们和其他人已经证明，这些微生物能够在肠道中产生化学物质，这些化学物质可以改变大脑中发生的过程，对认知和整体健康产生影响。重要的是，肠道中存在的微生物类型及其整体活动随着年龄和肥胖而变化，我们现在有初步数据表明，肠道微生物群及其化学物质输出与正常的年龄相关的认知衰退有关。为了进一步研究这一点，我们将测量不同年龄和体重指数（BMI；肥胖的一种衡量标准）人类肠道微生物群产生的化学物质，并探索这些信号与大脑结构和功能之间的关系。使用不同的分析化学技术，我们将测量从1000多人（50-98岁）收集的血液和粪便样本中的微生物相关分子。研究人员测量了这些参与者的大脑结构和功能，以及粪便中存在的微生物（反映了他们的肠道微生物群）。这些数据将使我们能够识别与脑功能相关的微生物代谢物，负责其产生的微生物，以及年龄和肥胖对其产生和影响的影响。为了证实这些发现，我们将从第二组个体（共181人，年龄23-66岁）的血液和粪便样本中测量这些相同的化学信使，这些个体的大脑功能和肠道微生物群也已确定。这些人相隔一年提供了两个样本，其中一些样本是由肥胖参与者在减肥前后提供的。这些数据将使我们能够在一组单独的人群中证实我们的初步发现，评估同一个人体内微生物信号的稳定性，以及肥胖和减肥对它们产生的影响。最后，将在啮齿动物中研究这些微生物代谢物影响大脑结构和功能的过程。在这里，老鼠将接受这些化学物质，它们的认知功能将被评估，特定的大脑过程将被测量。这将提供详细的信息，促进我们对肠道微生物如何影响正常的与年龄相关的认知衰退的理解。这将指导制定旨在在衰老和肥胖期间保持健康微生物群（例如，高纤维饮食、益生元和益生菌）的战略，以帮助减少这种下降。

Cognition is a mental process for gaining knowledge and understanding of the world around us, and it usually gets worse with age. This deterioration often coincides with structural and functional changes in the brain. While healthy lifestyles can reduce the rate of age-associated cognitive decline, obesity has been implicated in its acceleration. This is important as obesity rates continue to rise in the UK, peaking in adults aged 45-54 years (36% obese) and remain high in older groups (33.5%, 55-74 years). A vast population of microorganisms are present in the human gut, collectively referred to as the gut microbiota. We, and others have shown that these microorganisms are able to produce chemicals in the gut that can modify processes occurring in the brain with implications for cognition and overall well-being. Importantly, the types of microbes present in the gut and their overall activities change with age and obesity, and we now have preliminary data suggesting that the intestinal microbiota and their chemical output is related to normal age-related cognitive decline. To further investigate this, we will measure the chemicals produced by the gut microbiota in humans of different ages and body mass index (BMI; a measure of obesity) and explore relationships between these signals and brain structure and function. Using different analytical chemistry techniques, we will measure microbial-related molecules in blood and stool samples collected from over 1,000 people (aged 50-98 years). These participants have had their brain structure and function measured as well as the microorganisms present in their stools (reflective of their gut microbiota). This data will allow us to identify microbial metabolites that are associated with brain function, the microorganisms responsible for their production, and the influence of age and obesity on their production and effects. To confirm these findings, we will measure these same chemical messengers in blood and stool samples from a second set of individuals (181 in total; aged 23-66 years) whose brain function and gut microbiota has also been determined. These individuals have provided two samples one year apart with some samples provided by obese participants before and after weight loss. This data will allow us to confirm our initial findings in a separate group of people, assess the stability of microbial signals within the same individual, and the impact of obesity and weight loss on their production. Finally, the processes through which these microbial metabolites affect brain structure and function will be studied in rodents. Here, rats will receive these chemicals and their cognitive functions will be assessed and specific brain processes will be measured. This will provide detailed information that will advance our understanding of how intestinal microorganisms can influence normal age-related cognitive decline. This will guide the development of strategies aimed at preserving a healthy microbiota (for example, high-fibre diets, prebiotics and probiotics) during ageing and in the presence of obesity to help reduce this decline.