Mechanisms for Selective Modulation of Beneficial Human Gut Microbes by Specific Dietary Plant Polysaccharides

 描述(申请人提供)：人体肠道中的微生物深刻影响我们从所吃食物中提取能量和营养的能力。在肥胖的背景下，这种影响越来越受到重视，肥胖困扰着超过三分之一的美国人口，并与严重的医疗并发症有关。肥胖的特征，包括脂肪质量增加和代谢功能障碍，可以传染给定居在肥胖者肠道微生物群中的无菌小鼠，但不会传染给瘦肉者的肠道微生物区系，这提供了肠道微生物群落之间的差异导致疾病的证据。饮食对人类肠道中存在的特定细菌种类有显著影响。无法被宿主衍生的酶消化的膳食植物多糖集中在大肠中，在那里它们为能够降解和消耗它们的微生物提供了竞争优势。在含有纯化碳水化合物的情况下培养的单个肠道细菌物种显示出广泛的碳水化合物降解和消耗能力，这并不能反映体内微生物的丰度。这表明，未知的机制为某些微生物在肠道中代谢特定多糖方面提供了竞争优势。目前，缺乏可用的工具来确定哪些饮食干预可以增加体内有益细菌的丰度，其中与其他微生物的相互作用影响营养的获取和处理。以下目的将检验这样一种假设，即选择性地增加有益细菌物种丰度的饮食植物多糖在体内被这些细菌物种捕获和降解。目的1在体内鉴定能增加特定细菌种类丰度的膳食多糖。初步结果表明，某些饮食多糖可以选择性地增加有益细菌物种的丰度。将筛选更多的多糖，以确定那些最有效和最有选择性的作用。然后，这些多糖将被喂给被来自肥胖人类捐赠者的微生物定居的小鼠，以确定哪些饮食干预措施可以恢复生理和代谢健康。目的2将确定增加有益肠道微生物丰度的饮食多糖是否在体内被这些微生物捕获和降解。一种新的基于质谱学的分析方法将被用来确定在特定微生物存在和不存在的情况下多糖的降解程度。一种新的基于DNA测序的分析将被用于鉴定能够捕获肠道中特定多糖的细菌菌株。这项研究将对决定肠道微生物群落结构和代谢功能的机制有一个基本的了解，并可能为开发基于植物的新型饮食干预措施提供信息，以操纵人类微生物群落以促进健康。

 DESCRIPTION (provided by applicant): The microbes that reside in the human intestine profoundly influence our ability to extract energy and nutrients from the foods we eat. This influence is increasingly appreciated in the context of obesity, which afflicts over 1/3 of the US population and is associated with serious medical complications. Features of obesity, including increased fat mass and metabolic dysfunction, can be transmitted to germ-free mice colonized with the intestinal microbiota of obese individuals, but not that of lean individuals, providing evidence that differences between gut microbial communities contribute to disease. Diet has a marked impact on the particular bacterial species that are present in the human gut. Dietary plant polysaccharides that cannot be digested by host- derived enzymes become concentrated in the large intestine, where they provide a competitive advantage to microbes that can degrade and consume them. Cultures of individual gut bacterial species grown in the presence of purified carbohydrates have revealed broad capacities for carbohydrate degradation and consumption that do not reflect microbial abundances in vivo. This suggests that undefined mechanisms provide certain microbes with a competitive advantage in metabolizing specific polysaccharides in the gut. At present there is a lack of available tools for determining which dietary interventios can increase the abundance of beneficial bacteria in vivo, where interactions with other microbes influence nutrient acquisition and processing. The following aims will test the hypothesis that dietary plant polysaccharides that selectively increase the abundance of beneficial bacterial species are captured and degraded by those bacterial species in vivo. AIM 1 will identify dietary polysaccharides that increase the abundance of specific bacterial species in vivo. Preliminary results suggest that certain dietary polysaccharides can selectively increase the abundance of beneficial bacterial species. Additional polysaccharides will be screened to identify those with the most potent and selective effects. These polysaccharides will then be fed to mice colonized with microbes from obese human donors to determine which dietary interventions restore physiologic and metabolic health. AIM 2 will determine whether dietary polysaccharides that increase the abundance of beneficial gut microbes are captured and degraded by those microbes in vivo. A novel mass spectrometry-based assay will be used to determine the extent of polysaccharide degradation in the presence and absence of specific microbes. A novel DNA sequencing-based assay will be used to identify bacterial strains that capture specific polysaccharides in the gut. This research will provide a basic understanding of the mechanisms that determine gut microbial community structure and metabolic functions, and may inform the development of novel plant-based dietary interventions for manipulating human microbial communities to promote health.