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

 描述（由申请人提供）：驻留在人类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物质的能力。在肥胖症的背景下，这种影响越来越受到重视，肥胖症困扰着超过1/3的美国人口，并与严重的医疗并发症有关。肥胖的特征，包括脂肪量增加和代谢功能障碍，可以传播到无菌小鼠，这些小鼠的肠道微生物群是肥胖个体的肠道微生物群，而不是瘦个体的肠道微生物群，这提供了肠道微生物群落之间差异导致疾病的证据。饮食对人体肠道中存在的特定细菌种类有显著影响。不能被宿主来源的酶消化的膳食植物多糖在大肠中浓缩，在那里它们为可以降解和消耗它们的微生物提供竞争优势。在纯化的碳水化合物存在下生长的单个肠道细菌物种的培养物揭示了碳水化合物降解和消耗的广泛能力，这并不反映体内微生物的丰度。这表明，不确定的机制为某些微生物在肠道中代谢特定多糖提供了竞争优势。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物质的获取和加工。以下目的将测试这样的假设，即选择性地增加有益细菌物种丰度的膳食植物多糖被那些细菌物种在体内捕获和降解。目的1将确定膳食多糖，增加体内特定细菌物种的丰度。初步结果表明，某些膳食多糖可以选择性地增加有益细菌物种的丰度。将筛选其他多糖，以确定那些最有效和选择性的影响。然后将这些多糖喂给来自肥胖人类捐赠者的微生物定植的小鼠，以确定哪些饮食干预可以恢复生理和代谢健康。AIM 2将确定增加有益肠道微生物丰度的膳食多糖是否被这些微生物体内捕获和降解。一种新的基于质谱的测定将用于确定在存在和不存在特定微生物的情况下多糖降解的程度。一种新的基于DNA测序的检测方法将用于鉴定捕获肠道中特定多糖的细菌菌株。这项研究将提供对决定肠道微生物群落结构和代谢功能的机制的基本了解，并可能为开发新型植物性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.