Modulation of the Intestinal Microbiome in Obesity by a High Protein Diet

高蛋白饮食对肥胖症肠道微生物组的调节

• 批准号: 10409701
• 负责人: Jonathan Patrick Jacobs
• 金额: --
• 依托单位: VA GREATER LOS ANGELES HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10409701
• 关键词: 16S ribosomal RNA sequencing; Affect; Animal Model; Bacterial Genes; Bioinformatics; Body Weight decreased; Body fat; Body mass index; C-reactive protein; Caloric Restriction; Calories; Carbohydrates; Clinical; Clinical Research; Clinical Trials; Complement; Data; Development; Diet; Dietary Intervention; Fatty Liver; Fatty acid glycerol esters; Feces; Freezing; Funding; Gastrointestinal Hormones; Gastrointestinal Physiology; Genes; Germ-Free; Glucagon; Glycosylated hemoglobin A; Gnotobiotic; Hormones; Human; Hunger; Intervention; Kinetics; Leptin; Lipids; Los Angeles; Mediating; Medical; Medical center; Mentors; Mentorship; Metabolic; Metabolic syndrome; Metagenomics; Microbe; Mus; Obesity; Overweight; Pancreatic Polypeptide; Peptide YY; Physiological; Physiology; Play; Positioning Attribute; Predisposition; Proteins; Public Health; Publications; Randomized; Reporting; Research; Research Personnel; Research Project Grants; Rodent Model; Role; Sampling; Satiation; Shotguns; System; Testing; Therapeutic; Therapeutic Uses; Time; Training; Veterans; Weight; Weight Gain; Weights and Measures; base; career development; clinical efficacy; clinical infrastructure; clinical predictors; diet-induced obesity; dietary; dietary restriction; experimental study; fecal microbiome; ghrelin; glucagon-like peptide 1; glucose tolerance; gut microbiome; gut microbiota; human microbiota; innovation; insight; insulin sensitivity; metabolic phenotype; metabolome; metabolomics; metagenome; microbial; microbial composition; microbiome; microbiome alteration; microbiome research; microbiota; novel; obese patients; obese person; obesity treatment; pre-clinical; predicting response; research study; response; response biomarker; skills; stool sample; translational study; treatment response; western diet

ABSTRACT A high protein diet has been shown in preclinical rodent models and clinical trials to be an effective obesity treatment that is associated with greater loss of body weight and fat mass and increased satiety compared to isocaloric standard protein diets. However, the mechanisms of this response have not been fully elucidated. I recently demonstrated in a rodent model that a high protein diet induces shifts in the intestinal microbiome including a bloom of Akkermansia muciniphila, a microbe reported to have an anti-obesity effect. Based on these preliminary studies, I hypothesize that a high protein diet induces alterations in the intestinal microbiome that mediate its clinical efficacy for obesity. To test this, I will study 216 overweight and obese Veterans (BMI 27-40) who will be randomized 1:1 to isocaloric high protein (30%) or normal protein (15%) 1500 calorie diets for 16 weeks utilizing existing clinical infrastructure at the West Los Angeles VA Medical Center established for a recently completed clinical trial of a high protein diet. In Aim 1, the effect of a high protein diet on the composition and function of the intestinal microbiome will be assessed by 16S rRNA sequencing, shotgun metagenomics, and metabolomics. I predict that following a high protein diet, there will be a major shift in the composition of the intestinal microbiome to favor colonization with Akkermansia and other microbes that promote fat loss compared to the normal protein diet. I anticipate that this change in microbial composition will be associated with alterations in the metagenome – including reduced abundance of bacterial genes involved in carbohydrate utilization – and the metabolome. A total of 11 fecal samples will be collected during the study period to determine the kinetics of microbial changes. In Aim 2, fecal microbial, metagenomic, and metabolomic predictors of response to a high protein diet will be identified. Response will be measured by weight loss, reduced body fat, decreased hepatic steatosis, altered lipid profiles, reduced hemoglobin A1c, decreased high sensitivity C-reactive protein, and increased satiety. Predictors will be generated using the baseline microbiome data as well as samples collected at each time point during treatment. I will also evaluate whether specific microbes, genes, and metabolites are associated with circulating levels of hormones affecting satiety (leptin, ghrelin glucagon, glucagon-like peptide-1, peptide YY, and pancreatic polypeptide). In Aim 3, germ-free mice will be colonized with fresh frozen feces obtained at baseline or after 16 weeks of dietary intervention to establish a causal relationship between alteration of the microbiome on a high protein diet and susceptibility to obesity. These humanized gnotobiotic mice will be placed on a Western diet to induce obesity and compared for weight gain, body fat accumulation, insulin sensitivity, and satiety/hunger hormone levels. In parallel, mice with pre-existing diet-induced obesity will be colonized with post-dietary intervention human microbiota and placed on a standard diet. Weight loss, body fat reduction, insulin sensitivity, and hormone levels will be compared between the two groups. The results of the proposed study will provide insight into the specific microbes that drive the clinical response to a high protein diet and may identify candidate anti-obesity microbes that could be further developed into novel microbial therapeutics.

抽象的 临床前啮齿动物模型和临床试验中已经显示出高蛋白质饮食是有效的肥胖症 与更大的体重和脂肪质量减少以及与饱腹感相比增加的治疗 等量平衡的标准蛋白质饮食。但是，这种反应的机制尚未完全阐明。我 最近在啮齿动物模型中证明了高蛋白质饮食会诱导肠道微生物组的变化 包括akkermansia粘膜的花朵，据报道具有抗肥胖作用的微生物。基于 这些初步研究，我假设高蛋白质饮食会引起肠道微生物组的改变 这介导了其肥胖症的临床效率。为了测试这一点，我将研究216个超重和肥胖的退伍军人（BMI） 27-40）谁将被随机分配给等级高蛋白（30％）或正常蛋白（15％）1500卡路里饮食 使用现有的弗吉尼亚州弗吉尼亚州医疗中心的现有临床基础设施为16周 最近完成的高蛋白饮食临床试验。在AIM 1中，高蛋白饮食对 肠道微生物组的组成和功能将通过16S rRNA测序评估 宏基因组学和代谢组学。我预测，在高蛋白质饮食之后，将会发生重大转变 肠道微生物组的组成，有利于akkermansia和其他微生物定植 与正常蛋白质饮食相比，促进脂肪损失。我预计微生物组成的这种变化将会 与元基因组的改变有关 - 包括涉及细菌基因的丰度 在碳水化合物的利用中 - 代谢组。研究期间总共收集了11个粪便样品 确定微生物变化动力学的时期。在AIM 2中，粪便微生物，宏基因组和 将确定对高蛋白饮食反应的代谢组预测指标。响应将通过 体重减轻，体内脂肪减少，肝脂肪变性减少，脂质谱改变，血红蛋白A1c减少， 降低了高灵敏度C反应蛋白，并增加了饱腹感。将使用 基线微生物组数据以及处理过程中每个时间点收集的样品。我也会评估 特定的微生物，基因和代谢产物是否与影响激素的循环水平有关 饱腹感（瘦素，生长素素胰高血糖素，胰高血糖素样肽-1，胡椒YY和胰多肽）。在AIM 3中， 无菌小鼠将用基线或饮食16周后获得的新鲜冷冻粪便殖民 干预措施以建立微生物组在高蛋白饮食上的改变与 对肥胖症的敏感性。这些人源化的gnotobiotic小鼠将被放在西方饮食上以影响肥胖症 并比较体重增加，体内脂肪的积累，胰岛素敏感性和饱腹感/饥饿激素水平。在 平行于饮食诱发的肥胖症的小鼠将通过术后干预殖民 微生物群并以标准饮食进行。体重减轻，减轻体内脂肪，胰岛素敏感性和马酮 两组之间将比较水平。拟议研究的结果将为您洞悉 促进高蛋白质饮食的临床反应并可能识别候选抗肥胖的特定微生物 可以进一步发展为新型微生物疗法的微生物。