Host-microbiome interactions shape the metabolic effects of ketogenic diets

宿主-微生物组的相互作用塑造生酮饮食的代谢效应

• 批准号: 10583527
• 负责人: Peter James Turnbaugh
• 金额: $ 52.96万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10583527
• 关键词: Actinobacteria class; Adipose tissue; Adult; Affect; Animal Model; Animals; Antimicrobial Effect; Area; Bacteria; Bacterial Genes; Bifidobacterium; Body Weight decreased; Carbohydrates; Cells; Coenzyme A; Collection; Complex; Diet; Enteral; Enterocytes; Esterification; Esters; Extrahepatic; Fatty acid glycerol esters; Future; Genes; Genetic; Genetic Determinism; Gnotobiotic; Goals; Growth; Hepatocyte; High Fat Diet; Human; Immune; Immune system; In Vitro; Inflammatory; Insulin Resistance; Intervention; Intestines; Ketone Bodies; Ketones; Ketoses; Ketosis; Libraries; Lipids; Literature; Macronutrients Nutrition; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Michigan; Mus; Mutagenesis; Obesity; Oral Administration; Pathway interactions; Phenotype; Physiological; Positioning Attribute; Probiotics; Production; Protocols documentation; Publishing; Research; Rodent Model; Role; Series; Shapes; Source; Specificity; Structure; Testing; Tissues; Transgenic Mice; Work; beta-Hydroxybutyrate; carbohydrate metabolism; diet-induced obesity; dietary restriction; experimental study; genetic manipulation; global health; glucose tolerance; gut bacteria; gut inflammation; gut microbiome; gut microbiota; host microbiome; host microbiota; host-microbe interactions; human disease; human model; immune activation; immunoregulation; improved; innovation; ketogenesis; ketogenic diet; liver metabolism; metabolic phenotype; metabolomics; microbiome; microbiome research; mouse genetics; mouse model; novel; pharmacologic; prebiotics; programs; screening; sugar; tool

Obesity and its associated metabolic diseases represent a global health crisis, affecting more than one third of US adults. Studies in humans and animal models indicate that very low-carbohydrate, high-fat ketogenic diets (KDs) promote weight loss, improve glucose tolerance, and decrease insulin resistance and intestinal inflammation. While the primary mechanisms involved are thought to be due to a shift in hepatic metabolism from carbohydrates to lipids, the role of extrahepatic cells in mediating the systemic effects of KDs remains unclear. The goal of this RO1 application (PA-19-056) is to test the hypothesis that diet-induced shifts in the host production of ketone bodies selectively inhibit the growth of gut bacteria leading to a decrease in immune cell activation and improved metabolic phenotypes. Our extensive Preliminary Results, together with the growing body of scientific literature in this area, provide strong support for the scientific premise of our hypothesis. This work is conceptually innovative as it shifts the focus from the direct impact of diet on the gut microbiota to the role of host-microbiota interactions in mediating the effects of common diets used to treat human disease. We believe that these studies are also technically innovative as we will leverage the paired genetic manipulation of the host and the gut microbiome, a general goal that remains elusive in the microbiome field for many areas of study. We will pursue the following Specific Aims: (Aim I) the use of a new transgenic mouse model to test the impact of enteric ketogenesis on the gut microbiota; (Aim II) the use of natural strain collections and transposon mutagenesis to evaluate the specificity and genetic determinants of bacterial sensitivity to ketone bodies; and (Aim III) the use of conventional and gnotobiotic mice to test the role of KD-associated bacterial immune activation in diet-induced obesity. This research plan represents a departure from the current focus of the gut microbiome field on macronutrients, expanding the scope of microbiome studies to assess the importance of host-microbiome interactions in modulating the physiological consequences of a given diet. If successful, these studies could significantly advance our long-term goal of developing microbiome-based strategies to treat metabolic disease, with an emphasis on beneficial interactions that might be harnessed to develop the prebiotics and probiotics of the future.

肥胖及其相关的代谢性疾病是一场全球性的健康危机，影响着超过三分之一的美国成年人。对人类和动物模型的研究表明，非常低碳水化合物、高脂肪生酮饮食（KD）可促进体重减轻、改善葡萄糖耐量、降低胰岛素抵抗和肠道炎症。虽然所涉及的主要机制被认为是由于肝脏代谢从碳水化合物转变为脂质，但肝外细胞在介导KD全身效应中的作用仍不清楚。本RO 1申请（PA-19-056）的目的是检验以下假设：饲料诱导的宿主酮体产生变化选择性抑制肠道细菌生长，导致免疫细胞活化减少和代谢表型改善。我们广泛的初步结果，以及该领域越来越多的科学文献，为我们假设的科学前提提供了强有力的支持。这项工作在概念上是创新的，因为它将重点从饮食对肠道微生物群的直接影响转移到宿主-微生物群相互作用在介导用于治疗人类疾病的常见饮食的影响中的作用。我们相信这些研究在技术上也是创新的，因为我们将利用宿主和肠道微生物组的配对遗传操作，这是微生物组领域许多研究领域的一个总体目标。我们将追求以下具体目标：（目标I）使用新的转基因小鼠模型来测试肠道生酮对肠道微生物群的影响;（目标II）使用天然菌株收集和转座子诱变来评估细菌对酮体敏感性的特异性和遗传决定因素;和（目的III）使用常规和无菌小鼠来测试KD相关的细菌免疫激活在饮食诱导的肥胖中的作用。这项研究计划偏离了目前肠道微生物组领域对常量营养素的关注，扩大了微生物组研究的范围，以评估宿主-微生物组相互作用在调节给定饮食的生理后果方面的重要性。如果成功，这些研究可以大大推进我们开发基于微生物组的策略来治疗代谢疾病的长期目标，重点是可能用于开发未来益生元和益生菌的有益相互作用。

项目成果

Effects of long-term high dose aspartame on body mass, bone strength, femoral geometry, and microbiota composition in a young and aged cohort of male and female mice.

长期高剂量阿斯巴甜对年轻和老年雄性和雌性小鼠的体重、骨强度、股骨几何形状和微生物群组成的影响。

• DOI: 10.1101/2024.01.02.573970
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Cyphert,ErikaL;Liu,Chongshan;Morales,AngieL;Nixon,JacobC;Blackford,Emily;Garcia,Matthew;Cevallos,Nicolas;Turnbaugh,PeterJ;Brito,IlanaL;Booth,SarahL;Hernandez,ChristopherJ
• 通讯作者: Hernandez,ChristopherJ

Human gut bacterial metabolism drives Th17 activation and colitis.

• DOI: 10.1016/j.chom.2021.11.001
• 发表时间: 2022-01-12
• 期刊: Cell host & microbe
• 影响因子: 30.3
• 作者: Alexander M;Ang QY;Nayak RR;Bustion AE;Sandy M;Zhang B;Upadhyay V;Pollard KS;Lynch SV;Turnbaugh PJ
• 通讯作者: Turnbaugh PJ