Diet-microbe interactions modulating host energy balance

饮食-微生物相互作用调节宿主能量平衡

基本信息

批准号：
10478121
负责人：
Jordan Adam Bisanz
金额：
$ 24.87万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10478121
关键词：
Acute Disease Adult Advisory Committees Affect Americas Animals Antibiotics Award Bile Acid Biosynthesis Pathway Bile Acids Body Weight decreased Body fat Caloric Restriction Calories Cell Culture Techniques Cell physiology Centers for Disease Control and Prevention (U.S.)Child Clostridium difficile Communicable Diseases Communities Data Development Diagnostic Diet Dietary Intervention Disease Ecology Energy Intake Energy Metabolism Environment Environmental Risk Factor Gastrointestinal tract structure Gene Expression Profile Germ-Free Gnotobiotic Goals Health Human Individual Infection Intervention Intestines Knock-out Link Macronutrients Nutrition Measures Metabolic Metabolic Diseases Metabolism Metagenomics Methodological Studies Methods Microbe Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Nutrient Obesity Organism Organoids Pathogenesis Pathogenicity Phase Phenotype Play Population Positioning Attribute Prevention Public Health Quality of life Reproduction spores Research Role Shotguns Stroke Structure System Testing Toxic effect Toxin Training United States Work antibiotic-associated diarrhea base bile acid metabolism clinical practice combinatorial cost design diet-induced obesity energy balance experimental study fecal transplantation glucose tolerance gut microbiome gut microbiota heart disease risk host-microbe interactions human subject humanized mouse in vitro Model intestinal epithelium intestinal homeostasis member metabolomics microbial microbial community microbiome microbiome research microbiota mouse model mutant new therapeutic target novel novel therapeutic intervention nutrient absorption nutrition pathobiont pathogen post-transplant programs reconstruction skills uptake weight maintenance

项目摘要

PROJECT SUMMARY/ABSTRACT Obesity affects approximately 35% of adults and 17% of children in the United States increasing the risks of heart disease, stroke and type 2 diabetes. The human gut microbiota, the trillions of microbes that inhabit the gastrointestinal tract, have been implicated as an environmental factor linked to obesity and energy balance; however, the mechanisms are not fully understood. Diet remains the first line intervention to induce weight loss, but its impact on the microbiota, and how this may affect weight loss and regain remain unclear. My preliminary results from a very-low calorie diet intervention in human subjects reveal that caloric restriction induces antibiotic-like disturbances in microbiota composition and function. Fecal transplant from post-diet humans to germ-free mice induces weight loss. Analysis of both human and mouse microbiotas revealed that the diet-induced reconfiguration of the microbiota allowed for expansion of Clostridioides [Clostridium] difficile, best known as a major cause of antibiotic-associated diarrhea and its severe complications. In a colonization model, C. difficile was sufficient to drive weight loss, reduce body fat, and increase glucose tolerance without causing acute disease. These observations have led to the hypothesis that diet interactions with the gut microbiota and C. difficile disrupt nutrient uptake contributing to energy imbalance. The first aim of these studies will focus on the ability of C. difficile to affect host energy balance while characterizing the mechanisms through which it occurs. Preliminary data strongly implicates the C. difficile toxins TcdA and/or TcdB. Using combinatorial and individual knockouts, the causative toxin will be identified and its effects on host energy balance will be extensively characterized. To define the mechanisms through which C. difficile acts at the level of the intestinal epithelium, the effect of sub-toxic purified toxin(s) on nutrient absorption and cell physiology will be examined in organoid models of both the human and mouse intestine. Finally, the ability of asymptomatic colonization to counter diet-induced obesity will be examined. The second aim of this work will examine the mechanism through which caloric restriction affects C. difficile permissibility. Specifically, this aim will test the hypothesis that caloric restriction depletes microbes that produce C. difficile-inhibitory secondary bile acids. Through a humanized mouse model of caloric restriction, and sequence-guided isolation and metabolic characterization, synthetic communities will be designed replicating diet-responsive microbes to specifically test the role of secondary bile acid biosynthesis, and potentially identify new antagonistic interactions which are of great relevance to C. difficile treatment and prevention. The proposed experiments in these aims will leverage my expertise in the microbiome field with new training in obesity and metabolic disease research. An expert interdisciplinary advisory committee, and an institutional focus on microbiome and metabolism research, will provide the ideal environment for the proposed scientific and professional development leading to the creation of an independent research program.

项目概要/摘要在美国，肥胖影响着大约 35% 的成年人和 17% 的儿童，增加了肥胖的风险心脏病、中风和 2 型糖尿病。人类肠道微生物群，栖息在肠道中的数万亿微生物胃肠道，被认为是与肥胖和能量平衡相关的环境因素；然而，其机制尚不完全清楚。饮食仍然是诱导体重的一线干预措施体重减轻，但它对微生物群的影响，以及这如何影响体重减轻和恢复仍不清楚。我的对人类受试者进行极低热量饮食干预的初步结果表明，热量限制引起微生物群组成和功能的抗生素样干扰。饮食后粪便移植人类对无菌小鼠的研究会导致体重减轻。对人类和小鼠微生物群的分析表明饮食诱导的微生物群重组使得艰难梭菌 [Clostridium] difficile 得以扩张，众所周知，它是抗生素相关性腹泻及其严重并发症的主要原因。在殖民时期模型中，艰难梭菌足以推动体重减轻、减少体内脂肪并增加葡萄糖耐量，而无需引起急性疾病。这些观察结果得出这样的假设：饮食与肠道相互作用微生物群和艰难梭菌会破坏营养吸收，导致能量失衡。这些的第一个目标研究将重点关注艰难梭菌影响宿主能量平衡的能力，同时表征其机制它通过它发生。初步数据强烈暗示艰难梭菌毒素 TcdA 和/或 TcdB。使用组合和个体敲除，将识别致病毒素及其对宿主能量的影响平衡将得到广泛的表征。定义艰难梭菌在水平上发挥作用的机制肠上皮细胞的亚毒性纯化毒素对营养吸收和细胞生理学的影响将在人类和小鼠肠道的类器官模型中进行检查。最后，无症状感染者的能力将检查对抗饮食引起的肥胖的定植。这项工作的第二个目标将检查热量限制影响艰难梭菌允许性的机制。具体而言，该目标将测试假设热量限制会消耗产生艰难梭菌抑制性次级胆汁酸的微生物。通过热量限制的人源化小鼠模型以及序列引导的分离和代谢表征，合成群落将被设计复制饮食响应微生物，以专门测试次级胆汁酸生物合成的作用，并可能识别新的拮抗相互作用与艰难梭菌的治疗和预防密切相关。这些目标所提出的实验将利用我在微生物组领域的专业知识与肥胖和代谢疾病研究方面的新培训。一个跨学科专家咨询委员会，以及微生物组和代谢研究的机构重点，将为拟议的科学和专业发展提供理想的环境，从而实现创建独立的研究计划。