Relating impacts of antibiotics on the gut metabolome and microbiome to host physiology and weight

将抗生素对肠道代谢组和微生物组的影响与宿主生理和体重联系起来

基本信息

批准号：
10623244
负责人：
Peter Belenky
金额：
$ 50.31万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10623244
关键词：
Adult American Amoxicillin Animals Antibiotic Therapy Antibiotics Bacteria Bacteroidetes Blood Glucose Butyrates Cellular Metabolic Process Child Clinical Communities Data Diabetes Mellitus Diet Dietary Component Digestive System Disorders Dose Environment Farm Fermentation Firmicutes Genetic Transcription Glucose Goals Health Human Hyperglycemia Inflammation Inflammatory Response Insulin Resistance Intervention Laboratory mice Lead Link Livestock Malnutrition Mediating Metabolic Metabolic dysfunction Metabolism Methodology Morbidity - disease rate Motivation Mus Nutrient Nutrition Disorders Obesity Outcome Penicillins Pharmaceutical Preparations Physiology Probiotics Public Health Publishing Research Signaling Molecule Taxonomy Testing Toxic effect United States National Institutes of Health Vitamins Weight Weight Gain Work Xenobiotics antimicrobial beta-Lactams clinically relevant combat cost dietary fighting gut bacteria gut microbiome health determinants insight metabolome microbial community microbial composition microbiome microbiome alteration microbiome composition microbiota multiple omics nutrient absorption pathobiont pathogen response restoration systemic inflammatory response theories

项目摘要

In the US, the obesity crisis is severe—approximately 40% of American adults and 18.5% of American children are clinically obese. Robust evidence suggests that antibiotic overuse may be one contributing factor. The human gut microbiome is a key determinant of health and one crucial function of this community is to regulate host metabolism by fermenting host-indigestible dietary components. A significant body of work also indicates that in both humans and animals, antibiotic use – and especially the use of penicillins and other β-lactams – is strongly associated with obesity. The mechanism of this antibiotic-associated weight gain is not fully understood, although many theories exist, ranging from the induction of systemic inflammation to the reduction of pathogen burden. Understanding how antibiotic-induced perturbations of the microbiome lead to complications such as obesity is an essential step towards alleviating this problem. The proposed work will contribute to this goal by defining the impacts of antibiotics on the metabolic environment of the murine gut, host metabolite availability, and weight gain. Antibiotics can disrupt the microbiome, but what is less appreciated is that this perturbation is associated with a disruption of the metabolic capacity of gut bacteria and a concomitant perturbation of the gut metabolome. The Belenky Lab has defined the impacts of several clinically-relevant antibiotics on the composition and transcriptional response of the murine microbiome. This previous work identified that antibiotics, specifically amoxicillin, change the composition, transcriptional activity, and the metabolome of the murine cecal microbiome. The resulting microbial community is metabolically deficient, enriched for Bacteroidetes, and devoid of Firmicutes. These changes are associated with reduced cecal glucose, reduced butyrate, elevated blood glucose, systemic inflammation, and weight gain. The core hypothesis of this work is that β-lactam antibiotics contribute to inflammation and obesity by eliminating critical bacteria in the Firmicutes phylum, subsequently inducing metabolic dysfunction. The resulting metabolically-deficient gut microbiome is unable to provide critical nutrients and signaling molecules to reduce inflammation and regulate host metabolism. This hypothesis will be tested in the following three aims: Aim 1 – Determine the impact of clinically-relevant antibiotics on the metabolome and taxonomic composition of the murine gut, host physiology, and weight gain. Aim 2 – Utilize microbial consortia to determine if microbial composition associated with antibiotic therapy is linked to the detected metabolite shifts and host impacts. Aim 3 – Microbiome restoration and diet modulation to reduce antibiotic-induced perturbations of the gut metabolome and weight gain. The insight gained from this work will help to identify methodologies that reduce antibiotic-mediated microbiome disruption and may help to combat the obesity crisis. Antibiotics have been miracle drugs, but now that we understand the significant cost to microbiome function, we must find better ways to use them.

在美国，肥胖危机非常严重——大约 40% 的美国成年人和 18.5% 的美国儿童患有临床肥胖症。强有力的证据表明，抗生素的过度使用可能是影响健康的关键因素之一。该群落的关键功能是通过发酵宿主难以消化的饮食成分来调节宿主新陈代谢。大量研究工作还表明，在人类和动物中，抗生素的使用，尤其是青霉素和抗生素的使用。其他β-内酰胺——与肥胖密切相关，尽管存在许多理论，包括从诱导全身炎症到减少病原体负担等，但这种与抗生素相关的体重增加的机制尚不完全清楚。微生物组导致肥胖等并发症是缓解这一问题的重要一步，这项工作将通过确定抗生素对小鼠肠道代谢环境、宿主代谢物可用性和体重增加的影响来实现这一目标。可以扰乱微生物组，但较少被重视的是，这种扰动与肠道细菌代谢能力的破坏以及肠道代谢组的伴随扰动有关，贝伦基实验室已经定义了几种临床相关抗生素对组成和转录的影响。先前的研究发现抗生素，特别是阿莫西林，会改变小鼠盲肠微生物组的组成、转录活性和代谢组。微生物群落代谢缺陷，拟杆菌门丰富，并且缺乏厚壁菌门，这些变化与盲肠葡萄糖减少、丁酸盐减少、血糖升高、全身炎症和体重增加有关。这项工作的核心假设是β-内酰胺抗生素。通过消除厚壁菌门中的关键细菌，从而导致代谢功能障碍，从而导致炎症和肥胖，由此产生的代谢缺陷的肠道微生物组无法提供关键的营养物质和信号分子来减少炎症。该假设将在以下三个目标中得到检验：目标 1 – 确定临床相关抗生素对小鼠肠道代谢组和分类组成、宿主学和体重增加的影响。确定与抗生素治疗相关的微生物组成是否与检测到的代谢物变化和宿主影响有关。目标 3 – 微生物组恢复和饮食调节，以减少抗生素引起的干扰。从这项工作中获得的见解将有助于确定减少抗生素介导的微生物组破坏的方法，并可能有助于对抗肥胖危机。抗生素一直是神奇的药物，但现在我们了解了抗生素的巨大成本。微生物组的功能，我们必须找到更好的方法来利用它们。