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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：
10744539
负责人：
Peter Belenky
金额：
$ 9.94万
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/10744539
关键词：
Antibiotics Physiology Weight metabolome microbiome

项目摘要

PROJECT SUMMARY 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 ~-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 ~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.

项目摘要在美国，肥胖危机是严重的-大约40%的美国成年人和18.5%的美国儿童临床上是肥胖的。强有力的证据表明，抗生素的过度使用可能是一个因素。人类肠道微生物组是健康的关键决定因素，该群落的一个关键功能是调节宿主通过发酵宿主不能消化的饮食成分进行代谢。大量的研究也表明，无论是人类还是动物，抗生素的使用，尤其是青霉素和其他内酰胺类抗生素的使用，与肥胖有关。这种与肥胖相关的体重增加的机制尚未完全了解，尽管存在从诱导全身炎症到减少病原体负荷的许多理论。了解抗生素引起的微生物组扰动如何导致肥胖等并发症，这是缓解这一问题的重要一步。拟议的工作将有助于实现这一目标，抗生素对小鼠肠道代谢环境的影响，宿主代谢物的利用率，体重增加抗生素可以破坏微生物组，但不太受重视的是，这种干扰是与肠道细菌代谢能力的破坏和肠道的伴随扰动相关代谢组Belenky实验室已经确定了几种临床相关抗生素对小鼠微生物组的组成和转录应答。先前的研究发现抗生素，特别是阿莫西林，改变小鼠盲肠的组成、转录活性和代谢组微生物组产生的微生物群落代谢缺陷，富含拟杆菌，并且缺乏的Firmicutes这些变化与盲肠葡萄糖减少、丁酸盐减少、血液中葡萄糖、全身炎症和体重增加。这项工作的核心假设是~内酰胺抗生素通过消除厚壁菌门中的关键细菌而导致炎症和肥胖，引起代谢功能障碍。由此产生的代谢缺陷型肠道微生物组无法提供关键的营养素和信号分子，以减少炎症和调节宿主代谢。这一假设将是在以下三个目标中进行测试：目标1 -确定临床相关抗生素对代谢组和分类组成的小鼠肠道，宿主生理学，和体重增加。目标2 -利用微生物联合体，以确定与抗生素治疗相关的微生物组成是否与检测代谢物的转移和宿主的影响。目标3 -微生物组恢复和饮食调节，以减少禁食诱导的肠道代谢紊乱和体重增加。从这项工作中获得的见解将有助于确定减少寄生虫介导的微生物组破坏的方法，肥胖危机抗生素一直是神奇的药物，但现在我们了解到，微生物组功能，我们必须找到更好的方法来使用它们。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxygen and Metabolism: Digesting Determinants of Antibiotic Susceptibility in the Gut.

氧气和代谢：肠道中抗生素易感性的消化决定因素。

DOI：
10.1016/j.isci.2020.101875
发表时间：
2020-12-18
期刊：
iScience
影响因子：
5.8
作者：
Heinzinger LR;Johnson A;Wurster JI;Nilson R;Penumutchu S;Belenky P
通讯作者：
Belenky P

Streptozotocin-Induced Hyperglycemia Is Associated with Unique Microbiome Metabolomic Signatures in Response to Ciprofloxacin Treatment.

DOI：
10.3390/antibiotics11050585
发表时间：
2022-04-27
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
0
作者：
通讯作者：

Trophic level and proteobacteria abundance drive antibiotic resistance levels in fish from coastal New England.

DOI：
10.1186/s42523-023-00236-w
发表时间：
2023-03-06
期刊：
Animal microbiome
影响因子：
4.7
作者：
通讯作者：

Streptozotocin-induced hyperglycemia alters the cecal metabolome and exacerbates antibiotic-induced dysbiosis.

DOI：
10.1016/j.celrep.2021.110113
发表时间：
2021-12-14
期刊：
Cell reports
影响因子：
8.8
作者：
Wurster JI;Peterson RL;Brown CE;Penumutchu S;Guzior DV;Neugebauer K;Sano WH;Sebastian MM;Quinn RA;Belenky P
通讯作者：
Belenky P

Candida albicans Isolates 529L and CHN1 Exhibit Stable Colonization of the Murine Gastrointestinal Tract.

DOI：
10.1128/mbio.02878-21
发表时间：
2021-12-21
期刊：
mBio
影响因子：
6.4
作者：
McDonough LD;Mishra AA;Tosini N;Kakade P;Penumutchu S;Liang SH;Maufrais C;Zhai B;Taur Y;Belenky P;Bennett RJ;Hohl TM;Koh AY;Ene IV
通讯作者：
Ene IV