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

项目总结 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 都是临床肥胖症患者。强有力的证据表明，抗生素的过度使用可能是一个促成因素。人类 肠道微生物群是健康的关键决定因素，这个群落的一个重要功能是调节宿主 通过发酵宿主不能消化的日粮成分进行代谢。大量工作也表明，在 无论是人类还是动物，抗生素的使用--尤其是青霉素和其他~-内酰胺类药物的使用--都是强烈的 与肥胖有关。这种与抗生素相关的体重增加的机制尚不完全清楚，尽管 存在许多理论，从诱导全身炎症到减少病原体负担。 了解抗生素诱导的微生物群扰动如何导致肥胖等并发症 这是缓解这一问题的关键一步。拟议的工作将通过以下方式促进这一目标： 抗生素对小鼠肠道代谢环境、宿主代谢产物利用度、 体重也增加了。抗生素可以破坏微生物群，但人们不太认识到的是，这种干扰是 与肠道细菌代谢能力的紊乱和伴随的肠道紊乱有关 代谢体。贝伦基实验室已经确定了几种与临床相关的抗生素对 小鼠微生物组的组成和转录反应。这项先前的工作发现，抗生素， 特别是阿莫西林，改变小鼠盲肠的成分、转录活性和代谢物 微生物组。由此产生的微生物群落新陈代谢不足，富含类杆菌，而且缺乏 菲尔米库特。这些变化与盲肠血糖降低、丁酸降低、血液升高有关。 葡萄糖、全身炎症和体重增加。这项研究的核心假设是内酰胺类抗生素 导致炎症和肥胖的原因是消除了Firmicuts门中的关键细菌，随后 导致代谢功能障碍。由此产生的代谢缺陷的肠道微生物群无法提供关键的 营养和信号分子，以减少炎症和调节宿主新陈代谢。这一假设将是 目标1--确定临床上相关的抗生素对 小鼠肠道的代谢组和分类组成、宿主生理和体重增加。目标2--利用 微生物联盟，以确定与抗生素治疗相关的微生物组成是否与 检测到代谢物转移和寄主影响。目标3-微生物组修复和饮食调节以减少 抗生素引起的肠道代谢紊乱和体重增加。从这项工作中获得的见解将 帮助确定减少抗生素介导的微生物群破坏的方法，并可能有助于对抗 肥胖危机。抗生素一直是灵丹妙药，但现在我们了解了 微生物组的功能，我们必须找到更好的方法来利用它们。

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.