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

在美国，肥胖危机是严重的——大约40%的美国成年人和18.5%的美国儿童被诊断为肥胖。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，该群落的一个关键功能是通过发酵宿主不消化的饮食成分来调节宿主的代谢。大量的研究还表明，在人类和动物中，抗生素的使用——尤其是青霉素和其他β-内酰胺类药物的使用——与肥胖密切相关。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。了解抗生素引起的微生物组紊乱如何导致肥胖等并发症是缓解这一问题的重要一步。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，拟议的工作将有助于实现这一目标。抗生素可以破坏微生物群，但人们不太了解的是，这种扰乱与肠道细菌代谢能力的破坏和肠道代谢组的伴随扰动有关。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组成和转录反应的影响。这项先前的工作发现抗生素，特别是阿莫西林，改变了小鼠盲肠微生物组的组成、转录活性和代谢组。由此产生的微生物群落代谢不足，富含拟杆菌门，缺乏厚壁菌门。这些变化与盲肠葡萄糖降低、丁酸降低、血糖升高、全身炎症和体重增加有关。本研究的核心假设是β-内酰胺类抗生素通过消除厚壁菌门中的关键细菌，进而诱导代谢功能障碍，从而导致炎症和肥胖。由此导致的代谢缺陷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和调节宿主代谢。这一假设将在以下三个目标中得到验证：目标1 -确定临床相关抗生素对小鼠肠道代谢组和分类学组成、宿主生理和体重增加的影响。目的2 -利用微生物联合体来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转移和宿主影响有关。目的3 -微生物组恢复和饮食调节减少抗生素引起的肠道代谢组紊乱和体重增加。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。抗生素一直是一种神奇的药物，但现在我们知道了微生物群功能的巨大成本，我们必须找到更好的方法来使用它们。

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.