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

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一个促成因素。人体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通过发酵宿主不能消化的饮食成分来调节宿主的新陈代谢。大量研究还表明，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。尽管有许多理论，从诱导全身炎症到减少病原体负担，但这种与抗生素相关的体重增加的机制尚不完全清楚。了解抗生素诱导的微生物群扰动是如何导致肥胖等并发症的，是缓解这一问题的关键一步。这项拟议的工作将通过确定抗生素对小鼠肠道代谢环境、宿主代谢物利用率和体重增加的影响来促进这一目标。抗生素可以破坏微生物群，但人们较少意识到的是，这种干扰与肠道细菌代谢能力的破坏和伴随的肠道代谢组的干扰有关。贝伦基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反应的影响。这项先前的工作发现，抗生素，特别是阿莫西林，可以改变小鼠盲肠微生物组的组成、转录活性和代谢产物。由此产生的微生物群落在新陈代谢方面存在缺陷，富含类杆菌，而缺乏菲米库特。这些变化与盲肠血糖降低、丁酸降低、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-内酰胺类抗生素通过消除Firmicuts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群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组成、宿主生理和体重增加的影响。目的2-利用微生物联盟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-微生物组修复和饮食调节以减少抗生素对肠道代谢组的干扰和体重增加。从这项工作中获得的洞察力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。抗生素一直是灵丹妙药，但现在我们了解了微生物组功能的巨大成本，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.