The Influence of the Glucoamylase Inhibitor Acarbose on Bacteroidetes Starch Utilization and Fitness in the Human Gut

摘要 阿卡波糖是FDA批准的用于2型糖尿病患者的药物，可抑制宿主葡糖淀粉酶， 沿着上消化道沿着的酶，负责将淀粉分解成葡萄糖。因此它 减轻餐后高血糖症并有助于改善血糖控制。然而，阿卡波糖显示， 由于其免疫调节和促进作用，有望改善许多其他疾病的症状。 心血管影响尽管阿卡波糖用于治疗各种疾病的前景很好， 知道它是如何激发宿主效应的一种解释在于观察到阿卡波糖改变了 小鼠和人类的肠道微生物群落。尽管如此，还没有发表的报告提供机械的见解 这些变化。因为阿卡波糖治疗后上消化道消化的淀粉较少， 进入大肠，在大肠中被海藻酸钠加工和发酵成短链脂肪酸（SCFA） 细菌由于阿卡波糖被宿主吸收最少，因此它可能与淀粉一起转运到大细胞中。 肠，其中它可能影响用于加工这种多糖的细菌葡糖淀粉酶。最近的数据 表明普通人类肠道定植者在体外对阿卡波糖表现出显著不同生长敏感性 当利用淀粉作为碳源时。一个占主导地位和研究充分的肠道门，拟杆菌，部署 淀粉利用系统，或SUS，识别，处理和输入淀粉，原型系统来自 多形拟杆菌作为模型。该提案的初步工作涉及不同的表型 两个著名的拟杆菌属物种之间的差异：B.多形核对阿卡波糖敏感， 卵形拟杆菌耐药。这一提议将确定这些不同反应的分子基础 并检验了猪的离散分子特征有助于不同拟杆菌生长的假设 抑制和整体健身在ACA的存在。目标1将系统地测试以下可能性： 阿卡波糖差异性地影响Sus酶抑制和寡糖识别和/或转运。目的2 将决定阿卡波糖敏感性在拟杆菌中的分布范围。体外阿卡波糖 表型将与体内适合度和相对丰度进行比较， 人类这些方法的组合将测试体外对阿卡波糖的敏感性转化为 减少肠道细菌的适应性。根据最近的工作，拟议的研究是及时的， 阿卡波糖可影响小鼠的全身信号传导，这是由于微生物群介导的胆汁酸库的改变。 最近的数据还表明，阿卡波糖可能是一个有用的工具，以控制拟杆菌在肠道中的丰度， 与许多疾病的病因学有关的门。由于阿卡波糖对宿主健康有积极影响， 对阿卡波糖如何影响胃肠道细菌生长的机制的理解是有必要的， 为设计其他比阿卡波糖更强或更有针对性的效果的外源性物质奠定了基础。

ABSTRACT Acarbose is an FDA approved medication prescribed to type 2 diabetics and inhibits host glucoamylases, enzymes along the upper gastrointestinal tract responsible for breaking down starch into glucose. As such, it mitigates hyperglycemia after meals and contributes to improved glycemic control. However, acarbose shows promise for ameliorating symptoms in a number of other diseases because of its immunomodulatory and pro- cardiovascular effects. Despite the prospect of re-purposing acarbose to treat a variety of conditions, little is known about how it elicits these host effects. One explanation lies in the observation that acarbose alters the gut microbial community in mice and humans. Still, there are no published reports offering mechanistic insight into these changes. Because less starch is digested in the upper GI tract upon acarbose treatment, it transits to the large intestine where it is processed and fermented into short-chain fatty acids (SCFA) by commensal bacteria. Since acarbose is minimally absorbed by the host, it likely transits with the starch to the large intestine where it might impact bacterial glucoamylases utilized to process this polysaccharide. Recent data suggest that common human gut colonizers exhibit remarkably different growth sensitivities to acarbose in vitro when utilizing starch as a carbon source. A dominant and well-studied gut phylum, the Bacteroidetes, deploys a starch utilization system, or Sus, to recognize, process, and import starch, with the prototypical system from Bacteroides thetaiotaomicron serving as a model. Initial work for this proposal invokes disparate phenotypes between two prominent species of Bacteroidetes: B. thetaiotaomicron is sensitive to acarbose while Bacteroides ovatus is resistant. This proposal will determine the molecular basis for these distinct responses and test the hypothesis that discrete molecular features of Sus contribute to differential Bacteroidetes growth inhibition and overall fitness in the presence of ACA. Aim 1 will systematically test the possibilities that acarbose differentially affects Sus enzyme inhibition and oligosaccharide recognition and/or transport. Aim 2 will determine how widespread acarbose sensitivity is amongst the Bacteroidetes. In vitro acarbose phenotypes will be compared to in vivo fitness and relative abundances by mining metagenomic data-sets from humans. The combination of approaches will test the notion that in vitro sensitivity to acarbose translates to reduced bacterial fitness in the gut. The proposed research is timely in light of recent work suggesting that acarbose may influence whole body signaling in mice due to microbiota mediated alterations in bile acid pools. Recent data also suggests that acarbose may be a useful tool to control Bacteroidetes abundance in the gut, a phylum implicated in the etiology of numerous diseases. Because acarbose positively impacts host health, a mechanistic understanding of how acarbose influences bacterial growth in the GI tract is warranted and will lay a foundation for the design of other xenobiotics with even stronger, or more tailored effects, than acarbose.