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

葡糖淀粉酶抑制剂阿卡波糖对拟杆菌淀粉利用和人体肠道适应性的影响

• 批准号: 10329912
• 负责人: Haley Ann Brown
• 金额: $ 7.13万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10329912
• 关键词: Acarbose; Affect; Aging; Anaerobic Bacteria; Bacteria; Bacteroides; Bacteroides fragilis; Bacteroides thetaiotaomicron; Bacteroidetes; Bile Acids; Binding; Binding Proteins; Biochemical; Bioinformatics; Biological Assay; Blood Glucose; Carbon; Cardiovascular Diseases; Chemical Structure; Colitis; Colon; Colorectal Cancer; Communities; Consumption; Data; Data Set; Diabetes Mellitus; Dietary Fiber; Digestion; Disease; Drug Prescriptions; Drug usage; Enzyme Inhibition; Enzyme Kinetics; Enzymes; Etiology; Exhibits; FDA approved; Foundations; Gastrointestinal tract structure; Glucan 1,4-alpha-Glucosidase; Glucose; Glycosides; Goals; Growth; Health; Health Benefit; Human; Hyperglycemia; Immune System Diseases; Impairment; In Vitro; Investigation; Large Intestine; Light; Longevity; Mediating; Metabolic; Metabolism; Metagenomics; Methods; Microbe; Microbiology; Mining; Modeling; Molecular; Molecular Diagnosis; Molecular Genetics; Mus; Natural Products; Non-Insulin-Dependent Diabetes Mellitus; Oligosaccharides; Organ; Outcome; Output; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Polysaccharides; Process; Protein Biochemistry; Proteins; Publishing; Reporting; Research; Resistance; Signal Transduction; Source; Starch; System; Testing; Time; Tissues; Toxic effect; Translating; Type 2 diabetic; Upper digestive tract structure; Volatile Fatty Acids; Work; Xenobiotics; bacterial fitness; base; cardiovascular effects; commensal bacteria; design; experimental study; fitness; glucose metabolism; glycemic control; gut bacteria; gut microbiota; immune function; immunoregulation; improved; in vivo; inhibitor; insight; member; metagenome; microbial; microbiome; microbiota; pathogen; prevent; receptor; reduce symptoms; response; skills; tool

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.

抽象的 Acarbose是FDA批准的药物，该药物规定了2型糖尿病患者，并抑制宿主葡萄糖酶， 沿着胃肠道的酶负责将淀粉分解为葡萄糖。因此，它 饮食后缓解高血糖，并有助于改善血糖控制。但是，Acarbose显示 由于其免疫调节性和促进性而有望减轻许多其他疾病的症状 心血管效应。尽管有重新使用Acarbose来治疗各种疾病的前景，但很少 知道它如何引起这些宿主效应。一种解释在于观察到，acarbose改变了 小鼠和人类中的肠道微生物群落。尽管如此，没有提供机械洞察力的已发表报告 进入这些变化。因为在阿卡巴塞治疗后，在胃肠道上的上胃肠道中消化了较少的淀粉，所以它过渡了 通过Comensal加工并发酵成短链脂肪酸（SCFA）的大肠 细菌。由于Acarbose被宿主最少吸收，因此它可能与淀粉交通到大 肠可能会影响用于处理该多糖的细菌葡萄糖酶。最新数据 表明普通的人类肠道殖民者表现出与体外acarbose的生长敏感性明显不同 当利用淀粉作为碳源时。杆菌的主​​导且研究充分的肠道门，部署 淀粉的利用系统或SUS，以识别，处理和进口淀粉，并从中使用原型系统 细菌的thetaiotaomicron作为模型。该建议的初始工作调用不同的表型 在两种突出的细菌植物中：B。thetaiotaomicron对acarbose敏感，而 细菌卵形具有抗性。该建议将确定这些不同响应的分子基础 并检验以下假设，即SUS的离散分子特征有助于差异细菌生长 在ACA存在下的抑制和整体适应性。 AIM 1将系统地测试 Acarbose会差异地影响SUS酶抑制和寡糖识别和/或运输。目标2 将确定种类群中广泛的acarbose敏感性。体外Acarbose 通过挖掘宏基因组数据集，将表型与体内适应性和相对丰度进行比较 人类。方法的组合将测试以下观点：体外对acarbose的敏感性转化为 肠道中的细菌健身降低。拟议的研究是及时的，鉴于最近的工作表明 由于微生物群介导的胆汁酸池的改变，阿卡布斯可能会影响小鼠的全身信号传导。 最近的数据还表明，Acarbose可能是控制肠中菌群丰度的有用工具，A 门与许多疾病的病因有关。由于Acarbose积极影响宿主健康，所以 有必要对Acarbose如何影响胃肠道细菌生长的机械理解，并将置于 与Acarbose相比，具有更强或更量身定制的效果的其他异生元的设计基础。