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 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， 沿着上胃肠道的酶负责将淀粉分解成葡萄糖。因此，它 减轻餐后高血糖并有助于改善血糖控制。然而，阿卡波糖显示 由于其免疫调节作用和亲和力，有望改善许多其他疾病的症状 心血管影响。尽管阿卡波糖有望重新用于治疗多种疾病，但进展甚微。 了解它如何引发这些宿主效应。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制方面的见解 融入这些变化。由于阿卡波糖治疗后上胃肠道消化的淀粉较少，因此它会转运 到达大肠，在那里通过共生体加工并发酵成短链脂肪酸（SCFA） 细菌。由于阿卡波糖被宿主吸收的程度极低，因此它很可能与淀粉一起转移到大分子中。 它可能会影响用于处理这种多糖的细菌葡糖淀粉酶。近期数据 表明常见的人类肠道定植者在体外对阿卡波糖表现出显着不同的生长敏感性 当利用淀粉作为碳源时。拟杆菌门是一个占主导地位且经过充分研究的肠道门 淀粉利用系统（Sus），用于识别、加工和进口淀粉，其原型系统来自 多形拟杆菌作为模型。该提案的初步工作涉及不同的表型 拟杆菌门的两个主要物种之间：B. thetaiotaomicron 对阿卡波糖敏感，而 卵形拟杆菌具有耐药性。该提案将确定这些不同反应的分子基础 并检验 Sus 的离散分子特征有助于拟杆菌生长差异的假设 ACA 存在下的抑制和整体适应性。目标 1 将系统地测试以下可能性： 阿卡波糖对 Sus 酶抑制和寡糖识别和/或转运有不同的影响。目标2 将确定拟杆菌中阿卡波糖敏感性的广泛程度。体外阿卡波糖 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。方法的结合将检验阿卡波糖的体外敏感性转化为这一概念 肠道细菌适应性降低。鉴于最近的工作表明，拟议的研究是及时的 由于微生物介导的胆汁酸库的改变，阿卡波糖可能会影响小鼠的全身信号传导。 最近的数据还表明，阿卡波糖可能是控制肠道中拟杆菌丰度的有用工具， 涉及许多疾病的病因学的门。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理解是有必要的，并将奠定基础 为设计比阿卡波糖具有更强或更针对性的效果的其他异生素奠定了基础。