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.

摘要