Mechanisms facilitating the persistent colonization of oxalate-degrading bacteria

促进草酸盐降解细菌持续定植的机制

• 批准号: 8996474
• 负责人: Aaron W Miller
• 金额: $ 5.8万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8996474
• 关键词: Acids; Adult; Affect; Animals; Anion Transport Proteins; Apoptosis; Automobile Driving; Bacteria; Biological Models; Blood; Cations; Communities; Complex; Diabetes Mellitus; Diet; Disease; Equilibrium; Exhibits; Exposure to; Gastrointestinal tract structure; Gene Expression; Genes; Genetic; Goals; Growth; Health; Healthcare Systems; Hindgut; Human; Hyperoxaluria; Individual; Integration Host Factors; Intestinal Diseases; Intestines; Kidney; Kidney Calculi; Kidney Diseases; Lead; Lithiasis; Maintenance; Mammals; Metabolic; Metabolic Pathway; Metabolism; Metagenomics; Microbe; Molecular; Obesity; Outcome; Oxalates; Patients; Population; Prevalence; Preventive measure; Probiotics; Protein Family; Rattus; Research; Risk Factors; Role; Sprague-Dawley Rats; Stress; System; Taxon; Techniques; Testing; Time; Tissues; Transplantation; United States; cost; gut microbiome; gut microbiota; improved; loss of function; microbial; microbial community; microbiome; microbiota; organic acid; probiotic supplementation; repaired

DESCRIPTION (provided by applicant): Renal lithiasis, or kidney stones, and associated complications are a major burden on our health care system affecting 8.8% of the population in the United States. Oxalate is a simple organic acid widely consumed by humans and is also a constituent in 80% of all kidney stones. Many adults host intestinal oxalate-degrading bacteria, which can degrade oxalate and significantly reduce the amount circulating in the blood. Individuals who do not host oxalate-degrading bacteria can acquire them and the benefits they confer, as probiotic supplements. However, these probiotics are often lost in the intestines over time, and a high oxalate diet is required for their maintenance. The mechanisms driving the loss of probiotic oxalate-degrading bacteria on a low oxalate diet represents a considerable gap in our understanding of the gut microbiome and is a challenge for the successful treatment of hyperoxaluria. My long-term goal is to understand the mechanisms that facilitate the persistent colonization of bacteria in the gut and develop effective probiotics to treat oxalate-related illnes. The overall objectives of this application are to use molecular techniques such as metagenomics and qPCR to identify the mechanisms behind the loss of oxalate-degrading bacteria inoculated into a host. We hypothesize that the oxalate-degrading function is supported by the metabolic activity of the non- degrading proportion of the gut microbiota. Three specific aims are proposed to test this hypothesis: (1) Determine the persistence of the oxalate-degrading community on variable oxalate loads; (2) Identify the unique metabolic pathways and microbial taxa that are present in persistent oxalate-degrading microbiota; and (3) Quantify the differences in the relative expression of genes encoding for oxalate-sensitive anion-transport proteins in animals with or without natural communities of oxalate-degrading bacteria. Completion of the specific aims will identify the mechanisms facilitating the persistence and loss of oxalate-degrading communities in the gut. Outcomes will have a positive impact by identifying the molecular mechanisms that lead to the persistence and loss of oxalate-degrading bacteria, which is an important step in making oxalate-degrading bacteria a viable treatment for hyperoxaluria.

描述（由申请人提供）：肾脏岩性或肾结石以及相关的并发症是我们的医疗保健系统的重大负担，影响了美国8.8％的人口。草酸盐是一种被人类广泛消耗的简单有机酸，也是所有肾结石的80％的组成部分。许多成年人携带肠道降解细菌，可降解草酸盐并显着减少血液中循环的量。不容纳草酸盐含量的细菌的人可以获取它们以及作为益生菌补充剂所赋予的好处。但是，随着时间的流逝，这些益生菌通常在肠道中流失，维持需要高草酸盐饮食。在低氧饮食中推动益生菌降解细菌丧失的机制是我们对肠道微生物组的理解的巨大差距，这是成功治疗高氧化尿症的挑战。我的长期目标是了解促进肠道中细菌持续定殖的机制，并开发有效的益生菌来治疗与草酸盐相关的Illnes。该应用的总体目标是使用分子技术（例如宏基因组学和QPCR）来识别接种到宿主中的草酸盐降解细菌丧失的机制。我们假设草酸根降解功能由肠道菌群的非降解比例的代谢活性支持。提出了三个特定的目的来检验这一假设：（1）确定草酸盐降解群落在可变的草酸盐负载上的持久性； （2）确定持续的草酸盐降解微生物群中存在的独特代谢途径和微生物分类群； （3）量化有或没有天然降解细菌自然群落的动物中草酸盐敏感阴离子 - 转运蛋白编码基因的相对表达的差异。具体目标的完成将确定促进肠道中草酸盐降解群落的持久性和丧失的机制。结局将通过确定导致草酸根降解细菌的持续性和丧失的分子机制产生积极的影响，这是使草酸盐降解细菌成为高氧甲尿症的可行治疗的重要一步。