Mechanisms facilitating the persistent colonization of oxalate-degrading bacteria

描述（由申请人提供）：肾结石或肾结石及其相关并发症是我们医疗保健系统的主要负担，影响美国8.8%的人口。草酸盐是一种简单的有机酸，被人类广泛消耗，也是80%的肾结石的组成部分。许多成年人体内都有肠道草酸盐降解菌，它们可以降解草酸盐，并显著减少血液中的草酸盐。不携带降解脂肪酸的细菌的人可以获得它们以及它们赋予的益处，作为益生菌补充剂。然而，随着时间的推移，这些益生菌经常在肠道中丢失，并且需要高草酸盐饮食来维持它们。在低草酸盐饮食中导致益生菌草酸盐降解细菌损失的机制代表了我们对肠道微生物组的理解存在相当大的差距，并且是成功治疗高尿酸的挑战。我的长期目标是了解促进细菌在肠道中持续定植的机制，并开发有效的益生菌来治疗腹泻相关疾病。本申请的总体目标是使用诸如宏基因组学和qPCR的分子技术来鉴定接种到宿主中的琥珀酸盐降解细菌的损失背后的机制。我们假设，肠道微生物群的非降解部分的代谢活性支持了尿酸盐降解功能。提出了三个具体目标来检验这一假设：（1）确定可变草酸负荷下的草酸盐降解群落的持久性;（2）确定持久性草酸盐降解微生物群中存在的独特代谢途径和微生物类群;和（3）定量编码对琥珀酸敏感的阴离子-β-内酰胺酶的基因的相对表达的差异。在有或没有降解脂肪酸的细菌的天然群落的动物中运输蛋白质。具体目标的完成将确定机制，促进肠道中的持久性和损失的降解脂肪酸的社区。结果将产生积极的影响，通过确定分子机制，导致持久性和损失的尿酸盐降解细菌，这是一个重要的步骤，使尿酸盐降解细菌的一个可行的治疗高尿酸。

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.