Mechanisms facilitating the persistent colonization of oxalate-degrading bacteria

描述（由申请人提供）：肾性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，影响了美国8.8%的人口。草酸盐是一种简单的有机酸，被人类广泛食用，也是80%肾结石的组成成分。许多成年人肠道中都有降解草酸的细菌，这些细菌可以降解草酸，并显著减少血液中的循环量。没有草酸降解细菌的个体可以获得它们，并作为益生菌补充剂获得它们所带来的好处。然而，随着时间的推移，这些益生菌经常在肠道中丢失，需要高草酸盐饮食来维持它们。低草酸饮食导致草酸降解益生菌流失的机制表明，我们对肠道微生物群的理解存在相当大的差距，这对成功治疗高草酸尿是一个挑战。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草酸盐相关疾病。本应用程序的总体目标是使用宏基因组学和qPCR等分子技术来确定接种到宿主体内的草酸降解细菌损失背后的机制。我们假设草酸降解功能是由肠道微生物群中非降解部分的代谢活动支持的。为了验证这一假设，本文提出了三个具体目标：(1)确定草酸降解群落在不同草酸负荷下的持久性；(2)确定持久的草酸降解微生物群中存在的独特代谢途径和微生物类群；(3)量化在有或没有草酸降解菌天然群落的动物中编码草酸敏感阴离子转运蛋白的基因相对表达的差异。具体目标的完成将确定促进肠道中草酸降解群落的持续和丧失的机制。通过确定导致草酸降解细菌持续存在和丧失的分子机制，结果将产生积极影响，这是使草酸降解细菌成为高草酸尿可行治疗方法的重要一步。

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.