Probiotic-Induced Elimination of Oxalate to treat Hyperoxaluria

益生菌诱导消除草酸盐治疗高草酸尿症

• 批准号: 8719418
• 负责人: Marguerite Hatch
• 金额: $ 4.62万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719418
• 关键词: APPBP2 gene; Accounting; Address; Alanine-glyoxylate aminotransferase; American; Animal Model; Animals; Bacteria; Bariatrics; Bifidobacterium; Body Burden; Calcium Oxalate; Calculi; Carrier Proteins; Cells; Cessation of life; Chronic Kidney Failure; Clinical; Clinical Management; Colon; Consensus; Deposition; Development; Diet; Dietary Supplementation; Disease; Distal; Effectiveness; Ensure; Enteral; Enzymes; Epithelial; Equilibrium; Excretory function; Food; Gastric Bypass; Gene Family; General Practitioners; Goals; Health Care Costs; Hereditary Disease; Human; Hyperoxaluria; Incidence; Intestinal Mucosa; Intestines; Kidney; Kidney Calculi; Kidney Failure; Kidney Transplantation; Knockout Mice; Lactobacillus; Large Intestine; Liver; Maintenance; Mammals; Measures; Metabolic; Metabolism; Modeling; Movement; Mucous Membrane; Mus; Obesity; Oxalates; Oxalobacter; Patients; Pattern; Pharmacological Treatment; Pilot Projects; Population; Primary Hyperoxaluria; Probiotics; Production; Rattus; Renal Tissue; Site; Source; Surgical Models; System; Techniques; Testing; Therapeutic; Time; Tissues; Urine; Water; Weight; Western Blotting; absorption; alanine-glyoxylate transaminase 1; bariatric surgery; base; dietary restriction; drinking; effective therapy; human disease; hypercalciuria; interest; intestinal epithelium; liver metabolism; mRNA Expression; member; microbial; microorganism; mouse model; novel; oxalosis; patient population; protein expression; solute; urinary

DESCRIPTION (provided by applicant): In this application we are proposing to examine the promotion of active intestinal elimination and luminal degradation of oxalate by probiotics as a way of managing two different clinical entities having in common an increased urinary excretion of oxalate leading to kidney stone formation. 1) In the genetic disease of Primary Hyperoxaluria Type 1 (PH1), an increased endogenous production of oxalate, due to a deficiency of the liver enzyme alanine-glyoxylate aminotransferase (AGT), results in hyperoxaluria and calcium oxalate kidney stone formation in addition to tissue deposition of oxalate (oxalosis), renal failure and death unless early aggressive clinical management is instigated. Unfortunately, the only known cure for PH1 is a liver or liver-kidney transplant. 2) A new population of hyperoxaluric patients who have undergone bariatric surgery for obesity has been steadily emerging and the increased incidence of kidney stone formation in this group is significant. In addition to the population of patients with PH1 and bariatric surgery, the potential impact of this therapeutic approach, if effective, will extend to a much larger population of idiopathic calcium oxalate stone formers who comprise ~12% of Americans and is associated with a substantial health care cost. Several key pieces of information have emerged from our studies of intestinal oxalate transport in rats and mice have provided the direction for the studies proposed here. First, the large intestine is the primary site for compensatory enteric excretion of oxalate in oxalate-challenged rats and in rats with chronic renal failure. Second, we have shown that the substrate/oxalate-specific microorganism, Oxalobacter sp., which resides exclusively in the large intestine, can significantly lower urinary oxalate excretion by altering the direction of colonic oxalate transport from absorption to active secretion/excretion. Third, we have acquired results from a pilot study using a mouse model of PH1 (AGT knockout mouse) showing the entire large intestine of the Oxalobacter-colonized AGT knockout mouse functions in an oxalate secretory mode that is correlated with a normalization of oxalate excretion in otherwise hyperoxaluric animals. Other bacteria including Lactobacillus sp. and Bifidobacterium sp. that are "generalists" in terms of their oxalate-degrading activity have been demonstrated to significantly reduce urinary oxalate excretion in humans and in rats; however, it is not known whether these bacteria can interact with the intestinal mucosa to promote changes in oxalate transport similar to Oxalobacter. Regardless of the precise mechanism, perhaps it is possible to exploit the activities of these intestinal bacteria, either individually or together, in order to reduce the oxalate burden in PH1. Now that we have an animal model of PH1 as well as a rat model for bariatric surgery, we have a unique opportunity to directly address these questions and obtain novel information regarding a treatment for hyperoxaluria. Thus in Aims 1 and 2 we will test the hypothesis that normalization of urinary oxalate excretion can occur in AGT KO mice and in the rat bariatric surgical model due to an induction of enteric oxalate elimination following the administration of either a pure culture or a combination of pure cultures of interest, including Oxalobacter sp., Lactobacillus sp., and Bifidobacterium sp. In Aim 3, we will test the hypothesis that compensatory adaptations in the expression patterns of intestinal oxalate transport proteins can explain changes in function. The results from these studies should reveal a novel direction leading to the development of a probiotic system based upon bacteria/bacterial products that promote both enteric oxalate excretion and degradation thereby normalizing urinary oxalate excretion.

描述(申请人提供)：在这项申请中，我们建议研究益生菌促进草酸的主动肠道消除和腔内降解，作为一种管理两种不同临床实体的方式，这两种不同的临床实体都有共同的尿草酸排泄增加，导致肾结石形成。1)在原发性高草酸尿症1型(PH1)的遗传病中，由于肝酶丙氨酸乙二酸氨基转移酶(AGT)的缺乏，内源性草酸生成增加，导致高草酸尿和草酸钙肾结石形成，以及草酸(草酸中毒)的组织沉积、肾功能衰竭和死亡，除非及早采取积极的临床治疗。不幸的是，唯一已知的治疗PH1的方法是肝脏或肝肾移植。2)因肥胖而接受减肥手术的高草酸尿症患者的新群体正在稳步出现，这一群体的肾结石形成的发生率显著增加。除了PH1和减肥手术的患者群体外，如果有效，这种治疗方法的潜在影响将延伸到更多的特发性草酸钙结石患者，他们约占美国人的12%，并与巨额医疗费用相关。我们对大鼠和小鼠肠道草酸转运的研究中出现了几个关键信息，为这里提出的研究提供了方向。首先，在草酸盐攻击的大鼠和慢性肾功能衰竭大鼠中，大肠是草酸的代偿性肠道排泄的主要部位。其次，我们已经证明了底物/草酸专一性微生物草酸草杆菌，它只存在于大肠，通过改变结肠草酸的运输方向，从吸收到活跃的分泌/排泄，可以显著降低尿草酸的排泄。第三，我们已经获得了使用PH1(AGT基因敲除小鼠)小鼠模型的初步研究结果，该结果显示了被草酸杆菌定居的AGT基因敲除小鼠的整个大肠功能处于草酸分泌模式，这与其他高草酸动物草酸排泄的正常化相关。其他细菌包括乳杆菌属。和双歧杆菌属。就其草酸降解活性而言，这些细菌是“多面手”，已被证明可显著减少人类和大鼠的尿草酸排泄；然而，尚不清楚这些细菌是否能与肠道粘膜相互作用，促进类似于草酸杆菌的草酸运输的变化。不管确切的机制是什么，或许可以单独或共同利用这些肠道细菌的活性，以减少PH1中的草酸负担。既然我们已经有了PH1的动物模型和减肥手术的大鼠模型，我们就有了一个独特的机会来直接解决这些问题，并获得关于高草酸尿治疗的新信息。因此，在目标1和2中，我们将测试这一假设，即在AGT KO小鼠和大鼠减肥手术模型中，由于在给药纯培养物或感兴趣的纯培养物的组合(包括草杆菌、乳杆菌和双歧杆菌)后诱导肠道草酸消除，可以发生尿草酸排泄正常化。在目标3中，我们将检验这样一个假设，即肠道草酸运输蛋白表达模式的代偿适应可以解释功能的变化。这些研究的结果应该揭示一个新的方向，导致以细菌/细菌产品为基础的益生菌系统的发展，促进肠道草酸排泄和降解，从而使尿草酸排泄正常化。