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: 8136624
• 负责人: Marguerite Hatch
• 金额: $ 29.69万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8136624
• 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; 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; public health relevance; 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. PUBLIC HEALTH RELEVANCE: The studies proposed will examine the activity and effectiveness of several non-pathogenic bacteria, either individually or combined, to promote intestinal oxalate excretion and degradation in the setting of Primary Hyperoxaluria, Type 1 (PH1) and following bariatric surgery which is associate with hyperoxaluria and kidney stone disease. Especially important and relevant to the present application is the availability of a knockout mouse model that mimics PH1, namely the AGT (alanine-glyoxylate aminotransferase) null mouse as well as an obese rat bariatric surgical model which affords us a unique opportunity to evaluate the interaction between these bacteria and the oxalate-transporting mucosa of the large intestine.

描述（由申请人提供）：在本申请中，我们建议检查益生菌对主动肠道消除和草酸盐管腔降解的促进作用，作为管理两种不同临床实体的方法，这两种临床实体的共同点是尿液中草酸盐排泄增加，导致肾结石形成。 1) 在原发性高草酸尿症 1 型 (PH1) 遗传性疾病中，由于肝酶丙氨酸-乙醛酸转氨酶 (AGT) 缺乏，内源性草酸盐生成增加，除了导致高草酸尿症和草酸钙肾结石形成外，还会导致高草酸尿症和草酸钙肾结石形成。除非早期采取积极的临床治疗，否则会导致草酸盐的组织沉积（草酸中毒）、肾衰竭和死亡。不幸的是，唯一已知的 PH1 治疗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新人群不断出现，该人群肾结石形成的发生率显着增加。除了 PH1 和减肥手术患者群体之外，这种治疗方法的潜在影响如果有效的话，将扩展到更多的特发性草酸钙结石形成者群体，他们约占美国人的 12%，并且与大量的特发性草酸钙结石形成者相关。医疗保健费用。 我们对大鼠和小鼠肠道草酸盐转运的研究得出了一些关键信息，为本文提出的研究提供了方向。首先，大肠是草酸盐攻击大鼠和慢性肾功能衰竭大鼠代偿性肠内排泄草酸盐的主要部位。其次，我们已经证明，底物/草酸盐特异性微生物草酸杆菌仅存在于大肠中，可以通过改变结肠草酸盐转运从吸收到主动分泌/排泄的方向来显着降低尿草酸盐排泄。第三，我们获得了使用 PH1 小鼠模型（AGT 敲除小鼠）进行的初步研究结果，显示草酸杆菌定植的 AGT 敲除小鼠的整个大肠以草酸分泌模式发挥功能，该模式与草酸排泄正常化相关。否则高草酸尿的动物。 其他细菌包括乳酸杆菌。和双歧杆菌属。就其草酸盐降解活性而言，它们是“多面手”，已被证明可以显着减少人类和大鼠的尿草酸盐排泄；然而，目前尚不清楚这些细菌是否可以与肠粘膜相互作用，促进草酸盐转运的变化，类似于草酸杆菌。不管具体的机制如何，也许可以单独或一起利用这些肠道细菌的活性，以减少 PH1 中的草酸盐负担。现在我们拥有 PH1 动物模型以及用于减肥手术的大鼠模型，我们有一个独特的机会来直接解决这些问题并获得有关高草酸尿症治疗的新信息。因此，在目标 1 和 2 中，我们将检验以下假设：由于施用纯培养物或联合培养物后诱导肠内草酸盐消除，AGT KO 小鼠和大鼠减肥手术模型中尿草酸盐排泄可能发生正常化。感兴趣的纯培养物，包括草酸杆菌属、乳杆菌属和双歧杆菌属。在目标 3 中，我们将检验肠道草酸转运蛋白表达模式的补偿性适应可以解释功能变化的假设。这些研究的结果应该揭示一个新的方向，导致开发基于细菌/细菌产品的益生菌系统，促进肠道草酸盐排泄和降解，从而使尿草酸盐排泄正常化。 公共健康相关性：拟议的研究将检查几种非致病性细菌的活性和有效性，无论是单独的还是组合的，以促进原发性高草酸盐尿症，1型（PH1）和减肥手术后肠道草酸盐的排泄和降解。与高草酸尿症和肾结石疾病有关。与本申请特别重要且相关的是模拟 PH1 的敲除小鼠模型，即 AGT（丙氨酸乙醛酸转氨酶）无效小鼠以及肥胖大鼠减肥手术模型，这为我们提供了评估相互作用的独特机会这些细菌和大肠的草酸转运粘膜之间。