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，我们提出检查益生菌对草酸盐的主动肠消除和管腔降解的促进作用，作为管理两种不同临床实体的方式，所述两种不同临床实体共同具有导致肾结石形成的草酸盐的尿排泄增加。1)在原发性高尿酸1型（PH 1）遗传疾病中，由于肝酶丙氨酸-乙醛酸转氨酶（AGT）缺乏，导致草酸盐内源性产生增加，导致高尿酸和草酸钙肾结石形成，以及草酸盐组织沉积（草酸盐沉积）、肾衰竭和死亡，除非早期积极的临床治疗。不幸的是，PH 1唯一已知的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尿酸患者的新人群一直在稳步出现，这一人群中肾结石形成的发病率显著增加。除了PH 1和减肥手术患者人群外，如果有效，这种治疗方法的潜在影响将扩展到更大的特发性草酸钙结石形成人群，这些人群占美国人的约12%，并且与大量医疗保健费用相关。 我们对大鼠和小鼠肠道草酸盐转运的研究中出现了几条关键信息，这些信息为本文提出的研究提供了方向。首先，大肠是草酸盐激发大鼠和慢性肾功能衰竭大鼠中草酸盐代偿性肠道排泄的主要部位。第二，我们已经表明，底物/代谢产物特异性微生物，草酸杆菌属，其仅存在于大肠中，可通过改变结肠草酸盐转运的方向从吸收到主动分泌/排泄而显著降低尿草酸盐排泄。第三，我们已经获得的结果，从一个试点研究使用的小鼠模型PH 1（AGT基因敲除小鼠）显示整个大肠的草酸盐细菌定植AGT基因敲除小鼠功能的草酸盐分泌模式，这是与正常化的草酸排泄在其他高尿酸动物。 其他细菌，包括乳杆菌属和双歧杆菌属，就其草酸盐降解活性而言是“多面手”，已被证明可显著减少人类和大鼠的尿草酸盐排泄;然而，尚不清楚这些细菌是否能与肠粘膜相互作用，以促进类似于草酸盐的草酸盐转运变化。不管确切的机制，也许有可能利用这些肠道细菌的活动，无论是单独或一起，以减少PH 1中的草酸负荷。现在，我们有了PH 1的动物模型以及减肥手术的大鼠模型，我们有了一个独特的机会来直接解决这些问题，并获得关于高尿酸治疗的新信息。因此，在目的1和2中，我们将检验以下假设：由于在施用纯培养物或感兴趣的纯培养物的组合（包括草酸盐属物种，乳杆菌属，在目标3中，我们将测试这一假设，即肠道草酸盐转运蛋白表达模式的代偿性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，导致基于细菌/细菌产物的益生菌系统的发展，促进肠道草酸盐排泄和降解，从而使尿草酸盐排泄正常化。 公共卫生相关性：拟议的研究将检查几种非致病性细菌的活性和有效性，无论是单独或组合，以促进肠道草酸盐排泄和降解的设置原发性高尿症，1型（PH 1）和减肥手术后，这是与高尿症和肾结石疾病。与本申请特别重要和相关的是模拟PH 1的敲除小鼠模型，即AGT（丙氨酸-乙醛酸转氨酶）缺失小鼠以及肥胖大鼠减肥手术模型的可用性，这为我们提供了评估这些细菌与大肠的谷氨酸盐转运粘膜之间的相互作用的独特机会。