Microbiome-Derived Therapeutic Targets for Chronic Kidney Disease

项目摘要 慢性肾脏病（CKD），肾功能的进行性下降，是一个日益严重的健康问题：13% 在美国，有10%的成年人患有CKD，2%的晚期病例发生在儿童中。儿童CKD是毁灭性的， 死亡率是普通儿科人群的30倍。在40%的病例中，CKD导致不可逆的 肾功能丧失、终末期肾病（ESRD）。对于终末期肾病，除了透析和肾移植， 不存在治疗。对于0-14岁接受透析的儿童， 预期寿命只有20年。CKD 增加体液中的尿素水平，导致肠道中含尿素酶的细菌占优势。等 生态失调导致含氮废物的消耗减少和上皮屏障的侵蚀。 因此，细菌 毒素转移到血液中，促进炎症。尿毒症的产生 毒素如吲哚酚和对甲苯基硫酸盐也增加，导致进一步的肾损伤。CKD患者 被规定的饮食低蛋白质和共生有机体，这是更容易对肾脏，但也 导致了生态失调重新制定CKD饮食可能会改善临床实践。 拟议的COBRE项目的长期目标是开发CKD的新疗法。短期 目标是将肠道微生物组定义为治疗靶点，这将为申请NIH R 01级提供数据。 为实现长期目标提供资金。这个COBRE项目的假设是，微生物的变化 多样性、异种蛋白和异种代谢物与CKD进展相关， 治疗可以用来减缓疾病。 抗性淀粉（RS）是一种未被完全分解和吸收的益生元， 转化为短链脂肪酸。富含RS的饮食被证明可以减少血浆毒素， CKD-大鼠模型。最近的一项随机临床研究表明，RS饮食可减少患者的炎症 患有2型糖尿病确定RS饮食对健康人和人类CKD的微生物组的影响 研究人员将招募≥3岁的健康或CKD 3A期患者 或4，并持续8周，将给予含有RS或对照淀粉的饮食。节食后，病人 将被跟踪一年。具体目的是（1）确定RS饮食对微生物组的影响 （2）确定RS饮食对毒素产生的影响， 氮平衡和（3）确定8周RS饮食治疗对CKD进展的影响， 年和肠道微生物组变化的稳定性水平。

PROJECT SUMMARY Chronic kidney disease (CKD), a progressive decline in kidney function, is a growing health problem: 13% of adults in the US have CKD, and 2% of advanced cases are in children. CKD in children is devastating, with 30 times higher mortality than in the general pediatric population. In 40% of cases, CKD leads to irreversible loss of kidney function, end-stage renal disease (ESRD). For ESRD, apart from dialysis and kidney transplant, no treatment exists. For a child 0-14 years of age on dialysis, the expected lifetime is only 20 years. CKD increases urea levels in bodily fluids leading to a dominance of urease-containing bacteria in the gut. Such dysbiosis results in decreased consumption of nitrogenous waste and erosion of the epithelial barrier. Consequently, bacterial toxins translocate into the bloodstream, promoting inflammation. Production of uremic toxins such as indoxyl and p-cresyl sulfates is also increased, resulting in further kidney injury. CKD patients are prescribed a diet low in protein and symbiotic organisms, which is easier on the kidneys but also contributes to the dysbiosis. Re-formulating the CKD diet may improve the clinical practice. The long-term goal of the proposed COBRE project is to develop new therapies for CKD. The short-term goal is to define the gut microbiome as a therapeutic target, which will provide data to apply for NIH R01-level funding to pursue the long-term goal. The hypothesis for this COBRE project is that changes in the microbial diversity, xeno-proteins and xeno-metabolites correlate with CKD progression, and microbiome-directed therapies can be used to slow the disease. Resistant starch (RS) is a type of pre-biotic that is not fully broken down and absorbed, but rather turned into short-chain fatty acids by intestinal bacteria. A diet rich in RS was shown to reduce plasma toxins in a CKD-rat model. A recent randomized clinical study demonstrated the RS diet reduces inflammation in patients with type 2 diabetes. To define the effects of RS diet on the microbiome of healthy humans and human CKD patients, the researchers will recruit patients who are ≥3 years of age and either healthy or in CKD Stages 3A or 4, and, for 8 weeks, will administer a diet containing either RS or a control starch. After the diet, the patients will be followed for one year. The Specific Aims are (1) Determine the effect of an RS diet on the microbiomes of healthy subjects and of patients with CKD, (2) Determine the effect of an RS diet on toxin production and nitrogen balance and (3) Determine the effect of 8 weeks of RS diet treatment on progression of CKD at one year and the level of stability of changes to the gut microbiome.