Microbiome-Derived Therapeutic Targets for Chronic Kidney Disease

点击翻译按钮获取中文摘要

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.