Chronic kidney disease (CKD) affects many patients, particularly in the aging population with significant morbidity resulting in a costly public health problem. There is increasing realization for the importance of early detection and prevention, but to date there are few effective preventive measures. We have exciting preliminary data that suggest a novel, diet-induced gut microbiota-mediated pathway may serve as direct contributor to CKD susceptibility and adverse prognosis. In the present application we will interrogate each facet of the dietary-induced gut microbial pathway at the biochemical, animal model, and human clinical level. We will examine the role of specific chronic dietary exposures in risk for adverse CKD progression. We will examine the role of gut microbes in CKD susceptibility, and specific microbial enzyme systems in this process. We also will perform large scale human clinical studies testing whether gut microbial generated products detected in the circulation predict incident risk for development and progression of CKD. Finally, we will explore the potential efficacy of novel anti-microbial targeted therapy and dietary modifications for the prevention of dietary-induced CKD. Successful completion of the proposed studies should provide both important mechanistic insights into a new pathway that contributes to CKD development, as well as develop novel diagnostic tests and therapeutic approaches for the prevention of CKD.

Public Health Relevance

Our overall goal is to test the hypothesis that gut microbes, via metabolism of specific dietary nutrients, participate in the development of progressive renal impairment. The proposed studies may further identify and target individuals at greater risk for developing chronic kidney disease, and associated adverse cardiovascular diseases. They also are focused on the identification of novel diagnostic tests and therapeutic strategies to modulate gut microbiota pathways linked to development and progression of chronic kidney disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK106000-02
Application #
9129779
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kusek, John W
Project Start
2015-08-20
Project End
2019-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Ahmadmehrabi, Shadi; Tang, W H Wilson (2018) Hemodialysis-induced cardiovascular disease. Semin Dial 31:258-267
Tang, W H Wilson; Li, Daniel Y; Hazen, Stanley L (2018) Dietary metabolism, the gut microbiome, and heart failure. Nat Rev Cardiol :
Smits, Loek P; Kootte, Ruud S; Levin, Evgeni et al. (2018) Effect of Vegan Fecal Microbiota Transplantation on Carnitine- and Choline-Derived Trimethylamine-N-Oxide Production and Vascular Inflammation in Patients With Metabolic Syndrome. J Am Heart Assoc 7:
Li, Daniel Y; Tang, W H Wilson (2018) Contributory Role of Gut Microbiota and Their Metabolites Toward Cardiovascular Complications in Chronic Kidney Disease. Semin Nephrol 38:193-205
Norheim, Frode; Bjellaas, Thomas; Hui, Simon T et al. (2018) Genetic, dietary, and sex-specific regulation of hepatic ceramides and the relationship between hepatic ceramides and IR. J Lipid Res 59:1164-1174
Haghikia, Arash; Li, Xinmin S; Liman, Thomas G et al. (2018) Gut Microbiota-Dependent Trimethylamine N-Oxide Predicts Risk of Cardiovascular Events in Patients With Stroke and Is Related to Proinflammatory Monocytes. Arterioscler Thromb Vasc Biol 38:2225-2235
Albert, Chonyang L; Tang, W H Wilson (2018) Metabolic Biomarkers in Heart Failure. Heart Fail Clin 14:109-118
Li, Wei; Kennedy, David; Shao, Zhili et al. (2018) Paraoxonase 2 prevents the development of heart failure. Free Radic Biol Med 121:117-126
Li, Xinmin S; Wang, Zeneng; Cajka, Tomas et al. (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI Insight 3:
Skye, Sarah M; Zhu, Weifei; Romano, Kymberleigh A et al. (2018) Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res 123:1164-1176

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