Role of gut bacteria and renal lipids in obesity-related kidney disease

肠道细菌和肾脂质在肥胖相关肾脏疾病中的作用

• 批准号: 9752559
• 负责人: Ion Alexandru Bobulescu
• 金额: $ 34.43万
• 依托单位: TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752559
• 关键词: Acids; Adult; Affect; Aftercare; Alkalies; Ammonium; Animal Model; Animals; Area; Attenuated; Bicarbonates; Biochemistry; Biology; Cells; Chronic Kidney Failure; Citric Acid Cycle; Comorbidity; Data; Defect; Development; Diabetes Mellitus; Diet; Disease Progression; Equilibrium; Excretory function; Fatty Acids; Feces; Functional disorder; Genetic; Germ-Free; Glutamine; Health; Histologic; Human; Hypertension; Impairment; In Vitro; Intake; Intervention; Intestines; Kidney; Knowledge; Lead; Link; Lipids; Magnetic Resonance Imaging; Matched Group; Measurement; Measures; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Methods; Microbe; Mission; Modeling; Molecular; Mus; NMR Spectroscopy; Nonesterified Fatty Acids; Obesity; Obesity associated kidney disease; Pathogenicity; Pathway interactions; Physiology; Pilot Projects; Production; Publishing; Rattus; Research; Risk; Risk Factors; Role; Science; Source; Techniques; Technology; Testing; Thinness; Time; Toxic effect; Transplantation; United States; United States National Institutes of Health; Urine; base; enzyme activity; feeding; field study; gut bacteria; gut microbiota; high risk; human model; human subject; improved; in vivo; innovation; lipid metabolism; microbial; microbiota; mouse model; novel; oxidation; prevent; randomized trial; uptake

PROJECT SUMMARY / ABSTRACT Obesity affects 1 in 3 adults in the United States. Among the health problems associated with obesity is a higher risk for the development of chronic kidney disease (CKD) and for CKD progression. The association between obesity and CKD persists even after statistical adjustment for diabetes and hypertension, which are known CKD risk factors that are often present in people with obesity. This suggests that obesity itself, independent of other comorbid conditions, contributes to CKD. The pathogenic mechanisms linking obesity to CKD are incompletely understood. This project tests a highly innovative model integrating existing knowledge with new findings in multiple areas of human pathophysiology and microbial biology. This model is divided into three hypotheses that are conceptually interrelated but independently testable: 1. Obesity-associated alterations in the microbes that normally reside in the intestine lead to excess acid production by microbial metabolism. This excess acid is absorbed by the intestine and then excreted by the kidney, as the kidney is tasked with preventing excess acid from accumulating in the body. 2. Excess acid excretion by the kidney mandates increased glutamine metabolism to generate ammonium (important for acid excretion), but since the resulting glutamine metabolites are used in the cell to generate energy, this reduces the utilization of other energy substrates such as fatty acids by substrate competition. In turn, this makes more fatty acids available for entry into alternative metabolic pathways, resulting in renal lipid accumulation (steatosis) and toxic effects (lipotoxicity). 3. Finally, excess acid excretion contributes to CKD progression via decreased fatty acid utilization, steatosis and lipotoxicity, and this effect is made worse by the fact that kidney lipid metabolism is already disturbed in obesity. These hypotheses will be tested using a combination of in vitro, animal and human studies employing some of the latest technologies in magnetic resonance imaging, nuclear magnetic resonance spectroscopy, germ-free mouse research and targeted mouse genetics, combined with classical physiology and biochemistry. In summary, this project aims to advance the field by testing previously unexplored, but clear and plausible hypotheses linking obesity, intestinal microbes, increased acid excretion by the kidney, kidney lipid abnormalities, and CKD progression. This project will generate new knowledge that will form the basis for new logical interventions to prevent CKD progression. This is in keeping with the overarching mission of the NIH of improving human health through science.

项目摘要 /摘要 肥胖会影响美国三分之一的成年人。在与肥胖相关的健康问题中有一个 慢性肾脏疾病（CKD）和CKD进展的较高风险。协会 肥胖和CKD之间即使在统计糖尿病和高血压调整后仍然存在 肥胖者经常存在的已知CKD风险因素。这表明肥胖本身， 独立于其他合并条件，对CKD造成了贡献。将肥胖与 CKD不完全理解。该项目测试一个高度创新的模型，整合了现有知识 在人类病理生理学和微生物生物学的多个领域中有新发现。该模型分为 在概念上相互关联但可以独立检验的三个假设：1。与肥胖相关 通常驻留在肠道中的微生物的改变导致微生物产生过量的酸 代谢。这种多余的酸被肠吸收，然后被肾脏排泄，因为肾脏是 任务是防止过量的酸积聚在体内。 2。肾脏过量排泄 授权增加了谷氨酰胺代谢产生铵（对于排泄酸重要），但由于 所得的谷氨酰胺代谢物在细胞中用于产生能量，这降低了其他 通过底物竞争等能量底物，例如脂肪酸。反过来，这使更多的脂肪酸可用 进入替代代谢途径，导致肾脏脂质积累（脂肪变性）和有毒作用 （脂肪毒性）。 3。最后，多余的酸排泄有助于通过降低脂肪酸进展 利用，脂肪变性和脂肪毒性，由于肾脏脂质代谢是 已经在肥胖症中打扰了。这些假设将通过体外，动物和 人类研究采用磁共振成像中的一些最新技术，核磁 共振光谱，无菌小鼠研究和靶向小鼠遗传学，结合经典 生理和生物化学。总而言之，该项目旨在通过先前测试来推进该领域 未开发的，但明确且合理的假设将肥胖，肠道微生物联系起来，增加酸排泄。 肾脏，肾脏脂质异常和CKD进展。该项目将产生新知识 构成新的逻辑干预措施以防止CKD进展的基础。这与总体一致 NIH的使命是通过科学改善人类健康。