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: 9398774
• 负责人: Ion Alexandru Bobulescu
• 金额: $ 36.45万
• 依托单位: UT SOUTHWESTERN MEDICAL 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/9398774
• 关键词: Acids; Adult; Affect; Aftercare; Alkalies; Ammonium; Animal Model; Animals; Area; Attenuated; Bacteria; 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 microbiota; high risk; 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.

项目概要/摘要 在美国，三分之一的成年人患有肥胖症。与肥胖相关的健康问题包括 罹患慢性肾脏病 (CKD) 和 CKD 进展的风险较高。协会 即使在对糖尿病和高血压进行统计调整后，肥胖和慢性肾病之间的差异仍然存在。 已知的 CKD 危险因素通常存在于肥胖人群中。这表明肥胖本身， 独立于其他合并症，有助于 CKD。肥胖与肥胖相关的致病机制 对 CKD 的了解还不完全。该项目测试了整合现有知识的高度创新模型 在人类病理生理学和微生物生物学的多个领域有新发现。该模型分为 三个在概念上相互关联但可独立检验的假设： 1. 与肥胖相关 通常存在于肠道中的微生物的改变导致微生物产生过量的酸 代谢。这些多余的酸被肠道吸收，然后由肾脏排出体外，因为肾脏 其任务是防止体内积聚过多的酸。 2.肾脏排泄过多的酸 要求增加谷氨酰胺代谢以产生铵（对于酸排泄很重要），但由于 产生的谷氨酰胺代谢物在细胞中用于产生能量，这减少了其他物质的利用率 通过底物竞争产生能量底物，例如脂肪酸。反过来，这使得更多的脂肪酸可用 进入替代代谢途径，导致肾脏脂质积累（脂肪变性）和毒性作用 （脂毒性）。 3. 最后，过量的酸排泄通过减少脂肪酸导致 CKD 进展 利用率、脂肪变性和脂毒性，并且由于肾脏脂质代谢受到影响，这种影响变得更糟。 已经受到肥胖的困扰。这些假设将通过体外、动物和 人体研究采用了磁共振成像、核磁等一些最新技术 共振光谱、无菌小鼠研究和靶向小鼠遗传学，结合经典 生理学和生物化学。总之，该项目旨在通过之前的测试来推进该领域的发展 尚未探索但明确且合理的假设将肥胖、肠道微生物、胃酸排泄增加联系起来 肾脏、肾脂质异常和 CKD 进展。该项目将产生新知识 为预防 CKD 进展的新逻辑干预措施奠定基础。这与总体方针是一致的 NIH 的使命是通过科学改善人类健康。