Acute kidney injury and microbiome

急性肾损伤和微生物组

• 批准号: 10628833
• 负责人: HAMID RABB
• 金额: $ 2.58万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628833
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Antibiotics; Antibodies; Antiinflammatory Effect; Applications Grants; Bacteria; Binding; Blood; Bone Marrow Transplantation; CD3 Antigens; CD8-Positive T-Lymphocytes; CD8B1 gene; Cardiac Surgery procedures; Cells; Cellular Metabolic Process; Cisplatin; Clinic; Clinical; Creatinine; Data; Endothelium; Endotoxins; Ensure; Epithelial; Evaluation; FFAR3 gene; Feces; Germ-Free; Human; Immune; Immunologics; Immunophenotyping; Inflammation; Inflammatory; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knockout Mice; Link; LoxP-flanked allele; Measures; Mediating; Metabolic; Metabolism; Metagenomics; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patients; Phase; Phenotype; Population; Predisposition; Probiotics; Process; Property; Publishing; Receptor Signaling; Recovery; Regulatory T-Lymphocyte; Reperfusion Therapy; Research; Role; Serum; Signal Transduction; Smell Perception; Source; T-Lymphocyte; TLR4 gene; Testing; Therapeutic Studies; Tissues; Translating; Transplant Recipients; Tubular formation; Volatile Fatty Acids; Wild Type Mouse; Work; endotoxin receptor; experimental study; gut bacteria; gut microbiome; gut microbiota; hemodynamics; human microbiota; immune activation; improved; injury and repair; injury recovery; kidney cell; metabolomics; microbial; microbial community; microbiome; microbiota; microbiota metabolites; mortality; murine colitis; novel; novel marker; novel therapeutics; olfactory receptor; pregnant; programmed cell death ligand 1; programmed cell death protein 1; receptor; renal ischemia; repaired; response; stool sample; tool

Contact PD/PI: RABB, HAMID Project Summary /Abstract Acute kidney Injury (AKI) associated morbidity and mortality is a major clinical problem that involves multiple overlapping pathophysiological mechanisms. Recent observations from our team and others demonstrated that intestinal microbiota modulates AKI outcome, however the underlying mechanism involved in intestinal microbiota-kidney crosstalk, especially during the recovery phase, remain poorly understood. Our working hypothesis for this grant application is that gut microbiota induces specific changes in the kidney T cell population to mediate AKI outcome and recovery. Furthermore, we hypothesize that short chain fatty acids (SCFAs) produced by certain gut microbiota communicate with kidney tissue via specific smell receptors, such as G protein coupled receptor 41 (Gpr41), olfactory receptor 78 (Olfr78) and Olfr558 present in the kidney. To test our hypotheses, we will (AIM 1) immunophenotype kidney immune cells from wild type (WT), antibiotic treated (AB) and germ free (GF) mice at baseline, during the early phase of AKI, and during recovery of ischemic and cisplatin induced AKI. We will conduct mechanistic studies using T cell deficient mice, T cell antibody depletion and adoptive transfer studies targeting select T cells (e.g. CD4, Tregs, CD3+CD4-CD8- double neg) to determine roles of select T cells on microbiome effects on AKI. Metagenomic and metabolomics with focus on immune inflammatory pathways will be measured in AKI and recovery for identification of microbial communities and metabolites. We will also perform colonization studies with specific bacteria, anti-inflammatory stool (from pregnant mice) and probiotics in AB treated, GF and WT mice. Furthermore, effect of endotoxin released from leaking gut on renal immune cells population will be investigated in studies using toll like receptor 4 (TLR4) deficient mice. To study the role of SCFA signaling receptors in intestinal microbiota–kidney crosstalk (AIM 2) we will induce AKI in Gpr41-/-, Olfr78-/- and Olfr558-/- mice to delineate role of SCFA signaling during AKI recovery. We will identify immune cell or resident kidney endothelium/epithelial source of SCFA interaction with Gpr41, Olfr78 and Olfr558 by evaluating kidney and immune cell specific SCFA receptor deficient mice and performing bone marrow transplants. Additionally, SCFA producing bacteria and exogenous SCFAs will be administered to Gpr41-/-, Olfr78-/- and Olfr558-/- mice and its effect examined on AKI outcomes. To make our lab studies more relevant to human AKI, we will (AIM 3) perform metagenomics of pre and post stool samples and blood metabolomics from patients undergoing cardiac surgery to find gut microbiota differences between those that develop AKI and those that are protected. We will investigate the effect of human microbiota from patients that develop AKI in AB treated, GF mice and SCFA receptor deficient mice. Successful completion of these studies will help understand immunological effects of gut microbiota-kidney crosstalk and potentially novel treatment options involving SCFAs and targeting intestinal microbiota, for AKI and recovery. Project Summary/Abstract Page 7

联系人 PD/PI：RABB、HAM​​ID 项目概要/摘要 急性肾损伤 (AKI) 相关的发病率和死亡率是一个主要的临床问题，涉及多种因素 重叠的病理生理机制。我们团队和其他人最近的观察表明 肠道微生物群调节 AKI 结局，然而肠道微生物群参与的潜在机制 微生物群与肾脏的相互作用，尤其是在恢复阶段，人们仍然知之甚少。我们的工作 本次资助申请的假设是肠道微生物群会诱导肾脏 T 细胞群发生特定变化 介导 AKI 结局和恢复。此外，我们假设短链脂肪酸（SCFA） 由某些肠道微生物群产生，通过特定的嗅觉受体（例如 G）与肾组织通讯 肾脏中存在蛋白偶联受体 41 (Gpr41)、嗅觉受体 78 (Olfr78) 和 Olfr558。来测试我们的 假设，我们将 (AIM 1) 对来自野生型 (WT)、抗生素处理 (AB) 的肾脏免疫细胞进行免疫表型 和无菌 (GF) 小鼠在基线、AKI 早期以及缺血和顺铂恢复期间 诱发 AKI。我们将使用 T 细胞缺陷小鼠、T 细胞抗体耗竭和 针对特定 T 细胞（例如 CD4、Treg、CD3+CD4-CD8- 双阴性）的过继转移研究以确定 选择 T 细胞对微生物组对 AKI 影响的作用。以免疫为重点的宏基因组学和代谢组学 将在 AKI 和恢复中测量炎症途径，以识别微生物群落和 代谢物。我们还将对特定细菌、抗炎粪便（来自 怀孕小鼠）和 AB 处理、GF 和 WT 小鼠中的益生菌。此外，内毒素释放的影响 使用 Toll 样受体 4 (TLR4) 的研究将调查肠道渗漏对肾脏免疫细胞群的影响 缺乏的老鼠。研究 SCFA 信号受体在肠道微生物群-肾脏串扰中的作用 (AIM 2) 我们将在 Gpr41-/-、Olfr78-/- 和 Olfr558-/- 小鼠中诱导 AKI，以描述 SCFA 信号在 AKI 过程中的作用 恢复。我们将确定 SCFA 与免疫细胞或常驻肾内皮/上皮来源的相互作用 通过评估肾脏和免疫细胞特异性 SCFA 受体缺陷小鼠的 Gpr41、Olfr78 和 Olfr558 进行骨髓移植。此外，产生 SCFA 的细菌和外源 SCFA 将被 给予 Gpr41-/-、Olfr78-/- 和 Olfr558-/- 小鼠，并检查其对 AKI 结果的影响。为了让我们的 与人类 AKI 更相关的实验室研究，我们将 (AIM 3) 对粪便前后样本进行宏基因组学 和接受心脏手术的患者的血液代谢组学，以发现肠道微生物群的差异 那些发生 AKI 的人和受到保护的人。我们将研究人类微生物群的影响 AB 治疗小鼠、GF 小鼠和 SCFA 受体缺陷小鼠中发生 AKI 的患者。顺利完成 这些研究将有助于了解肠道微生物群-肾脏串扰的免疫学影响以及潜在的新颖性 涉及 SCFA 和针对肠道微生物群的治疗方案，用于 AKI 和康复。 项目总结/摘要第 7 页