Acute kidney injury and microbiome

急性肾损伤和微生物组

• 批准号: 10214606
• 负责人: HAMID RABB
• 金额: $ 60.26万
• 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/10214606
• 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; Cisplatin; Clinic; Clinical; Colitis; Creatinine; Data; Endothelium; Endotoxins; Ensure; Epithelial; Evaluation; FFAR3 gene; Feces; Germ-Free; Human; Immune; Immunologics; Immunology; Immunophenotyping; Inflammation; Inflammatory; Injury; Injury to Kidney; Ischemia; Kidney; Kidney Diseases; Kidney Transplantation; Knockout Mice; Link; LoxP-flanked allele; Measures; Mediating; Metabolic; Metagenomics; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Patient-Focused Outcomes; Patients; Phase; Phenotype; Population; 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; 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; mortality; 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

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.

项目总结/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，涉及多个 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结果，然而，肠道微生物群参与的潜在机制 微生物群-肾串扰，特别是在恢复阶段，仍然知之甚少。我们的工作 这项拨款申请的假设是肠道微生物群诱导肾脏T细胞群的特异性变化 介导AKI结局和恢复。此外，我们假设短链脂肪酸（SCFAs） 由某些肠道微生物群产生的气味通过特定的嗅觉受体与肾脏组织沟通，例如G 蛋白偶联受体41（Gpr41）、嗅觉受体78（Olfr 78）和Olfr 558存在于肾脏中。来测试我们 假设，我们将（AIM 1）对来自野生型（WT）、抗生素处理（AB）的肾免疫细胞进行免疫表型分析。 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 靶向选定T细胞（例如CD4、TcB、CD3 + CD4-CD8-双阴性）的过继转移研究，以确定 选择性T细胞对微生物群系对AKI的作用。宏基因组学和代谢组学，重点关注免疫 将在AKI和恢复中测量炎症途径，以鉴定微生物群落， 代谢物。我们还将进行特定细菌的定植研究，抗炎粪便（来自 妊娠小鼠）和益生菌在AB处理的、GF和WT小鼠中的作用。此外，从细胞中释放的内毒素的作用 将在使用Toll样受体4（TLR4）的研究中研究肾免疫细胞群上的肠漏 缺陷小鼠目的：研究SCFA信号受体在肠道菌群-肾脏串扰（AIM 2）中的作用 我们将在Gpr41-/-、Olfr 78-/-和Olfr 558-/-小鼠中诱导AKI，以描述SCFA信号传导在AKI期间的作用。 复苏我们将鉴定免疫细胞或驻留肾内皮/上皮来源的SCFA与 通过评估肾脏和免疫细胞特异性SCFA受体缺陷小鼠和 进行骨髓移植此外，SCFA生产细菌和外源性SCFA将被 向Gpr41-/-、Olfr 78-/-和Olfr 558-/-小鼠施用其并检查其对AKI结果的作用。使我们的 与人类AKI更相关的实验室研究，我们将（AIM 3）对粪便前和粪便后样本进行宏基因组学研究 以及接受心脏手术的患者的血液代谢组学， 那些发展AKI的人和那些受到保护的人。我们将研究人类微生物群的影响， 在AB治疗的GF小鼠和SCFA受体缺陷小鼠中发生AKI的患者。成功完成 这些研究将有助于了解肠道微生物群-肾脏串扰的免疫学效应， 包括SCFA和靶向肠道微生物群的治疗选择，用于AKI和恢复。