Valerobetaine is a microbe-generated metabolite that induces mitochondrial biogenesis and maintains epithelial integrity

缬甜菜碱是一种微生物产生的代谢物，可诱导线粒体生物发生并维持上皮完整性

基本信息

批准号：
10680153
负责人：
Lauren Casey Askew
金额：
$ 5.27万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680153
关键词：
3-Dimensional Affect Animals Bioenergetics Biogenesis Biology Biopsy Carnitine Cell Proliferation Cells Cellular Metabolic Process Chronic Colitis Colon Colonoscopes Communication Complex Data Development Disease Energy Metabolism Epithelial Cells Epithelium Etiology Event Experimental Models Family Forcep Foundations Functional disorder Gastroenterology Gastrointestinal Diseases Gastrointestinal tract structure Gene Expression Generations Germ-Free Gnotobiotic Goals Grant Health Hepatocyte Homeostasis Immune response In Vitro Indoles Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intestines Knowledge Leaky Gut Maintenance Mass Spectrum Analysis Mediating Metabolism Methodology Methods Microbe Mitochondria Modeling Modification Molecular Morbidity - disease rate Mus Organoids Persons Phenotype Physiology Play Proliferating Quality of life Research Risk Factors Role Science Scientist Signal Pathway Testing Therapeutic Tissues Training Volatile Fatty Acids Work Wound models beneficial microorganism body system commensal bacteria fatty acid oxidation functional plasticity gastrointestinal epithelium gut health gut homeostasis gut inflammation gut microbiome gut microbiota host microbiome in vivo interest intestinal crypt intestinal epithelium metabolomics microbial microbiome microbiome composition microbiota microorganism antigen mitochondrial metabolism mouse model murine colitis novel preservation response small molecule stem cell niche therapeutic target

项目摘要

SUMMARY Inflammatory Bowel Disease (IBD) is a debilitating condition that contributes to high morbidity and poor quality of life. A risk factor for the development of IBD is a ‘leaky gut’ phenotype where elevated amounts of microbially- derived antigenic material traverse the gut epithelium into sub-epithelial compartments provoking a dysregulated inflammatory loop. Therefore, maintaining a strong intestinal epithelial barrier is vital to avoid overt gut inflammation. By extension, identifying the molecular mechanisms that function in preserving gut epithelial barrier integrity is critical for understanding optimal intestinal health. There is mounting evidence that bioactive metabolites generated by the gut microbiome exert profound influence on gut epithelial barrier integrity. However, we know little about how these bioactive metabolites mechanistically influence host biology. Employing mass spectrometry-based metabolomics platforms for analysis of small molecules, our research group demonstrated remarkable differences in the metabolite composition of germ-free and conventional mice, and identified novel small molecules of microbial origin. The most discriminative molecule was δ-valerobetaine (VB). VB structurally resembles γ-butyrobetaine, the immediate biosynthetic precursor to carnitine, which is required for mitochondrial fatty acid oxidation, suggesting a role for VB in controlling energy metabolism in the mitochondria. We also confirmed that VB is undetectable in germ-free mice and their mitochondria, but present in conventionalized mice and their mitochondria. In vivo and in vitro studies showed that VB inhibits mitochondrial fatty acid oxidation through decreasing cellular carnitine levels. Importantly, the intestinal stem cell (ISC) niche is tightly regulated by numerous host-derived and luminal-derived factors, while the plasticity of the ISC niche is associated with cellular metabolism and mitochondrial function. In addition, some gastrointestinal diseases such as IBD are characterized by modifications in mitochondrial function. In preliminary data, we show that VB administration to germ-free mice induces mitochondrial biogenesis in the gut epithelium, and induces cell proliferation in the intestinal crypt. We hypothesize that VB derived from the microbiome can influence mitochondrial bioenergetics in cells within the intestinal epithelium, and functions as a central integrator whereby the microbiota influences gut cell homeostasis, gut epithelia barrier integrity, and tissue restitution following injury. I will test this hypothesis by the following specific aims, 1) to characterize the effect of VB on mitochondria function in gut tissue homeostasis, and 2) to determine the impact of VB on gut epithelial restitution in murine injury models. These aims will be carried out using a variety of methods in which I will be trained, including 3D ex vivo organoid models, mouse models of colitis and epithelial restitution, and gnotobiotic mice. The long-term goal of this research is to understand the role of VB in gut health and identify the therapeutic potential of VB as a treatment for IBD.

概括炎症性肠病 (IBD) 是一种使人衰弱的疾病，导致高发病率和低质量发生 IBD 的一个危险因素是“肠漏”表型，其中微生物数量增加。衍生的抗原物质穿过肠上皮进入上皮下隔室，引起失调因此，维持强大的肠上皮屏障对于避免明显的肠道至关重要。通过扩展，确定保护肠道上皮屏障的分子机制。完整性对于了解最佳肠道健康至关重要有越来越多的证据表明具有生物活性。肠道微生物组产生的代谢物对肠道上皮屏障的完整性具有深远的影响。我们对这些生物活性代谢物如何影响宿主生物学知之甚少。我们的研究小组展示了基于光谱分析的小分子代谢组学平台无菌小鼠和常规小鼠的代谢物组成存在显着差异，并鉴定出新的微生物来源的小分子在结构上是δ-戊甜菜碱（VB）。类似于 γ-丁甜菜碱，肉碱的直接生物合成前体，是线粒体所需的脂肪酸氧化，表明 VB 在控制线粒体能量代谢中发挥作用。证实 VB 在无菌小鼠及其线粒体中检测不到，但在常规小鼠中存在及其线粒体体内和体外研究表明，VB 抑制线粒体脂肪酸氧化。重要的是，肠道干细胞（ISC）生态位受到严格调节。受到许多宿主衍生和管腔衍生因素的影响，而 ISC 生态位的可塑性与此外，一些胃肠道疾病，如IBD，也与细胞代谢和线粒体功能有关。初步数据表明，VB 给药可改变线粒体功能。无菌小鼠诱导肠道上皮中的线粒体生物发生，并诱导肠道中的细胞增殖我们认为源自微生物组的 VB 可以影响线粒体生物能学。在肠上皮细胞内，作为中央整合器，微生物群影响肠道细胞稳态、肠道上皮屏障完整性和损伤后的组织恢复我将检验这个假设。通过以下具体目标，1) 表征 VB 对肠道组织线粒体功能的影响稳态，2) 确定 VB 对小鼠损伤模型中肠上皮恢复的影响。将使用我接受培训的各种方法来实现目标，包括 3D 离体类器官模型，结肠炎和上皮恢复的小鼠模型以及无菌小鼠这项研究的长期目标是。了解 VB 在肠道健康中的作用，并确定 VB 作为 IBD 治疗的治疗潜力。