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

• 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
• 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

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）是一种令人衰弱的疾病，有助于高发病率和质量差 生活。 IBD发展的危险因素是一种“肠道肠道”表型，其中微生物的数量升高 - 衍生的抗原材料将肠道上皮横穿到上皮室，引起失调 炎症循环。因此，保持强肠上皮屏障对于避免明显的肠道至关重要 炎。通过扩展，识别在保留肠道上皮屏障中起作用的分子机制 完整性对于理解最佳肠道健康至关重要。有越来越多的证据表明生物活性 肠道微生物组产生的代谢产物对肠道上皮屏障完整性产生深远的影响。然而， 我们对这些生物活性代谢产物如何机械影响宿主生物学了解一无所知。使用质量 基于光谱法的代谢组学平台用于分析小分子，我们的研究小组证明了 无菌和常规小鼠的代谢产物组成的显着差异，并确定了新颖的 微生物起源的小分子。最歧视的分子是δ-valerobetaine（VB）。 VB在结构上 类似于γ-叔丁烷，这是肉碱的直接生物合成前体，这是线粒体所必需的 脂肪酸氧化，表明VB在控制线粒体中的能量代谢中的作用。我们也是 证实Vb在无菌小鼠及其线粒体中是无法检测的，但存在于常规小鼠中 和他们的线粒体。体内和体外研究表明，VB抑制线粒体脂肪酸氧化 通过降低细胞肉碱水平。重要的是，肠道干细胞（ISC）小众被严格调节 通过众多宿主衍生和腔内衍生的因素，而ISC的可塑性与 细胞代谢和线粒体功能。另外，某些胃肠道疾病（例如IBD） 以线粒体功能的修改为特征。在初步数据中，我们表明VB给药 无菌小鼠影响肠道上皮的线粒体生物发生，并诱导细胞增殖 肠道隐窝。我们假设源自微生物组的VB会影响线粒体生物能力 在肠上皮内的细胞中，并用作中心积分器，从而使菌群产生影响 肠道细胞体内稳态，肠道上皮屏障完整性和损伤后组织限制。我将检验这个假设 通过以下特定目的，1）表征Vb对肠道组织中线粒体功能的影响 稳态和2）确定VB对鼠损伤模型中肠道上皮修复的影响。这些 将使用多种方法进行培训的方法，包括3D Ex Vivo类型模型， 结肠炎和上皮恢复的小鼠模型以及gnotobiotic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。