Microbiome Induced Epigenetic Changes in Intestinal Inflammation and Necrotizing Enterocolitis

微生物组诱导肠道炎症和坏死性小肠结肠炎的表观遗传变化

• 批准号: 9893335
• 负责人: Mohan Pammi
• 金额: $ 23.09万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-17 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893335
• 关键词: Adult; Anti-Inflammatory Agents; Antibiotics; Bacteroidetes; Bioinformatics; Birth Weight; Blood; Blood specimen; Bronchopulmonary Dysplasia; Butyrates; Cardiovascular system; Cells; Chronic lung disease; Clinical; DNA Methylation; Data; Disease; Enrollment; Epigenetic Process; Epithelial; Epithelial Cells; Epithelium; Exposure to; Feces; Firmicutes; Follow-Up Studies; Functional disorder; Genes; Genetic Transcription; Gestational Age; Goals; Growth; Histone Deacetylation; Human Milk; Immune response; Immunity; Infection; Inflammation; Inflammatory; Inflammatory Response; Intestines; Knowledge; Lead; Link; Lipopolysaccharides; Literature; Malignant Neoplasms; Measures; Medical center; Metadata; Metagenomics; Modification; Mononuclear; Morbidity - disease rate; Necrotizing Enterocolitis; Neonatal; Neonatology; Nested Case-Control Study; Neuronal Injury; Obesity; Operative Surgical Procedures; Organ; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Premature Infant; Prevention strategy; Proteobacteria; Publishing; Research; Research Design; Retinopathy of Prematurity; Sampling; Science; Serum; Stimulus; Testing; Texas; Therapeutic; Tissue-Specific Gene Expression; Urine; Volatile Fatty Acids; Work; base; cohort; design; epigenome; fatty acid-binding proteins; fecal microbiome; feeding; follow-up; gut bacteria; gut microbiome; inflammatory disease of the intestine; inflammatory marker; innovation; insight; intestinal epithelium; lipid metabolism; liquid biopsy; metabolome; metabolomics; methylation pattern; microbial; microbiome; microbiota; multiple omics; neonate; novel; nutrition; organ injury; preterm newborn; stool sample; tool; transcriptome; transcriptomics; urinary

PROJECT SUMMARY In preterm neonates, excessive inflammatory responses have been implicated in necrotizing enterocolitis (NEC), the mechanisms for which are unclear. Microbiota and their metabolites including short chain fatty acids may modify the epigenome by DNA methylation and/or histone deacetylation, and specific microbiome patterns have been associated with altered DNA methylation of genes linked to lipid metabolism, obesity and inflammation. The long term goal of this research is to determine the mechanism for excessive inflammatory responses that lead to NEC and devise anti-inflammatory therapeutic and preventative strategies. The specific hypothesis of the proposed research is that epigenetic changes induced by the developing intestinal microbiome result in excessive immune and inflammatory responses that predispose to necrotizing enterocolitis in the preterm neonate. We intend to test this hypothesis by first establishing DNA methylation alterations in preterm infants with NEC compared to matched controls, in a nested cohort clinical design in Specific Aim 1. DNA methylation patterns will be delineated in intestinal epithelial cells and peripheral blood mononuclear cells and confirm differential gene expressions with transcriptomics in the intestinal epithelial cells from the stools and assess systemic and intestinal inflammation. In our second Specific Aim, we will test the hypothesis that specific microbiome and metabolomic signatures are associated with changes in the epigenome and transcriptome in preterm neonates with NEC. In the cohort enrolled, we will evaluate stool microbiome by metagenomics and stool and urine metabolome for microbial metabolites and record clinical metadata (e.g. gestational age, feeding) for multi-variable analysis. We anticipate distinct microbiome and metabolome signatures associated with DNA methylation alterations in NEC. Follow up studies of enteroids from surgical samples will be used to mechanistically test our hypothesis by measuring epigenetic changes after exposure to specific inflammatory, microbial or metabolomic stimuli that are identified from the proposed research. The proposed research is innovative as the epigenome alterations in relation to the microbiome and inflammation in the preterm infant have not been evaluated. We propose a holistic, multi-omics approach to delineate the mechanisms for excessive inflammation in the preterm infant. Our research will not only make an impact in the field of neonatology where major organ morbidity is related to inflammation but in also in other patients and diseases where inflammation is an inciting and key factor in the pathogenesis. Exploring the relationship between microbiota induced epigenetic changes and inflammatory responses may underpin the pathophysiology of NEC and lead to novel preventive strategies in the preterm neonate. Our research is significant because our work will provide new knowledge on microbiome-induced epigenetic changes that is relevant to a broad-spectrum of diseases such as cancer, infection and immunity.

项目摘要 在早产新生儿中，过度炎症反应与坏死性小肠结肠炎有关 （NEC），其机制尚不清楚。微生物群及其代谢产物，包括短链脂肪酸 可以通过DNA甲基化和/或组蛋白脱乙酰化以及特定的微生物组模式来修饰表观基因组 与脂质代谢，肥胖和 炎。 这项研究的长期目标是确定过度炎症反应的机制 导致NEC并制定抗炎治疗和预防策略。特定假设 拟议的研究是，发育中的肠道微生物组引起的表观遗传变化导致 过度的免疫和炎症反应使早产中的坏死性小肠结肠炎易于 新生儿。我们打算通过首先建立早产儿的DNA甲基化改变来检验这一假设 与匹配对照相比，NEC与特定目标的嵌套队列临床设计相比。DNA甲基化 将在肠上皮细胞和外周血单核细胞中描绘模式，并确认 从粪便中的肠上皮细胞中具有转录组学的差异基因表达式，并评估 系统性和肠炎。在我们的第二个特定目标中，我们将检验以下假设 微生物组和代谢组学特征与表观基因组和转录组的变化有关 NEC的早产新生儿。在注册的队列中，我们将通过宏基因组学评估粪便微生物组 用于微生物代谢物的粪便和尿液代谢组和记录临床元数据（例如胎龄， 进食）用于多变量分析。我们预计与与之相关的独特微生物组和代谢组特征 NEC中的DNA甲基化改变。对手术样本中肠托的后续研究将用于 通过测量暴露于特定炎症的表观遗传变化，从机械上测量我们的假设， 从提出的研究中鉴定出的微生物或代谢组刺激。 拟议的研究具有创新性，因为与微生物组和 早产婴儿的炎症尚未评估。我们提出了一种整体，多派的方法 描述早产儿过度炎症的机制。我们的研究不仅会使 在新生儿病学领域的影响，主要器官发病与炎症有关，但在其他方面也 炎症是发病机理中煽动性和关键因素的患者和疾病。探索 菌群诱导的表观遗传变化和炎症反应之间的关系可能是 NEC的病理生理学并导致早产新生儿的新预防策略。我们的研究是 意义重大，因为我们的工作将提供有关微生物组引起的表观遗传变化的新知识，那就是 与癌症，感染和免疫等广泛疾病有关。