The role of the gut microbiome as a non-genetic factor in influencing excessive alcohol drinking.

肠道微生物组作为非遗传因素在影响过量饮酒中的作用。

• 批准号: 9978443
• 负责人: Yanjiao Zhou
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-20 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978443
• 关键词: Acetylation; Acute; Affect; Alcohol consumption; Alcohols; Amygdaloid structure; Antibiotics; Attention; Bacteria; Behavior; Biological Markers; Biotin; Blood; Blood - brain barrier anatomy; Brain; Brain Diseases; Butyrates; Chromatin; Chromatin Structure; Chronic; Colon; Controlled Environment; Development; Disease; Economics; Environment; Epigenetic Process; Ethanol; Etiology; Feces; Fermentation; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Genomics; Goals; Health; Heavy Drinking; Histone Deacetylase Inhibitor; Immune; Individual; Linear Regressions; Mass Spectrum Analysis; Measures; Mediating; Medical; Microbe; Modification; Molecular; Mus; Neurons; Neuropsychology; Oral Administration; Pathway interactions; Phenotype; Physiological Processes; Population; Predisposition; Prefrontal Cortex; Prevention; Prevention strategy; Preventive; Property; Public Health; Rattus; Regulation; Risk; Role; Sample Size; Testing; Therapeutic; Transplant Recipients; Transplantation; Variant; Vitamins; Volatile Fatty Acids; Work; alcohol abuse therapy; alcohol exposure; alcohol measurement; alcohol use disorder; biomarker identification; brain tissue; chronic alcohol ingestion; data reduction; drinking; drinking behavior; drinking water; dysbiosis; epigenetic regulation; epigenome; experimental study; fecal transplantation; gut microbes; gut microbiome; histone modification; improved; individual variation; insight; metagenomic sequencing; microbial; microbiome; microbiome analysis; microbiota; neurophysiology; non-genetic; novel; novel therapeutics; prebiotics; preference; sex; social; transcriptome

Alcohol Use Disorder (AUD) is a devastating disease with negative health, social, and economic consequences. AUD susceptibility is regulated by both genetic and non-genetic factors. While advances in genetics and genomics have allowed us to gain insight into the role of host genes in AUD, environmental contributions to AUD such as the microbiome, have not been well defined. The gut microbiome represents a non-genetic contributor to many neuro-psychological conditions. Although several studies have established that acute and chronic alcohol use is associated with dysbiosis of the gut microbiome, no study has investigated whether the basal gut microbiome (before drinking) influences the risk of developing excessive drinking. Work by us and others showed that genetically identical C57BL/6J (B6J) mice varied widely in alcohol intake and blood ethanol concentration (BEC). Our microbiome and metabolite analysis showed mice with lower levels of butyrate in stool, prior to alcohol intake, had higher levels of alcohol intake and BEC, and harbored a lower level of Clostridia bacteria, compared to low-drinking mice. Butyrate is a group of short-chain fatty acids (SCFAs) produced by gut microbes through fermentation. Clostridia possess strong immune-modulatory properties and are a major producer of butyrate. Butyrate can function as histone deacetylase inhibitors (HDACi), which affect gene expression by histone modification. Epigenetic regulation of gene expression has emerged as a potentially important mechanism in the regulation of alcohol intake. We hypothesize that the gut microbiome /microbial metabolites can regulate chromatin plasticity in brain, and subsequently altering neuronal transcription and eventually affecting behavior. In Aim 1, we will establish correlations between the gut microbiome/metabolites, alcohol drinking, and epigenetic alterations of B6J mice. This aim will confirm our preliminary findings with a large sample size and extend to epigenetic characterization of mice with differential drinking. In Aim 2, we will test whether high- and low- drinking phenotypes are transmissible using fecal transplantation, and further test whether specific microbes and/or metabolites are responsible for differential drinking behavior. Epigenetic characterization including histone modification and global gene expression will be performed to gain mechanistic insight into the influence of the microbiome on alcohol preference. Our proposed work will test the role of the gut microbiome in alcohol preference, improve our understanding of the etiology of AUD, and lay the groundwork to develop novel therapeutic strategies for AUD, including pro- and/or prebiotic manipulation of the gut microbiome.

酒精使用障碍（AUD）是一种破坏性疾病，对健康，社会和经济产生负面影响 后果AUD易感性受遗传和非遗传因素的共同调控。而 遗传学和基因组学的进步使我们能够深入了解宿主基因在 AUD，环境对AUD的贡献，如微生物组，尚未得到很好的定义。 肠道微生物组是许多神经心理疾病的非遗传因素。 尽管一些研究已经确定，急性和慢性饮酒与 肠道微生物组的生态失调，没有研究调查基础肠道微生物组是否 （饮酒前）影响过度饮酒的风险。我们和其他人的工作 结果表明，遗传相同的C57 BL/6 J（B6 J）小鼠在酒精摄入量和血液中的差异很大， 乙醇浓度（BEC）。我们的微生物组和代谢物分析显示， 在酒精摄入之前，粪便中的丁酸盐水平具有较高的酒精摄入量和BEC水平， 与低饮酒量的小鼠相比，具有较低水平的梭状芽孢杆菌。丁酸盐是一个基团 短链脂肪酸（SCFA）是由肠道微生物通过发酵产生的。梭菌 具有很强的免疫调节特性，是丁酸盐的主要生产者。丁酸 可以作为组蛋白去乙酰化酶抑制剂（HDACi），通过组蛋白去乙酰化酶抑制剂影响基因表达， 改性基因表达的表观遗传调控已经成为一个潜在的重要 调节酒精摄入的机制。我们假设肠道微生物组/微生物 代谢物可以调节脑中染色质的可塑性， 转录并最终影响行为。在目标1中，我们将建立 肠道微生物组/代谢物、饮酒和B6 J小鼠的表观遗传改变。这一目标 将证实我们的初步发现与大样本量，并扩展到表观遗传 对具有差异饮水的小鼠的表征。在目标2中，我们将测试高-和低- 饮酒表型可以通过粪便移植传播，并进一步测试是否 特定的微生物和/或代谢物导致不同的饮酒行为。后生 将进行包括组蛋白修饰和整体基因表达的表征， 获得对微生物组对酒精偏好影响的机械见解。我们提出的 这项工作将测试肠道微生物组在酒精偏好中的作用，提高我们对 的病因学，并为开发新的治疗策略奠定基础， 包括肠道微生物组的亲生物和/或益生元操纵。