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

酒精使用障碍(AUD)是一种破坏性的疾病，对健康、社会和经济都有负面影响 后果。AUD的易感性受遗传和非遗传因素的调节。而当 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，还没有很好的定义。 肠道微生物群代表了许多神经心理疾病的非遗传因素。 尽管一些研究已经证实，急性和长期饮酒与 肠道微生物群失调，目前还没有研究表明肠道微生物群的基础是否 (饮酒前)会影响过度饮酒的风险。我们和其他人的工作 显示基因相同的C57BL/6J(B6J)小鼠在酒精摄入量和血液方面差异很大 乙醇浓度(BEC)。我们的微生物组和代谢物分析显示，小鼠的 在酒精摄入之前，粪便中丁酸的水平具有更高的酒精摄入量和BEC水平，并且 与低饮酒的小鼠相比，小鼠体内的梭状芽胞杆菌含量较低。丁酸酯是一个基团 肠道微生物通过发酵产生的短链脂肪酸(SCFA)。梭状芽胞杆菌 具有很强的免疫调节特性，是丁酸盐的主要生产商。丁酸盐 可以作为组蛋白脱乙酰酶抑制剂(HDACi)发挥作用，通过组蛋白影响基因表达 修改。基因表达的表观遗传调控已经成为一个潜在的重要因素 酒精摄入量的调节机制。我们假设肠道微生物群/微生物 代谢物可以调节大脑中染色质的可塑性，从而改变神经元 转录并最终影响行为。在目标1中，我们将建立 B6J小鼠肠道微生物群/代谢产物、饮酒和表观遗传学改变。这一目标 将用大样本证实我们的初步发现，并扩展到表观遗传学 有差别饮酒的小鼠的特征。在目标2中，我们将测试高-和低- 饮酒表型可通过粪便移植传播，并进一步测试 特定的微生物和/或代谢物是导致不同饮酒行为的原因。表观遗传 包括组蛋白修饰和全局基因表达在内的表征将被执行以 从机理上洞察微生物群对酒精偏好的影响。我们的建议 这项工作将测试肠道微生物群在酒精偏好中的作用，提高我们对 AUD的病因，并为开发AUD的新治疗策略奠定基础， 包括肠道微生物组的益生素和/或益生素操作。

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.