Role of urolithin A in progression of alcohol-associated liver disease

尿石素 A 在酒精相关性肝病进展中的作用

• 批准号: 10574163
• 负责人: Venkatakrishna Rao Jala
• 金额: $ 22.5万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574163
• 关键词: Accounting; Alcoholic Liver Diseases; Alcohols; Attenuated; Bacteria; Berry; Cessation of life; Chronic; Cirrhosis; Colitis; Collaborations; Consumption; Development; Diet; Diet Habits; Dietary Practices; Disease; Disease Progression; Disease model; Ellagi-Tannins; Ellagic Acid; Endotoxins; Exhibits; Fatty Liver; Fibrosis; Genetic; Germ-Free; Goals; Health; Heavy Drinking; Hepatitis; Human; In Vitro; Inflammation; Intestinal permeability; Juglans; Laboratories; Liver diseases; Mediating; Modeling; Molecular; Mus; Obesity; Pathogenesis; Patients; Pilot Projects; Play; Pomegranate; Pre-Clinical Model; Preventive; Primary carcinoma of the liver cells; Production; Regulation; Rest; Risk Factors; Role; Sampling; Supplementation; Testing; Therapeutic; Treatment Efficacy; alcohol research; alcohol use disorder; cigarette smoking; clinically significant; deter alcohol use; dietary; disability; dysbiosis; epidemiologic data; experience; experimental study; fecal transplantation; gut microbiota; high reward; high risk; human subject; liver inflammation; liver injury; microbial; microbiome; microbiota; mouse model; prevent; problem drinker; stool sample

Abstract Excessive consumption of alcohol is a global problem and is the world’s third largest risk factor for diseases and disabilities, and accounting for 5.9% of all deaths worldwide. Alcohol-associated liver disease (ALD) is a spectrum of disease that starts with steatosis progressing to fibrosis and finally cirrhosis in ~20 to 30% patients of in chronic excessive alcohol drinkers. However, rest of the 70-80% with alcohol use disorders (AUD) patients may not progress into severe ALD. Therefore, we asked what are factors that potentially prevent AUD patients to progress in to ALD. The composition of gut microbiota and their metabolites are significantly vary in ALD patients compared to AUD and healthy subjects and play a critical role in manifesting ALD pathogenesis. Our pilot studies in mouse of ALD showed that treatment with gut microbial metabolite Urolithin A (UroA) significantly reduced ALD pathogenesis. UroA treatment decreased EtOH-induced gut permeability, hepatic steatosis and hepatitis in chronic, chronic+binge ALD mouse models. UroA is a dietary microbial metabolite produced from ellagitannin/ellagic acid-rich diets such as pomegranate, walnuts and berries. We postulate that harboring UroA- producing bacteria in healthy or AUD subjects may prevent from developing severe ALD. In this exploratory project, we will test the hypothesize that microbiota and their metabolites (urolithins) in healthy and AUD without ALD differ from AUD patients with ALD, and presence of UroA-producing bacteria when combined with diets rich in EA/ET or with direct supplementation of UroA will protect from ALD progression. To test this hypothesis, we proposed two specific aims. In aim 1, we will collect stool samples from healthy, AUD and severe ALD patients and determine their ability to produce UroA in vitro cultures. Next, we will generate humanized microbiota mice (HMM) by fecal microbiota transplantation (FMT) of UroA-producing or non-producing stool samples (collected from healthy/AUD/ALD subjects) in to germ free mice. In aim 2, these humanized microbiota mice (UroA producers vs non-producers) will subjected to chronic+binge (10+1) ALD model and determine extent of ALD development in these mice upon supplementing with EA. Further, we will test whether direct supplementation of UroA mitigate severe ALD in these humanized microbiota mice. Upon successful completion of these studies, we will determine whether UroA-producing microbiota and/or direct supplementation of UroA provides protection against ALD in humanized microbiota mice. These studies would unravel potential of microbiota dependent personalized dietary patterns to control ALD.

抽象的 过量饮酒是一个全球性问题，是世界上疾病和疾病的第三大危险因素。 酒精相关性肝病 (ALD) 是一种导致残疾的疾病，占全球死亡人数的 5.9%。 约 20% 至 30% 的患者从脂肪变性开始发展为纤维化，最后发展为肝硬化的一系列疾病 然而，其余 70-80% 患有酒精使用障碍 (AUD) 患者。 可能不会进展为严重 ALD 因此，我们询问哪些因素可能会预防 AUD 患者。 进展为 ALD 时肠道菌群的组成及其代谢物存在显着差异。 与 AUD 和健康受试者相比，患者在 ALD 发病机制中发挥着关键作用。 对 ALD 小鼠的初步研究表明，用肠道微生物代谢物尿石素 A (UroA) 治疗可显着改善 减少 ALD 发病机制。UroA 治疗可降低乙醇诱导的肠道通透性、肝脂肪变性和 慢性、慢性+暴食 ALD 小鼠模型中的肝炎 UroA 是由饮食微生物产生的代谢产物。 富含鞣花单宁/鞣花酸的饮食，如石榴、核桃和浆果，我们假设含有 UroA-。 在本次探索性研究中，健康或 AUD 受试者中产生的细菌可能会预防严重的 ALD。 项目中，我们将测试微生物群及其代谢物（尿石素）在健康和 AUD 中的领导地位，而无需 ALD 与患有 ALD 的 AUD 患者不同，当与富含 UroA 的饮食结合时，存在产生 UroA 的细菌 EA/ET 或直接补充 UroA 将防止 ALD 进展 为了检验这一假设。 在目标 1 中，我们提出了两个具体目标，我们将从健康、AUD 和严重 ALD 患者中收集粪便样本。 并确定它们在体外培养物中产生 UroA 的能力 接下来，我们将生成人源化微生物群小鼠。 (HMM) 通过粪便微生物群移植 (FMT) 产生 UroA 或不产生 UroA 的粪便样本（收集 在目标 2 中，这些人源化微生物群小鼠（UroA）被从健康/AUD/ALD 受试者中转化为无菌小鼠。 生产者与非生产者）将受到慢性+狂欢（10+1）ALD模型的影响并确定ALD的程度 补充 EA 后这些小鼠的发育情况此外，我们将测试是否直接补充 EA。 在成功完成这些研究后，UroA 可减轻这些人源化微生物群小鼠的严重 ALD。 我们将确定产生 UroA 的微生物群和/或直接补充 UroA 是否能提供保护 这些研究将揭示微生物群依赖性的潜力。 控制 ALD 的个性化饮食模式。