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.

摘要 过度饮酒是一个全球性的问题，是世界上第三大疾病和 残疾，占全世界所有死亡人数的5.9%。酒精相关性肝病(ALD)是一种 约20%至30%的患者中，疾病谱始于脂肪变性，进展为纤维化，最后发展为肝硬变 长期过量饮酒的人。然而，其余70%-80%的酒精使用障碍(AUD)患者 可能不会进展为严重的ALD。因此，我们询问了哪些因素可能会预防AUD患者 才能进入阿尔茨海默病。ALD患者肠道微生物区系组成及其代谢物存在显著差异 AUD患者与AUD和健康受试者相比，在ALD发病机制中起着关键作用。我们的 对ALD小鼠的初步研究表明，肠道微生物代谢物尿素A(UroA)对ALD有显著治疗作用 降低ALD的发病机制。Uroa治疗可降低乙醇诱导的肠通透性、肝脏脂肪变性和 慢性、慢性+暴饮性ALD小鼠模型中的肝炎。尿酸是一种饮食微生物代谢物，由 富含鞣花酸的饮食，如石榴、核桃和浆果。我们假设窝藏乌罗阿- 在健康或AUD受试者中产生细菌可能会防止发生严重的ALD。在这个探索性的 项目中，我们将测试微生物区系及其代谢物(尿激素类)在健康人群和澳大利亚人中的假设。 ALD不同于患有ALD的AUD患者，当与富含尿酸的饮食相结合时，ALD患者中存在产尿酸细菌 在EA/ET中或直接补充Uroa可以防止ALD的进展。为了检验这一假设，我们 提出了两个具体目标。在目标1中，我们将收集健康、AUD和严重ALD患者的粪便样本 并确定它们在体外培养产生尿酸的能力。接下来，我们将产生人源化的微生物区系小鼠 (HMM)通过粪便微生物区系移植(FMT)产生尿液或不产生尿液的粪便样本(收集 从健康/AUD/ALD受试者)到无菌小鼠。在目标2中，这些人源化的微生物群小鼠(Uroa 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。此外，我们将测试是否直接补充 Uroa可减轻这些人源化微生物区系小鼠的严重ALD。在成功完成这些研究后， 我们将确定产生尿酸的微生物区系和/或直接补充尿酸是否提供保护 在人源化微生物群小鼠中对抗ALD。这些研究将揭开依赖微生物区系的潜力 控制ALD的个性化饮食模式。