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 过度食用酒精是一个全球问题，是世界上第三大疾病的风险因素， 残疾，占全球所有死亡人数的5.9％。酒精相关肝病（ALD）是 从脂肪变性开始到纤维化的疾病范围，最终在约20％至30％的患者中肝硬化 在慢性饮酒者中。但是，患有酒精使用障碍（AUD）患者的70-80％的其余 可能不会发展为严重的ALD。因此，我们询问了哪些因素可能阻止AUD患者 进入ALD。肠道菌群及其代谢产物的组成在ALD中明显变化 与AUD和健康受试者相比，患者在表现ALD发病机理中起着至关重要的作用。我们的 对ALD小鼠小鼠的初步研究表明，用肠道微生物代谢产物尿石A（UROA）的治疗显着 减少了ALD发病机理。 UROA治疗降低了EtOH诱导的肠道通透性，肝脂肪变性和 慢性慢性+暴饮暴食小鼠模型中的肝炎。 UROA是一种由饮食中的微生物代谢产生的 伊拉吉宁/椭圆酸饮食，例如石榴，核桃和浆果。我们假设藏有uroa- 在健康或AUD受试者中产生细菌可能会阻止出现严重的ALD。在此探索性中 项目，我们将测试假设的菌群及其代谢产物（urolithins）的健康和AUD ALD与AUD ALD患者不同，并且与饮食富含饮食相结合时，存在UROA产生的细菌 在EA/ET或直接补充UROA中，将防止ALD进展。为了检验这一假设，我们 提出了两个具体目标。在AIM 1中，我们将从健康，AUD和严重ALD患者中收集粪便样品 并确定其在体外培养物中产生UROA的能力。接下来，我们将产生人源化的微生物群小鼠 （hmm）通过产生UROA的粪便菌群移植（FMT）或非生产粪便样品（收集 从健康/AUD/ALD受试者）到无细菌小鼠。在AIM 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+暴饮暴食（10+1）ALD模型，并确定ALD的程度 这些小鼠补充EA时的发展。此外，我们将测试是否直接补充 Uroa在这些人源性微生物群中减轻严重的ALD。成功完成这些研究后， 我们将确定产生UROA的微生物群和/或直接补充UROA是否提供保护 在人源化菌群小鼠中对抗ALD。这些研究将取消依赖菌群的潜力 个性化饮食模式以控制ALD。