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

摘要 过度饮酒是一个全球性问题，是世界上第三大疾病风险因素， 残疾，占全球死亡人数的5.9%。酒精相关性肝病（ALD）是一种 约20 - 30%患者的疾病谱开始于脂肪变性，进展为纤维化，最后为肝硬化 在慢性过量饮酒者中。然而，其余70-80%的酒精使用障碍（AUD）患者 不会发展成严重的ALD。因此，我们询问可能阻止AUD患者的因素是什么 进入ALD。ALD患者肠道菌群及其代谢产物的组成发生显著变化 患者与AUD和健康受试者相比，在显示ALD发病机制中起关键作用。我们 在ALD小鼠中的初步研究显示，用肠道微生物代谢物尿石素A（UroA）治疗显著地 降低ALD发病率。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+狂饮ALD小鼠模型中的肝炎。UroA是一种饮食微生物代谢产物， 鞣花单宁/鞣花酸丰富的饮食，如石榴，核桃和浆果。我们假设窝藏UroA- 在健康或AUD受试者中产生细菌可以防止发展严重的ALD。在这个探索性的 项目，我们将测试假设，微生物群及其代谢产物（尿石素）在健康和AUD没有 ALD与患有ALD的AUD患者不同，当与富含UroA的饮食结合时， 在EA/ET或直接补充UroA将防止ALD进展。为了验证这个假设，我们 提出了两个具体目标。在目标1中，我们将收集健康、AUD和重度ALD患者的粪便样本 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）产生或不产生UroA的粪便样品（收集的 来自健康/AUD/ALD受试者）至无菌小鼠。在目标2中，这些人源化微生物群小鼠（UroA 生产者与非生产者）将经受慢性+狂饮（10+1）ALD模型并确定ALD的程度 这些小鼠在补充EA后的发育。此外，我们将测试是否直接补充 UroA减轻这些人源化微生物群小鼠中的严重ALD。在成功完成这些研究后， 我们将确定产生UroA的微生物群和/或UroA的直接补充是否提供保护， 在人源化微生物群小鼠中对抗ALD。这些研究将揭示微生物群依赖的 个性化的饮食模式来控制ALD。

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.