Intestine FXR activation by LGG-derived nanoparticles in alcohol-associated liver disease

许多研究报告了益生菌对酒精相关性肝病（ALD）的疗效。这 反映了科学界和医学界对确定替代或替代药物的强烈兴趣。 目前尚无有效或广泛接受的治疗选择。但在 缺乏关于益生菌如何发挥其作用的深入分子知识。ALD患者经常表现出 胆汁淤积的表现，一种由肝胆汁酸（BA）积累定义的肝脏病理学， 是ALD肝细胞死亡和肝损伤的重要原因。肝BA过多 浓度增加部分是由于BA从头合成增加。我们已经鉴定了一种miRNA（miR 194）， 在喂食酒精的小鼠的肠上皮细胞中过度表达。MmiR 194抑制核受体 FXR由BA激活并调节酪氨酸衍生激素FGF 15的表达，FGF 15的表达在肿瘤的发生中起主要作用。 通过下调Cyp 7A 1抑制BA合成来维持肝脏BA稳态。而 BA对FXR的激活作用已被充分研究，但FXR如何被转录调控尚不清楚。我们的初步 数据显示益生菌鼠李糖乳杆菌GG衍生的纳米颗粒（LDNP）的施用减少了 肠miR 194和增加FXR和FGF 15表达，并减少小鼠肝脏BA和脂肪肝 关于ALD我们假设酒精抑制了转录表达和配体介导的 通过上调miR 194和干扰肠道微生物组-BA转化来激活肠道中的FXR， 分别导致肝脏从头BA合成，脂肪生成和ALD增加，LDNP 补充可减少酒精诱导BA合成和脂肪生成增加，并减弱ALD 通过抑制肠道miR 194表达和调节肠道微生物组BA转化。的 为了检验这一假设，将追求以下具体目标：目标1。确定肠道miR 194在 酒精诱导的肝脏BA合成和脂肪生成失调。目标二。确定LDNP在以下方面的作用： ALD中肠miR 194-FXR-FGF 15信号传导的调节。AIM 3.确定LDNP治疗是否 改变肠道微生物群和BA谱，有助于ALD中的FXR激活。目标4。评估肠道 AH患者的miR 194和FXR活性。总之，拟议的研究代表了第一个分子 肠道miRNA如何调节肝脏BA稳态以及益生菌产品如何靶向肠道的研究 ALD中的miRNA 194-FXR-FGF 15单一化。从这项研究中获得的结果可能会导致改善管理 的ALD。

Numerous studies have reported the efficacy of probiotics for alcohol associated liver disease (ALD). This reflects a strong interest among the scientific and medical communities in identifying alternative or adjunctive approaches for ALD, for which there is no current effective or widely accepted therapeutic option. However, in depth molecular knowledge on how probiotics render their effects is lacking. Patients with ALD often exhibit manifestations of cholestasis, a liver pathology defined by accumulation of hepatic bile acids (BAs), which are toxic and are an important causative factor in hepatocyte death and liver injury in ALD. Excess hepatic BA concentration is partially a result of increased BA de novo synthesis. We have identified a miRNA (miR194) that is overexpressed in the intestinal epithelial cells in mice fed alcohol. MmiR194 suppresses a nuclear receptor FXR that is activated by BAs and regulates intestine-derived hormone, FGF15, expression, which plays a major role in maintaining hepatic BA homeostasis by suppressing BA synthesis via down-regulation of Cyp7A1. While the BA activation of FXR is well-studied, how FXR is regulated transcriptionally is less clear. Our preliminary data showed that probiotic Lactobacillus rhamnosus GG-derived nanoparticles (LDNPs) administration reduced intestinal miR194 and increased FXR and FGF15 expression, and decreased hepatic BAs and fatty liver in mice with ALD. We hypothesize that alcohol suppresses both the transcriptional expression and ligand-mediated activation of FXR in the intestine through upregulating miR194 and disturbing gut-microbiome-BA transformation, respectively, which lead to the increases in hepatic de novo BA synthesis, lipogenesis and ALD and that LDNP supplementation can diminish alcohol-induced increases in BA synthesis and lipogenesis and attenuate ALD through suppressing intestinal miR194 expression and regulating gut microbiome BA transformation. The following specific aims will be pursued to test this hypothesis: Aim 1. Determine the role of intestinal miR194 in the alcohol-induced dysregulation of liver BA synthesis and lipogenesis. Aim 2. Determine the role of LDNPs in the regulation of intestinal miR194-FXR-FGF15 signaling in ALD. AIM 3. Determine whether LDNP treatment alters gut microbiota and BA profile that contribute to FXR activation in ALD. Aim 4. Evaluate the intestinal miR194 and FXR activity in patients with AH. In summary, the proposed study represents the first molecular study on how intestinal miRNA regulates liver BA homeostasis and how a probiotic product targets intestinal miRNA194-FXR-FGF15 singling in ALD. The results obtained from this study may lead to improved management of ALD.