The Effect of a Probiotic on Hepatic Steatosis

益生菌对肝脂肪变性的影响

基本信息

批准号：
7490760
负责人：
STEVEN F SOLGA
金额：
$ 9.24万
依托单位：
ST. LUKE'S HOSPITAL OF BETHLEHEM PA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-07-02 至 2009-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7490760
关键词：
alcoholic fatty liver biopsy biotherapeutic agent clinical research clinical trials fatty liver human subject human therapy evaluation lipopolysaccharides liver disorder chemotherapy nuclear magnetic resonance spectroscopy outcomes research patient oriented research

项目摘要

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the United States. NAFLD includes a spectrum of hepatic pathology that ranges from fatty liver (steatosis) at the most clinically indolent extreme, to cirrhosis at the opposite extreme where most liver specific morbidity and mortality occurs. Indeed, NAFLD is now thought to be responsible for most of what was once classified as 'cryptogenic cirrhosis'. Cryptogenic cirrhosis accounts for half of the annual liver-related deaths. The study of NAFLD has been hindered by the lack of an easily measurable, clinically relevant outcome measure. Safe, inexpensive, well-tolerated treatments for NAFLD are greatly needed. Recent breakthroughs using animal models have advanced understanding of the pathogenesis of NAFLD and provide hope for the development of effective treatments. Based on extensive work in our own laboratory, our OVERALL HYPOTHESIS is that alcohol and lipopolysacchride (LPS) production by intestinal bacterial overgrowth (IBO) cause inflammatory signaling in the liver that leads to hepatic insulin resistance and NAFLD. To evaluate this possibility, we treated a murine model of NAFLD with probiotics or anti-tumor necrosis factor a (TNF) antibodies. Indeed, both treatments decreased activation of well-defined molecular inflammatory pathways and improved steatosis by biopsy. This exciting preliminary data provides rationale for studying probiotics in humans. Therefore, this project has a single SPECIFIC AIM: to determine if probiotic therapy can decrease hepatic steatosis in humans with NAFLD. We propose a double-blinded, randomized, placebo-controlled four month pilot study of 30 patients with NAFLD. The main outcome measure will be grade of hepatic steatosis evaluated by biopsy. We will also measure steatosis by magnetic resonance spectroscopy (MRS). The possibility that probiotics, which are safe, well-tolerated and natural therapies, might improve NAFLD is exciting because liver-related morbidity and mortality are late complications of most chronic liver diseases, including NAFLD. Thus, the safety profile of probiotics makes them an attractive treatment option for a disease that will likely require chronic therapy. If the efficacy of probiotics is established one type of chronic liver disease, the possibility that similar biological therapies might benefit other chronic inflammatory states would merit further evaluation.

描述（由申请人提供）：非酒精性脂肪肝病（NAFLD）是美国慢性肝病的最常见原因。 NAFLD包括一系列肝病理学，范围从最临床上懒惰的极端脂肪肝（脂肪变性）到大多数肝脏特异性发病率和死亡率的相反极端的肝硬化。的确，现在认为NAFLD是曾经被归类为“隐秘肝硬化”的大多数造成的。隐性肝硬化是年肝有关的一半。由于缺乏易于测量的临床相关结果度量，NAFLD的研究受到了阻碍。非常需要安全，廉价，耐受性良好的NAFLD治疗方法。使用动物模型的最新突破对NAFLD的发病机理有了深入的了解，并为有效治疗的发展提供了希望。基于我们自己的实验室中的广泛工作，我们的总体假设是，肠道细菌过度生长（IBO）的酒精和脂多亚酸（LPS）产生会导致肝脏炎症信号传导，从而导致肝胰岛素抵抗和NAFLD。为了评估这种可能性，我们用益生菌或抗肿瘤坏死因子A（TNF）抗体处理了NAFLD的鼠模型。实际上，两种处理都降低了定义明确的分子炎症途径的激活，并通过活检改善了脂肪变性。这种令人兴奋的初步数据为研究人类益生菌提供了理由。因此，该项目具有一个特定的目的：确定益生菌治疗是否可以减少NAFLD人类的肝脂肪变性。我们建议对30例NAFLD患者进行一项双盲，随机，安慰剂对照的四个月初步研究。主要结果指标将是通过活检评估的肝脂肪变性等级。我们还将通过磁共振光谱（MRS）测量脂肪变性。安全，耐受性良好且自然疗法的益生菌可能会改善NAFLD的可能性令人兴奋，因为与肝脏有关的发病率和死亡率是包括NAFLD在内的大多数慢性肝脏疾病的晚期并发症。因此，益生菌的安全性使它们成为可能需要慢性治疗的疾病的有吸引力的治疗选择。如果确定益生菌的疗效是一种慢性肝病，那么类似的生物疗法可能使其他慢性炎症状态受益的可能性值得进一步评估。