The Effect of a Probiotic on Hepatic Steatosis

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)是美国慢性肝病最常见的原因。NAFLD包括一系列肝脏病理，从临床上最迟钝的脂肪肝(脂肪变性)到发生肝脏特异性发病率和死亡率最高的肝硬变。事实上，非酒精性脂肪肝现在被认为是曾经被归类为“隐源性肝硬变”的主要原因。隐源性肝硬变占每年与肝脏相关的死亡人数的一半。NAFLD的研究由于缺乏一种易于测量的、临床相关的结果指标而受到阻碍。治疗NAFLD非常需要安全、廉价、耐受性好的治疗方法。 最近在动物模型上的突破进一步加深了对NAFLD发病机制的理解，并为开发有效的治疗方法提供了希望。基于我们自己实验室的大量工作，我们的总体假设是，肠道细菌过度生长(IBO)产生的酒精和脂多糖(LPS)会导致肝脏中的炎症信号，从而导致肝脏胰岛素抵抗和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)抗体治疗了NAFLD小鼠模型。事实上，这两种治疗方法都减少了明确的分子炎症途径的激活，并通过活检改善了脂肪变性。这一令人兴奋的初步数据为研究人体益生菌提供了理论基础。因此，该项目只有一个特定的目的：确定益生菌治疗是否可以减少患有非酒精性脂肪肝的人类肝脏脂肪变性。我们建议对30名NAFLD患者进行4个月的双盲、随机、安慰剂对照的先导性研究。主要的观察指标将是通过活检评估肝脏脂肪变性的分级。我们还将通过磁共振波谱(MRS)测量脂肪变性。益生菌是安全、耐受性良好的自然疗法，可能会改善NAFLD，这是令人兴奋的，因为与肝脏相关的发病率和死亡率是大多数慢性肝病(包括NAFLD)的晚期并发症。因此，益生菌的安全性使其成为一种可能需要慢性治疗的疾病的有吸引力的治疗选择。如果益生菌的疗效被确定为一种慢性肝病，那么类似的生物疗法可能会使其他慢性炎症状态受益的可能性将值得进一步评估。

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.