Effect of Lactoferrin on Alcohol-Induced Dysbiosis and Gut Barrier Dysfunction

乳铁蛋白对酒精引起的生态失调和肠道屏障功能障碍的影响

• 批准号: 8568645
• 负责人: Cynthia Ju
• 金额: $ 22.23万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568645
• 关键词: Accounting; Adrenal Cortex Hormones; Affect; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacteria; Bifidobacterium; Biochemical Pathway; Cessation of life; Data; Development; Diet; Dose; Endotoxemia; Endotoxins; Enteral; Epithelial Cells; Equilibrium; Ethanol Metabolism; Extravasation; Female; Functional disorder; Gene Expression; Gene Expression Profile; Heavy Drinking; Hepatic; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Intestines; Lactobacillus; Lactoferrin; Lead; Liquid substance; Liver; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Mediating; Messenger RNA; Microbe; Modeling; Molecular Profiling; Mucous Membrane; Mus; Oral Administration; Pathology; Permeability; Pharmaceutical Preparations; Phenotype; Play; Portal vein structure; Prevalence; Risk Factors; Role; Severities; Therapeutic; Tissues; alcohol abuse therapy; cell growth; chronic liver disease; effective therapy; gut microbiota; health economics; innovation; liver transplantation; microbial host; microbiome; migration; next generation sequencing; novel therapeutics; prevent; protective effect; public health relevance; regenerative; Accounting; Adrenal Cortex Hormones; Affect; Alcohol consumption; Alcohol-Induced Disorders; Alcoholic Liver Diseases; Alcohols; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Attenuated; Bacteria; Bifidobacterium; Biochemical Pathway; Cessation of life; Data; Development; Diet; Dose; Endotoxemia; Endotoxins; Enteral; Epithelial Cells; Equilibrium; Ethanol Metabolism; Extravasation; Female; Functional disorder; Gene Expression; Gene Expression Profile; Heavy Drinking; Hepatic; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Intestines; Lactobacillus; Lactoferrin; Lead; Liquid substance; Liver; Liver Cirrhosis; Liver diseases; Malignant neoplasm of liver; Mediating; Messenger RNA; Microbe; Modeling; Molecular Profiling; Mucous Membrane; Mus; Oral Administration; Pathology; Permeability; Pharmaceutical Preparations; Phenotype; Play; Portal vein structure; Prevalence; Risk Factors; Role; Severities; Therapeutic; Tissues; alcohol abuse therapy; cell growth; chronic liver disease; effective therapy; gut microbiota; health economics; innovation; liver transplantation; microbial host; microbiome; migration; next generation sequencing; novel therapeutics; prevent; protective effect; public health relevance; regenerative

DESCRIPTION (provided by applicant): In the U.S., alcohol liver disease (ALD) affects more than 10 million people and accounts for 48% of liver cirrhosis-associated deaths. Currently, the only effective treatment option for alcohol-induced liver cirrhosis and cancer is liver transplantation. Therefore, it is imperative to develop new therapeutic strategies. Alcohol-induced endotoxemia is a critical factor in causing ALD. Accumulating data demonstrate that excess ethanol intake induces endotoxemia through two main mechanisms: 1) stimulation of bacterial overgrowth and 2) disruption of gut mucosal barrier dysfunction. Our preliminary studies demonstrate that lactoferrin (LF) suppresses alcohol-induced gut hyper-permeability. We will examine the hypotheses that lactoferrin can maintain the balance of gut microbiota and preserve the integrity of the intestines despite alcohol consumption, and as a result, lactoferrin prevents the transfer of endotoxin to the portal vein, reduces endotoxemia, and attenuates ALD. The Specific Aims of the proposed studies are: (Aim 1) Determine whether LF attenuates ALD by reducing alcohol-induced gut leakage and endotoxemia. Female C57Bl/6J mice will be divided into several groups and treated with: i) Liber-DeCarli control liquid diet, ii) alcohol-containing liquid diet, iii) LF (50 mg/kg), iv) alcohol plus various doses of LF. We will examine whether a) oral administration of LF prevents endotoxin transfer from the gut to the portal vein and decreases alcohol-induced hepatic inflammation and injury; and b) the protective effects of LF on gut barrier function are due to LF-induced gut epithelial cell growth/migration and/or suppression of the inflammatory response of epithelial cells to LPS stimulation. (Aim 2). Determine whether LF attenuates alcohol-induced enteric dysbiosis. This aim will profile and compare enteric microbiomes in 4 groups of mice treated with i) Liber-DeCarli control liquid diet, ii) alcohol-containing liquid diet, iii) LF, iv) alcohol plus LF. We will investigate whether a) alohol treatment increases the prevalence and/or abundance of pro-inflammatory enteric microbes (e.g., Gram-negative endotoxin producing bacteria) and reduces the occurrence of anti-inflammatory microbes (e.g., lactobacilli, bifidobacteria); and b) oral administration of LF restores the normal enteric microbiome. (Aim 3). Identify microbial and host gene-expression networks that differ following alcohol and alcohol plus LF administration. Microbial and host transcriptomes will be profiled in order to determine how alcohol and/or LF alter the metabolic networks operating in the enteric mucosa. We will determine whether a) oral administration of alcohol induces gene expression profiles in 1) metabolic networks of enteric microbes that produce pathogenic products of alcohol metabolism and 2) host intestines that are indicative of gut barrier dysfunction. We will also examine whether oral administration of LF ameliorates alcohol-induced changes in microbial and host enteric gene expression profiles.

描述（由申请人提供）：在美国，酒精肝病（ALD）影响超过1000万人，占肝硬化相关死亡的48％。目前，酒精诱导的肝硬化和癌症的唯一有效治疗方法是肝移植。因此，必须制定新的治疗策略。酒精引起的内毒素血症是引起ALD的关键因素。积累数据表明，过量的乙醇摄入量通过两种主要机制诱导内毒素血症：1）刺激细菌过度生长和2）破坏肠粘膜屏障功能障碍。我们的初步研究表明，乳铁蛋白（LF）抑制了酒精诱导的肠道超透度性。我们将研究乳铁蛋白可以维持肠道菌群的平衡并保持肠道的完整性的假设，结果，乳铁蛋白会阻止内毒素转移到门静脉静脉中，减少内毒素毒素，并减少内毒素。拟议的研究的具体目的是：（目标1）确定LF是否通过减少酒精诱导的肠道泄漏和内毒素血症来减轻ALD。雌性C57BL/6J小鼠将分为几组，并接受：i）自由核对液体饮食，ii）含酒精的液体饮食，iii）LF（50 mg/kg），iv），iv）酒精以及各种剂量的LF。我们将检查a）口服LF是否可以防止内毒素从肠道转移到门静脉，并减少酒精引起的肝炎和损伤； b）LF对肠道屏障功能的保护作用是由于LF诱导的肠道上皮细胞生长/迁移和/或抑制上皮细胞对LPS刺激的炎症反应。 （目标2）。确定LF是否会减弱酒精引起的肠性疾病障碍。该目标将介绍和比较4组用i）liber-decarli控制液体饮食的小鼠中的肠微生物组，ii）含酒精的液体饮食，iii）lf，iv），iv）酒精加LF。我们将研究A）A）丙赤而治疗是否会增加促炎性肠性微生物（例如革兰氏阴性内毒素产生细菌）的患病率和/或丰度，并降低了抗炎性微生物的发生（例如，乳酸菌，双杆菌，双杆菌）； b）口服LF恢复正常的肠微生物组。 （目标3）。确定在酒精和酒精以及LF给药后不同的微生物和宿主基因表达网络。微生物和宿主转录组将进行分析，以确定酒精和/或LF如何改变肠粘膜中运行的代谢网络。我们将确定a）酒精的口服是否在1）产生酒精代谢的致病产物的肠性微生物的代谢网络中诱导基因表达谱以及2）指示肠道屏障功能障碍的宿主肠。我们还将检查LF的口服是否可以改善酒精诱导的微生物和宿主肠基因表达谱的变化。