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

基本信息

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
项目类别：
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

项目摘要

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，酒精性肝病 (ALD) 影响着超过 1000 万人，占肝硬化相关死亡人数的 48%。目前，酒精性肝硬化和癌症唯一有效的治疗选择是肝移植。因此，开发新的治疗策略势在必行。酒精引起的内毒素血症是引起ALD的关键因素。越来越多的数据表明，过量的乙醇摄入通过两种主要机制诱发内毒素血症：1）刺激细菌过度生长；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) 可以抑制酒精引起的肠道通透性过高。我们将检验这样的假设：尽管饮酒，乳铁蛋白仍能维持肠道菌群的平衡并保持肠道的完整性，因此，乳铁蛋白可以防止内毒素转移至门静脉，减少内毒素血症，并减弱 ALD。拟议研究的具体目标是：（目标 1）确定 LF 是否通过减少酒精引起的肠漏和内毒素血症来减轻 ALD。将雌性 C57Bl/6J 小鼠分为几组并用以下药物治疗：i) Liber-DeCarli 对照流质饮食，ii) 含酒精流质饮食，iii) LF (50 mg/kg)，iv) 酒精加不同剂量的 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脏炎症和损伤； b) LF 对肠道屏障功能的保护作用是由于 LF 诱导肠道上皮细胞生长/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 是否可以减轻酒精引起的肠道菌群失调。该目标将分析和比较 4 组小鼠的肠道微生物群，这些小鼠分别接受 i) Liber-DeCarli 对照流质饮食、ii) 含酒精流质饮食、iii) LF、iv) 酒精加 LF 治疗。我们将研究 a) 酒精治疗是否会增加促炎性肠道微生物（例如，革兰氏阴性内毒素产生细菌）的流行率和/或丰度，并减少抗炎微生物（例如，乳酸杆菌、双歧杆菌）的出现； b) 口服 LF 可恢复正常的肠道微生物组。（目标 3）。识别酒精和酒精加 LF 给药后不同的微生物和宿主基因表达网络。将分析微生物和宿主转录组，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）口服酒精是否会诱导1）产生酒精代谢致病产物的肠道微生物代谢网络和2）表明肠道屏障功能障碍的宿主肠道的基因表达谱。我们还将研究口服 LF 是否可以改善酒精引起的微生物和宿主肠道基因表达谱的变化。