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

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导致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个主要机制诱导内毒素血症：1)刺激细菌过度生长和2)破坏肠道黏膜屏障功能障碍。我们的初步研究表明，乳铁蛋白（LF）抑制酒精诱导的肠道超通透性。我们将检验以下假设：尽管饮酒，乳铁蛋白仍能维持肠道微生物群的平衡，保持肠道的完整性，因此，乳铁蛋白可以阻止内毒素转移到门静脉，减少内毒素血症，并减轻ALD。拟议研究的具体目的是：（目的1）确定LF是否通过减少酒精诱导的肠漏和内毒素血症来减轻ALD。将雌性C57Bl/6J小鼠分为几组，分别给予：i)利伯-德卡利对照液体饮食，ii)含酒精液体饮食，iii) LF (50 mg/kg), iv)酒精加不同剂量的LF。我们将检验a)口服LF是否能阻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是否减轻酒精诱导的肠道生态失调。本研究将分析和比较4组小鼠的肠道微生物组：1)利伯-德卡利对照液体饮食，2)含酒精的液体饮食，3)低脂，4)酒精加低脂。我们将调查是否a)酒精治疗增加了促炎肠道微生物（如革兰氏阴性内毒素产生细菌）的患病率和/或丰度，并减少了抗炎微生物（如乳酸菌、双歧杆菌）的发生；b)口服LF可恢复正常肠道微生物群。(3)为目标。鉴定酒精和酒精加LF给药后微生物和宿主基因表达网络的差异。微生物和宿主转录组将被分析，以确定酒精和/或LF如何改变肠粘膜中的代谢网络。我们将确定a)口服酒精是否会诱导1)产生酒精代谢致病性产物的肠道微生物代谢网络中的基因表达谱，以及2)表明肠道屏障功能障碍的宿主肠道。我们还将研究口服LF是否能改善酒精诱导的微生物和宿主肠道基因表达谱的变化。