The role of alcohol-associated microbiota membrane vesicles in mucosal immunity

酒精相关微生物膜囊泡在粘膜免疫中的作用

• 批准号: 10751767
• 负责人: Daniel Villageliu
• 金额: $ 7.1万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-28 至 2026-04-27
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10751767
• 关键词: Accounting; Address; Alcohol consumption; Alcohols; Bacteria; Bacterial Antibiotic Resistance; Bacterial Pneumonia; Biological; Cells; Chemicals; Chronic; Cirrhosis; Clostridium; Data; Development; Disease; Epithelium; Ethanol; Excretory function; Frequencies; Functional disorder; Future; Gastrointestinal tract structure; Goals; Growth; Health; Host Defense; Human; In Vitro; Individual; Indoles; Infection; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Intestines; Klebsiella pneumoniae; Lung; Lung immune response; Malignant Neoplasms; Mediating; Membrane; Membrane Potentials; Morbidity - disease rate; Mucosal Immunity; Mucous Membrane; Mus; Pathogenesis; Pathogenicity; Predisposition; Property; Proteomics; Research; Respiratory System; Respiratory Tract Infections; Risk; Role; Sampling; Source; Streptococcus pneumoniae; Stress; Substance Use Disorder; TNF gene; Testing; Therapeutic; Therapeutic Intervention; Tryptophan; Vesicle; alcohol effect; alcohol exposure; alcohol misuse; alcohol use disorder; cytokine; dietary; disability-adjusted life years; dysbiosis; effector T cell; gut microbes; gut microbiota; host-microbe interactions; improved; infancy; insight; metabolomics; microbial; microbiota; mortality; novel; novel therapeutics; pathogen; tissue injury; years of life lost

A significant portion of the global burden of AUD (Alcohol use disorder) derives from an increased risk and susceptibility to diseases including infection, cirrhosis, and cancer. These diseases are influenced by the composition of the intestinal microbiota, which is altered by alcohol use. Though it has been accepted that change to the microbiota contributes to disease establishment and progression in AUD, our understanding of the mechanisms by which this occurs is inadequate. These mechanisms likely involve a variety of microbiota- derived products (membrane vesicles, excreted chemicals, cellular components, LPS, etc.). The preliminary data addressed herein support the proposition that microbiota-derived membrane vesicles (MVs) are an important driver of alcohol-driven tissue injury. To address this possibility, this proposal will examine the effects of alcohol on the composition and frequency of microbiota derived MVs. This proposal will also evaluate the effects of alcohol-associated MVs on promoting tissue injury and mucosal infection. Our preliminary data demonstrate that alcohol alters the composition of MVs generated by the gut microbiota, and that isolated alcohol-associated MVs increase susceptibility to respiratory infection, independent of alcohol use, suggesting that MVs influence mucosal host defense. We hypothesize that MVs from an alcohol-associated microbiota will have increased inflammatory properties and increase susceptibility to mucosal infections via epithelial inflammation and barrier dysfunction. Understanding the alterations to bacterial MVs following alcohol exposure may give new insight into disease pathogenesis, which may inspire future therapies centered on modulating MVs.

AUD（酒精使用障碍）的全球负担的很大一部分来自风险增加， 易患疾病，包括感染、肝硬化和癌症。这些疾病是受 肠道微生物群的组成，这是由酒精的使用改变。尽管大家都认为 微生物群的变化有助于AUD的疾病建立和进展，我们对 发生这种情况的机制是不充分的。这些机制可能涉及各种微生物群- 衍生产物（膜囊泡、排泄的化学物质、细胞组分、LPS等）。初步数据 本文提出的支持微生物来源的膜囊泡（MV）是一个重要的 酒精导致的组织损伤 为了解决这一可能性，本提案将研究酒精对以下物质的组成和频率的影响： 微生物群衍生的MV。该提案还将评估与酒精相关的MV对促进 组织损伤和粘膜感染。我们的初步数据表明，酒精改变了MV的组成 由肠道微生物群产生，并且孤立的酒精相关MV增加了对呼吸道感染的易感性。 感染，独立于酒精的使用，这表明MV影响粘膜宿主防御。我们假设 来自酒精相关微生物群的MV将具有增加的炎症特性，并增加 通过上皮炎症和屏障功能障碍对粘膜感染易感。了解 酒精暴露后细菌MV的改变可能会为疾病发病机制提供新的见解， 可能会激发未来以调节MV为中心的治疗方法。