Microbiota-Mediated Bidirectional Interactions Between Alcohol Misuse and Post-COVID-19 Syndrome

微生物介导的酒精滥用与 COVID-19 后综合症之间的双向相互作用

• 批准号: 10491242
• 负责人: Mohamed Abdel Mohsen
• 金额: $ 20.87万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10491242
• 关键词: 2019-nCoV; Academic Medical Centers; Acute; Acute Disease; Acute Respiratory Distress Syndrome; Alcohol consumption; Alcohols; Biological; Blood; COVID-19; COVID-19 long hauler; COVID-19 mortality; COVID-19 patient; COVID-19 risk; Cause of Death; Chronic; Cohort Studies; Communities; Critical Illness; Data; Development; Diabetes Mellitus; Drug usage; Endotoxins; Enrollment; Feces; Goals; Heavy Drinking; Hypertension; Immune response; Individual; Infection; Inflammation; Inflammatory; Intestines; Knowledge; Lead; Leaky Gut; Link; Long COVID; Longitudinal Studies; Lung; Mediating; Morbidity - disease rate; National Institute on Alcohol Abuse and Alcoholism; Obesity; Organ; Organoids; Patients; Pattern; Pneumonia; Predisposition; Public Health; Quality of life; Questionnaires; Recovery; Risk; Risk Factors; Role; SARS-CoV-2 infection; SARS-CoV-2 negative; Sampling; Serum; Severities; Severity of illness; Structure; Symptoms; Testing; TimeLine; United States; Virus; Work; alcohol effect; alcohol misuse; alcohol risk; alcohol use disorder; arm; associated symptom; coronavirus disease; design; dysbiosis; gut inflammation; gut microbiome; high risk; human disease; immune activation; immune system function; intestinal barrier; lipopolysaccharide-binding protein; low socioeconomic status; machine learning classifier; microbiota; modifiable lifestyle factors; mortality; novel strategies; pathogen; patient screening; patient subsets; phosphatidylethanol; post SARS-CoV-2 infection; post-COVID-19; prevent; recruit; resilience; response; severe COVID-19; socioeconomic disadvantage; zonulin

PROJECT SUMMARY Recent data show that 10-30% of coronavirus disease 2019 (COVID-19) patients do not fully recover and suffer from a wide range of symptoms that persist after the SARS-CoV-2 infection has been cleared (so-called post- COVID-19 syndrome or Long Hauler). Severe COVID-19 and associated risk factors appear to increase the risk of developing post-COVID-19 syndrome and yet a substantial number of patients without known risk factors also develop post-COVID-19 syndrome. Thus, additional risk factors leading to post-COVID-19 syndrome must exist. One potential risk factor is excessive alcohol consumption. (1) Alcohol is the most frequently used drug in the United States, and alcohol use increases during public health crises, especially in socioeconomic disadvantaged communities. (2) Alcohol results in inappropriate immune responses to pathogens. (3) Alcohol disrupts intestinal and lung barrier integrity which can further promote inflammation. We recently showed that increased serum Zonulin (a marker of disrupted intestinal barrier integrity) and increased endotoxin (LBP) are associated with inflammation during COVID-19 and can predict disease severity and mortality. Accordingly, we hypothesize that: (a) there is a bidirectional interaction between alcohol misuse and SARS-CoV-2 infection leading to increased risk of post-COVID-19 syndrome in patients with alcohol use disorder (AUD) and more severe AUD in COVID-19 patients; and (b) the underlying mechanism of these interactions is microbiota dysbiosis and/or disruption of intestinal barrier integrity, promoting inflammation and dysregulated immune-responses to the virus. To test our hypotheses, we will leverage our NIAAA supported COVID-19 supplement at Rush University Medical Center (RUMC), which is actively following more than 7,000 SARS-CoV-2 positive patients and 2,000 SARS- CoV-2 negative patients over 12 months using structured questionnaires. All patients are screened for alcohol use/misuse. Furthermore, we will recruit a subset of patients to provide biological samples to test our mechanistic hypothesis evaluating the link between AUD, post-COVID-19 syndrome, and gut-derived inflammation. In Aim 1, we will test the hypothesis that AUD increases the risk and severity of post-COVID-19 syndrome by promoting gut-derived inflammation. (1a) We will determine if increased alcohol use/misuse is associated with risk and severity of post-COVID-19 syndrome. (1b) We will elucidate the role of gut-derived inflammation in AUD promotion of the post-COVID-19 syndrome by interrogating stool microbiota composition/function, systemic markers of intestinal barrier integrity, inflammation, and immune activation. In Aim 2, we will test the hypothesis that COVID-19 increases the risk and severity of AUD and alcohol-induced intestinal barrier disruption. (2a) we will determine whether post-COVID-19 syndrome is associated with increased risk of AUD. (2b) We will determine if COVID-19 decreases resilience of intestinal barrier to the damaging effects of alcohol which would result in increased risk of alcohol-induced intestinal leak that could lead to organ damage using organoids generated from individuals with and without post-COVID-19 and/or AUD.

项目概要 最近的数据显示，10-30% 的 2019 年冠状病毒病 (COVID-19) 患者未完全康复并遭受痛苦 SARS-CoV-2 感染被清除后仍持续存在的一系列症状（所谓的后 COVID-19 综合症或长拖车）。严重的 COVID-19 和相关风险因素似乎会增加风险 发生 COVID-19 后综合症，但仍有大量患者没有已知的危险因素 出现 COVID-19 后综合症。因此，必然存在导致 COVID-19 后综合征的其他危险因素。 一种潜在的风险因素是过量饮酒。 (1)酒精是最常用的药物 美国，公共卫生危机期间饮酒量增加，特别是在社会经济弱势群体中 社区。 (2)酒精导致对病原体的不适当的免疫反应。 (3)酒精破坏肠道 和肺屏障的完整性，这可以进一步促进炎症。我们最近发现血清增加 连蛋白（肠道屏障完整性破坏的标志物）和内毒素 (LBP) 增加与 COVID-19 期间的炎症，可以预测疾病的严重程度和死亡率。据此，我们假设 (a) 酗酒和 SARS-CoV-2 感染之间存在双向相互作用，导致 酒精使用障碍 (AUD) 和更严重的 AUD 患者患 COVID-19 后综合症的风险增加 COVID-19 患者； (b) 这些相互作用的根本机制是微生物群失调和/或 破坏肠道屏障的完整性，促进炎症和对病毒的免疫反应失调。 为了检验我们的假设，我们将利用拉什大学医学院的 NIAAA 支持的 COVID-19 补充剂 中心（RUMC），正在积极跟踪 7,000 多名 SARS-CoV-2 阳性患者和 2,000 名 SARS- 使用结构化问卷调查超过 12 个月的 CoV-2 阴性患者。所有患者均接受酒精筛查 使用/误用。此外，我们将招募一部分患者提供生物样本来测试我们的机制 评估 AUD、COVID-19 后综合征和肠道源性炎症之间联系的假设。瞄准 1，我们将通过以下方式检验 AUD 会增加 COVID-19 后综合症的风险和严重程度的假设： 促进肠道源性炎症。 (1a) 我们将确定饮酒/滥用酒精的增加是否与之相关 与 COVID-19 后综合症的风险和严重程度有关。 (1b) 我们将阐明肠道源性炎症在 AUD 通过询问粪便微生物群组成/功能、系统性来促进 COVID-19 后综合症 肠道屏障完整性、炎症和免疫激活的标志物。在目标 2 中，我们将测试 假设 COVID-19 会增加 AUD 和酒精引起的肠道屏障的风险和严重程度 扰乱。 (2a) 我们将确定 COVID-19 后综合征是否与 AUD 风险增加相关。 (2b) 我们将确定 COVID-19 是否会降低肠道屏障对酒精破坏性影响的恢复能力 这将导致酒精引起的肠漏的风险增加，从而可能导致器官损伤 从患有或未患有 COVID-19 后和/或 AUD 的个体产生的类器官。