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.

项目摘要 最近的数据表明，2019年冠状病毒病（COVID-19）患者中有10-30％的患者无法完全康复和遭受痛苦 从SARS-COV-2感染后持续存在的广泛症状已清除（所谓的后， COVID-19综合征或长途运输综合征）。严重的Covid-19和相关风险因素似乎增加了风险 开发后covid-19综合征，还有大量没有已知危险因素的患者 发展后covid-19综合征。因此，必须存在导致Covid-19综合征的其他危险因素。 一个潜在的危险因素是过度饮酒。 （1）酒精是最常用的药物 在公共卫生危机期间，美国的饮酒增加，特别是在社会经济处境不利的情况下 社区。 （2）酒精会导致对病原体的不当免疫反应。 （3）酒精破坏肠道 和肺屏障完整性，可以进一步促进炎症。我们最近表明血清升高 Zonulin（肠道屏障完整性中断的标记）和内毒素增加（LBP）与 Covid-19期间的炎症，可以预测疾病的严重程度和死亡率。因此，我们假设 那是：（a）酒精滥用与SARS-COV-2感染之间存在双向相互作用，导致 在酒精使用障碍（AUD）患者和更严重的AUD患者中，COVID后19综合征的风险增加 在199名患者中； （b）这些相互作用的潜在机制是微生物群营养不良和/或 肠道屏障完整性的破坏，促进对病毒的炎症和免疫反应失调。 为了检验我们的假设，我们将利用Rush University Medical支持的NIAAA支持的Covid-19 中心（RUMC），该中心正在积极关注超过7,000名SARS-COV-2阳性患者和2,000个SARS- COV-2使用结构化问卷的12个月内的阴性患者。所有患者均被筛选 使用/滥用。此外，我们将招募一部分患者提供生物样品以测试我们的机械 假设评估AUD，COVID-19综合征和肠发炎之间的联系。目标 1，我们将检验以下假设：AUD通过 促进肠道炎症。 （1a）我们将确定是否与饮酒/滥用相关 与COVID后-19综合征的风险和严重程度。 （1B）我们将阐明肠发炎在 通过询问粪便微生物群的组成/功能，全身性促进COVID-19综合征的AUD促进 肠屏障完整性，炎症和免疫激活的标记。在AIM 2中，我们将测试 COVID-19增加了AUD和酒精引起的肠道屏障的风险和严重程度的假设 破坏。 （2a）我们将确定COVID-19-19综合征是否与AUD风险增加有关。 （2b）我们将确定COVID-19是否会降低肠道屏障对酒精的破坏作用的弹性 这将导致饮酒引起的肠道泄漏的风险增加，这可能会导致使用 从有或没有旋转后19和/或AUD的个体产生的类器官。