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

项目总结 近期数据显示，10-30%的冠状病毒病2019(新冠肺炎)患者未完全康复并遭受 从SARS-CoV-2感染被清除后持续存在的一系列症状(所谓的后 新冠肺炎综合征或长拖拉症)。严重的新冠肺炎和相关的风险因素似乎会增加风险 发生新冠肺炎后综合征的风险，然而大量没有已知危险因素的患者 发展为后新冠肺炎综合征。因此，导致后新冠肺炎综合征的其他危险因素肯定存在。 一个潜在的风险因素是过度饮酒。(1)酒精是老年人最常使用的药物 美国，在公共卫生危机期间酒精使用增加，特别是在社会经济不利的人 社区。(2)酒精引起对病原体的不适当免疫反应。(3)酒精扰乱肠道 和肺屏障的完整性，可以进一步促进炎症。我们最近发现，增加的血清 Zonlin(肠屏障完整性受损的标志)和内毒素(LBP)增加与 新冠肺炎期间的炎症，可以预测疾病的严重程度和死亡率。因此，我们假设 (A)酗酒与SARS-CoV-2感染之间存在双向相互作用，导致 酒精使用障碍和更严重的酒精使用障碍患者发生新冠肺炎后综合征的风险增加 和(B)这些相互作用的潜在机制是微生物区系失调和/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。 为了测试我们的假设，我们将利用我们在拉什大学医学学院支持的新冠肺炎补充剂 该中心正在积极跟踪7,000多名SARS-CoV-2阳性患者和2,000名SARS-CoV-2阳性患者。 对12个月以上的CoV-2阴性患者进行结构化问卷调查。所有患者都接受酒精筛查 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 评估澳州大学博士学位论文、新冠肺炎后综合征和肠源性炎症之间联系的假说。在AIM 1，我们将检验这样一个假设，即澳大利亚糖尿病通过以下方式增加新冠肺炎后综合征的风险和严重程度 促进肠源性炎症。(1A)我们将确定酒精使用/误用的增加是否与 与后新冠肺炎综合征的风险和严重程度有关。(1B)我们将阐明肠源性炎症在 通过询问粪便微生物区系组成/功能来促进新冠肺炎后综合征的发生 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 新冠肺炎增加急性尿崩症和酒精诱导的肠屏障的风险和严重程度的假说 颠覆。(2A)我们将确定新冠肺炎后综合征是否与澳大利亚糖尿病风险增加相关。 (2B)我们将确定新冠肺炎是否降低了肠道屏障对酒精破坏作用的弹性 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。 患有和不患有新冠肺炎后和/或澳大利亚糖尿病的个体产生的有机物质。

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.