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.

PROJECT NARRATIVE This study seeks to understand the role of alcohol consumption in COVID-19 long-term complications, hypothesizing that alcohol is an underappreciated risk factor for developing these complications. We also hypothesize that these effects are related to alcohol's ability to cause gut-leakiness during human diseases. The completion of this proposal may identify alcohol misuse (a modifiable lifestyle factor) as a yet unknown risk factor for COVID-19 long-term complications; therefore, it may lead to identify individuals at risk for these long-term complications and to design novel strategies to prevent/treat post-COVID-19 syndrome.