Search

In Dec. 2019‐January 2020, a pneumonia illness originating in Wuhan, China, designated as coronavirus disease 2019(COVID‐19) was shown to be caused by a novel RNA coronavirus designated as severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2). People with advanced age, male sex, and/or underlying health conditions (obesity, type 2 diabetes, cardiovascular disease, hypertension, chronic kidney disease, and chronic lung disease) are especially vulnerable to severe COVID‐19 symptoms and death. These risk factors impact the immune system and are also associated with poor health, chronic illness, and shortened longevity. However, a large percent of patients without these known risk factors also develops severe COVID‐19 disease that can result in death. Thus, there must exist risk factors that promote exaggerated inflammatory and immune response to the SARS‐CoV‐2 virus leading to death. One such risk factor may be alcohol misuse and alcohol use disorder because these can exacerbate viral lung infections like SARS, influenza, and pneumonia. Thus, it is highly plausible that alcohol misuse is a risk factor for either increased infection rate when individuals are exposed to SARS‐CoV‐2 virus and/or more severe COVID‐19 in infected patients. Alcohol use is a well‐known risk factor for lung diseases and ARDS in SARS patients. We propose that alcohol has three key pathogenic elements in common with other COVID‐19 severity risk factors: namely, inflammatory microbiota dysbiosis, leaky gut, and systemic activation of the NLRP3 inflammasome. We also propose that these three elements represent targets for therapy for severe COVID‐19. The COVID‐19 pandemic beginning in 2020 is associated with more than 600 million documented cases and over 6 million deaths worldwide. Disease severity risk factors include old age, and diseases of the lung, cardiovascular, kidney and obesity. This review proposes chronic alcohol use disorder (AUD) as a risk factor for COVID‐19 severity with evidence for three common pathologic mechanisms with these established COVID‐19 risk factors that include microbiome dysbiosis, leaky gut and activation of the NLRP3 inflammasome driving systemic inflammation.

Circadian rhythm disruption is a prevalent feature of modern day society that is associated with an increase in pro‐inflammatory diseases, and there is a clear need for a better understanding of the mechanism(s) underlying this phenomenon. We have previously demonstrated that both environmental and genetic circadian rhythm disruption causes intestinal hyperpermeability and exacerbates alcohol‐induced intestinal hyperpermeability and liver pathology. The intestinal microbiota can influence intestinal barrier integrity and impact immune system function; thus, in this study, we sought to determine whether genetic alteration of the core circadian clock gene, Clock, altered the intestinal microbiota community. Male ClockΔ19‐mutant mice (mice homozygous for a dominant‐negative‐mutant allele) or littermate wild‐type mice were fed 1 of 3 experimental diets: (i) a standard chow diet, (ii) an alcohol‐containing diet, or (iii) an alcohol‐control diet in which the alcohol calories were replaced with dextrose. Stool microbiota was assessed with 16S ribosomal RNAgene amplicon sequencing. The fecal microbial community of Clock‐mutant mice had lower taxonomic diversity, relative to wild‐type mice, and the ClockΔ19mutation was associated with intestinal dysbiosis when mice were fed either the alcohol‐containing or the control diet. We found that alcohol consumption significantly altered the intestinal microbiota in both wild‐type and Clock‐mutant mice. Our data support a model by which circadian rhythm disruption by the ClockΔ19mutation perturbs normal intestinal microbial communities, and this trend was exacerbated in the context of a secondary dietary intestinal stressor.

Chronic alcohol exposure exerts numerous adverse effects, although the specific mechanisms underlying these negative effects on different tissues are not completely understood. Alcohol also affects core properties of the circadian clock system, and it has been shown that disruption of circadian rhythms confers vulnerability to alcohol‐induced pathology of the gastrointestinal barrier and liver. Despite these findings, little is known of the molecular interactions between alcohol and the circadian clock system, especially regarding implications for tissue‐specific susceptibility to alcohol pathologies. The aim of this study was to identify changes in expression of genes relevant to alcohol pathologies and circadian clock function in different tissues in response to chronic alcohol intake. Wild‐type and circadian ClockΔ19mutant mice were subjected to a 10‐week chronic alcohol protocol, after which hippocampal, liver, and proximal colon tissues were harvested for gene expression analysis using a custom‐designed multiplex magnetic bead hybridization assay that provided quantitative assessment of 80 mRNAtargets of interest, including 5 housekeeping genes and a predetermined set of 75 genes relevant for alcohol pathology and circadian clock function. Significant alterations in expression levels attributable to genotype, alcohol, and/or a genotype by alcohol interaction were observed in all 3 tissues, with distinct patterns of expression changes observed in each. Of particular interest was the finding that a high proportion of genes involved in inflammation and metabolism on the array was significantly affected by alcohol and the ClockΔ19mutation in the hippocampus, suggesting a suite of molecular changes that may contribute to pathological change. These results reveal the tissue‐specific nature of gene expression responses to chronic alcohol exposure and the ClockΔ19mutation and identify specific expression profiles that may contribute to tissue‐specific vulnerability to alcohol‐induced injury in the brain, colon, and liver.