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Objective: Emerging evidence suggests a direct involvement of the gastrointestinal tract in COVID-19. Although the specific immune response is of paramount importance in the SARS-CoV-2 virus elimination process, aberrant immune activity could lead to severe disease and late inflammatory forms. In this context, the intestinal microbiota plays a primary role in the maturation and maintenance of the immune system. This study investigates whether the SARS-CoV-2 infection can be associated with alterations in the gut microbiome composition and if such variations could correlate with the severity of symptoms and disease outcomes. Patients and Methods: We performed shotgun metagenomic sequencing of stool samples of 45 patients, aged between 30 and 95 years, hospitalized with COVID-19. Patients were grouped by clinical severity (ie, non-critical or critical), type of hospitalization (non-intensive care or intensive therapy unit) and outcome (survival or deceased) to explore the impact of the gut microbiome changes on patients’ health. Results: COVID-19 severity is associated with alterations in the intestinal microbiome, reduced microbial biodiversity and increased Escherichia and Bacteroides genera. No statistical significance was found between the extent of dysbiosis and clinical severity. We found an enrichment of micro-eukaryotic species, eg, Candida albicans, Candida tropicalis, Saccharomyces cerevisiae and bacterial species previously associated with diseases as well as unhealthy cardiometabolic markers, eg, Escherichia coli, Bacteroides fragilis, Clostridium bolteae, Clostridium innocuum, Clostridium symbiosum, Eggerthella …