Microbiome–Metabolome Crosstalk as a Driver of COVID-19 Severity

<b>Background:</b> COVID-19, caused by SARS-CoV-2, exhibits highly variable severity, from mild symptoms to respiratory failure and multiorgan dysfunction. Traditional risk factors incompletely explain this heterogeneity, highlighting the potential role of gut microbiota and host metabolomics in modulating immune responses. <b>Methods:</b> Thus, this study investigates how gut microbiota variations are associated with plasma metabolite profiles in COVID-19, exploring relationships between microbial and metabolic signatures and disease severity and potential therapeutic targets. In a prospective cohort of 55 patients, stool and plasma samples were analyzed using 16S rRNA sequencing and untargeted LC-HRMS metabolomics. <b>Results:</b> Severe COVID-19 was associated with reduced microbial diversity and enrichment of pro-inflammatory taxa, including <i>Prevotella</i>, <i>Alistipes</i>, <i>Dialister</i>, and <i>Lachnoclostridium</i>, whereas mild cases showed higher abundance of protective commensals such as <i>Bacteroides</i>, <i>Faecalibacterium</i>, and <i>Blautia</i>. Metabolomic profiling revealed alterations in bile acids, unsaturated fatty acids, tryptophan, and inositol phosphate pathways. Notably, linoleate levels were elevated in severe cases, showing correlations with pro-inflammatory microbes, while acylcarnitines and inositol derivatives were enriched in mild disease. Predictive functional analysis suggested that severe-associated microbes showed enhanced amino acid catabolism, oxidative glucose metabolism, and xenobiotic degradation, which may be linked to host inflammation. <b>Conclusions:</b> These findings highlight associations between gut microbiota composition, microbial metabolism, and circulating metabolites in COVID-19 severity. Identified microbial and metabolomic signatures may represent potential candidates to be considered biomarkers and therapeutic targets to modulate disease progression.