LAUSR

Objective We investigate interrelationships between gut microbes, metabolites, and cytokines that characterize COVID-19 and its complications, and validate the results with follow-up, Japanese 4D microbiome cohort, and non-Japanese datasets. Design We performed shotgun metagenomic sequencing and metabolomics on stools and cytokine measurements on plasma from 112 hospitalized patients with SARS-CoV-2 infection and 112 non-COVID-19 controls matched by important confounders. Results Multiple correlations were found between COVID-19-related microbes (e.g., oral microbes and short-chain fatty acid [SCFA] producers) and gut metabolites (e.g., branched-chain and aromatic amino acids, SCFAs, carbohydrates, neurotransmitters, and vitamin B6). Both were also linked to inflammatory cytokine dynamics (e.g., IFN-γ, IFN-λ3, IL-6, CXCL-9, and CXCL-10). Such interrelationships were detected highly in severe disease and pneumonia, moderately in high D-dimer level, kidney dysfunction, and liver dysfunction groups, but rarely in the diarrhea group. We confirmed concordances of altered metabolites (e.g., branched-chain amino acids, spermidine, putrescine, and vitamin B6) in COVID-19 with their corresponding microbial functional genes. Results in microbial and metabolomic alterations with severe disease from the cross-sectional dataset were partly concordant with those from the follow-up dataset. Microbial signatures for COVID-19 were distinct from diabetes, inflammatory bowel disease, and proton-pump inhibitors, but overlapping for rheumatoid arthritis. Random forest classifier models using microbiomes can highly predict COVID-19 and severe disease. The microbial signatures for COVID-19 showed moderate concordance between Hong Kong and Japan. Conclusions Multi-omics analysis revealed multiple gut microbe-metabolite-cytokine interrelationships in COVID-19 and COVID-19-related complications, but few in GI complications, suggesting microbiota-mediated immune responses distinct between the organ sites. Our results underscore the existence of a gut–lung axis in COVID-19.