Gut Bacterial Dysbiosis and Instability is Associated with the Onset of Complications and Mortality in COVID-19

Objective There is a growing debate about the involvement of the gut microbiome in COVID-19, although it is not conclusively understood whether the microbiome has an impact on COVID-19, or vice versa, especially as analysis of amplicon data in hospitalized patients requires sophisticated cohort recruitment and integration of clinical parameters. Here, we analyzed fecal and saliva samples from SARS-CoV-2 infected and post COVID-19 patients and controls considering multiple influencing factors during hospitalization. Design 16S rRNA gene sequencing was performed on fecal and saliva samples from 108 COVID-19 and 22 post COVID-19 patients, 20 pneumonia controls and 26 asymptomatic controls. Patients were recruited over the first and second corona wave in Germany and detailed clinical parameters were considered. Serial samples per individual allowed intra-individual analysis. Results We found the gut and oral microbiota to be altered depending on number and type of COVID-19-associated complications and disease severity. The occurrence of individual complications was correlated with low-risk (e.g., Faecalibacterium prausznitzii ) and high-risk bacteria (e.g., Parabacteroides ). We demonstrated that a stable gut bacterial composition was associated with a favorable disease progression. Based on gut microbial profiles, we identified a model to estimate mortality in COVID-19. Conclusion Gut microbiota are associated with the occurrence of complications in COVID-19 and may thereby influencing disease severity. A stable gut microbial composition may contribute to a favorable disease progression and using bacterial signatures to estimate mortality could contribute to diagnostic approaches. Importantly, we highlight challenges in the analysis of microbial data in the context of hospitalization. ### Competing Interest Statement The authors have declared no competing interest. * AB T1 : Antibiotic therapy at the time of the first stool sampling AC : Asymptomatic controls AKI : Acute kidney injury AP : Alkaline phosphatase [U/l] ARDS : Acute respiratory distress syndrome Asympt. : Asymptomatic COVID-19 : Corona virus disease 2019 CRP : C-reactive protein [mg/dl] FiO2 : Fraction of inspired oxygen (%) GGT : Gamma-Glutamyltransferase [U/l] GI : Gastrointestinal Hb : Hemoglobin [g/dl] i.v. : intravenous IBD : Inflammatory bowel disease ICU : Intensive care unit ICU all T : Intensive care stay regarding all time points of stool sampling ICU T1 : Intensive care stay at the time of the first stool sampling N : Number of patients n : Number of samples NA : not available PA : Pressure assisted PC : Pressure controlled PCT : Procalcitonin [ng/ml] PE : Pulmonary embolism Rel. : Relative S.p. : Status post SARS-CoV-2 : Severe acute respiratory syndrome coronavirus 2 SC : Symptomatic pneumonia controls Sig. : Significant Sympt. : Symptomatic T1 : First sampling time point T2D : Type 2 diabetes mellitus Trp T : High-sensitive troponin T [ng/ml] TS : Tracheostomy VTE : Venous thromboembolism WBC : White blood cells counts [G/l] zOTU : Zero-radiation operational-taxonomic units