COVUR Tumor
Background: Cancer patients frequently face poor outcomes in severe viral infection, in particular Coronavirus disease 2019 (COVID-19). We hypothesize that impaired immune defense observed in cancer patients with COVID-19 is, in part, caused by disruptions of the immunomodulatory metabolome, deteriorating immune response and disease course.  Methods: We prospectively recruited patients in four cohorts: cancer patients (n=12) and non-cancer patients (n=13), both with severe COVID-19, ICU patients without both, COVID-19 and cancer (n=12) and non-infected cancer patients (n=13), matched by demographics and disease burden. Upon admission, we collected stool samples for 16S rRNA sequencing, serum metabolite for liquid chromatography-mass spectrometry, and peripheral T lymphocyte for multi-color flow cytometry analysis. Results: Patients with COVID-19 showed reduced bacterial diversity in the feces upon hospital admission similar to non-infected ICU patients. Anerobic commensals, in particular Lachnospiraceae, were strongly correlated with serum short chain fatty acids (SCFAs) and secondary bile acids (sBAs). COVID-19 patients had upregulated Indoleamine 2,3-dioxygenase (IDO)/Kynurenine metabolites. Cancer patients with COVID-19 showed lower SCFA and higher lactic acid than non-cancer patients. Primary bile acids, Kynurenines and lactic acid were linked to mortality and decreased, SCFAs and sBAs  to survival and increased T cell functionality. A novel metabolite risk index (MRI), combining four serum metabolites and Kynurenine/Tryptophan ratio, accurately predicted COVID-19 survival (AUC 92%, estimated 6 month survival rate 0% for positive vs. 92% for negative index), with cancer patients showing a higher MRI than non-cancer patients. Conclusions: Our data indicate that COVID-19 clinical outcomes are shaped by host and microbiota-derived metabolites. These likely directly influence T cells. We conclude that alterations in these metabolites contribute to the detrimental immune dysregulation seen in cancer patients.