Prolonged impairment of short-chain fatty acid and L-isoleucine biosynthesis in gut microbiome in patients with COVID-19

Zhang, Fen; Wan, Yating; Zuo, Tao; Yeoh, Yun Kit; Liu, Qin; Zhang, Lin; Zhan, Hui; Lu, Wenqi; Xu, Wenye; Lui, Grace C.Y.; Li, Amy Y.L.; Cheung, Chun Pan; Wong, Chun Kwok; Chan, Paul K.S.; Chan, Francis K.L.; Ng, Siew C.

Background & Aims SARS-CoV-2 infection is associated with altered gut microbiota composition. Phylogenetic groups of gut bacteria involved in the metabolism of short chain fatty acids were depleted in SARS-CoV-2-infected patients. We aimed to characterize functional profile of gut microbiome in patients with COVID-19 before and after disease resolution. Methods We performed shotgun metagenomic sequencing on fecal samples from 66 antibiotics-naïve patients with COVID-19 and 70 non-COVID-19 controls. Serial fecal samples were collected (up to 6 times points) during hospitalization and beyond one month after discharge. We assessed gut microbial pathways in association with disease severity and blood inflammatory markers. We also determined changes of microbial functions in fecal samples before and after disease resolution and validated these functions using targeted analysis of fecal metabolites. Results Compared with non-COVID-19 controls, COVID-19 patients with severe/critical illness showed significant alterations in gut microbiome functionality (P < .001), characterized by impaired capacity of gut microbiome for short chain fatty acid (SCFA) and L-isoleucine biosynthesis and enhanced capacity for urea production. Impaired SCFA and L-isoleucine biosynthesis in gut microbiome persisted beyond 30 days after recovery in COVID-19 patients. Targeted analysis of fecal metabolites showed significantly lower fecal concentrations of SCFAs and L-isoleucine in COVID-19 patients before and after disease resolution. Lack of SCFA and L-isoleucine biosynthesis significantly correlated with disease severity and increased plasma concentrations of CXCL-10, NT-proBNP, C-reactive protein (CRP) (all P < .05). Conclusions Gut microbiome of COVID-19 patients displayed impaired capacity for SCFA and L-isoleucine biosynthesis which persisted even after disease resolution. These two microbial functions correlated with host immune response underscoring the importance of gut microbial functions in SARS-CoV-2 infection pathogenesis and outcome.