Severe COVID-19 infection causes long-term alterations of the gut-liver axis

A proportion of patients after severe COVID-19 infection suffer from post-acute disease. We aimed to understand the role of the gut-liver axis in this setting. We compared a large panel of biomarkers related to post-acute COVID-19 disease in patients who previously suffered from severe COVID-19 disease (sCOV, n=21) to those who suffered from mild COVID-19 disease (mCOV, n=10). sCOV patients were studied on average 318 days after the infection, mCOV patients after 221 days (p=0.013). sCOV patients were older (p=0.031), had more comorbidities (p=0.02), higher BMI (p<0.01), and higher rate of arterial hypertension (p=0.023) although being physically more active (p=0.035). Quality of life questionnaires revealed lower general health (p=0.026), physical functioning (p<0.01) and more lower-airways symptoms (p=0.031). sCOV patients had lower serum albumin (p<0.01), total protein (p<0.01), serum calcium (p=0.02), and estimated glomerular filtration rate (p=0.022), but higher fasting glucose levels (p<0.01). sCOV patients also had higher serum DAO levels (p=0.017) indicating increased intestinal permeability and impaired neutrophil function with impaired directedness of chemotaxis (p=0.035), and lower ROS production in response to E. coli (p<0.01). Gut microbiome sequencing revealed lower microbial richness (p<0.01) and reorganization of Ruminococcaceae and Lachnospiraceae families, indicating long-term sequelae of the acute disease. Serum metabolome analysis showed higher glycoprotein to supramolecular phospholipid composite ratio (p<0.05), indicating inflammation, and lower levels of small-medium sized HDL particles (p<0.05). Stool metabolome analysis showed lower glycine and lactulose levels (p<0.05), and higher asparagine (p<0.001) and glycocholic acid (p<0.01) levels in sCOV patients. Multi-omics factor analysis showed higher VLDL particle number and predicted higher glucose and mannose metabolism capacity in sCOV patients. This study highlights the differences in biomarkers of the gut-liver axis in patients who previously had severe COVID-19 disease. The gut-liver axis may be a potential source of biomarkers and a therapeutic target in COVID-19 disease.