Immunomodulatory fecal metabolites are associated with mortality in COVID-19 patients with respiratory failure

Abstract

Respiratory failure and mortality from COVID-19 result from virus- and inflammation-induced lung tissue damage. The intestinal microbiome and associated metabolites are implicated in immune responses to respiratory viral infections, however their impact on progression of severe COVID-19 remains unclear. We prospectively enrolled 71 patients with COVID-19 associated critical illness, collected fecal specimens within 3 days of medical intensive care unit admission, defined microbiome compositions by shotgun metagenomic sequencing, and quantified microbiota-derived metabolites (NCT #04552834). Of the 71 patients, 39 survived and 32 died. Mortality was associated with increased representation of Proteobacteria in the fecal microbiota and decreased concentrations of fecal secondary bile acids and desaminotyrosine (DAT). A microbiome metabolic profile (MMP) that accounts for fecal secondary bile acids and desaminotyrosine concentrations was independently associated with progression of respiratory failure leading to mechanical ventilation. Our findings demonstrate that fecal microbiota composition and microbiota-derived metabolite concentrations can predict the trajectory of respiratory function and death in patients with severe SARS-Cov-2 infection and suggest that the gut-lung axis plays an important role in the recovery from COVID-19.

Prebiotic activity of lactulose optimizes gut metabolites and prevents systemic infection in liver disease patients

“…"the metabolome") remain unaddressed. Microbe-derived metabolites contribute to intestinal epithelial cell differentiation and barrier formation [27][28][29] and also regulate mucosal innate and adaptive immune defenses 26,30,31 . In the case of liver disease, fecal bile acid (BA) profiles have been correlated with progression of NAFLD to non-alcoholic steatohepatitis (NASH) and subsequently advanced fibrosis [32][33][34] .…”

Association between Gut Microbiota and SARS-CoV-2 Infection and Vaccine Immunogenicity

“…Similarly, secondary bile acids have also been shown to be able to inhibit NF-κB signaling pathways, inhibit IL-17 expressing helper T cells, and enhance differentiation of regulatory T cells [ 52 ]. In the context of COVID-19, secondary bile acids were found to be significantly associated with the progression of respiratory failure and patient’s survival [ 53 ]. Ursodeoxycholic acid has also been suggested as a therapeutic agent for the prevention of cytokine storms in COVID-19 management by inhibiting the production of pro-inflammatory cytokines [ 54 , 55 ].…”

Gut–lung crosstalk during critical illness

“…Conversely, in murine models of antibiotic-induced dysbiosis with decreased SCFA production, inoculation with Respiratory Syncytial Virus results in less effective immune response and viral clearance in lungs [47 ▪ ]. In COVID-19 patients upon admission to the ICU, reduced levels of fecal microbial metabolites, such as secondary bile acids and desaminotyrosine, were predictive of more severe respiratory failure and mortality, with postulated impact on T- regulatory (Treg) cell development and interferon-I signaling [48 ▪▪ ]. The demonstrated protective roles of microbial metabolites, such as SCFAs and bile acids, suggest that the optimal gut–lung interaction is not only about preventing a pathobiome, but also promoting a healthy gut microbiome.…”