Elevation of Gut-Derived p-Cresol Molecular Networks in Astronauts During Spaceflight Informs Drug Metabolism and Performance

Metabolites produced by enteric microbes may have important effects on astronauts on long-duration missions. The NASA Twins Study provided the most comprehensive multi-scale omics data to date from which to extract molecular features of potential clinical significance to spaceflight. From the multivariate data, we identified an elevation of the uremic toxin p-cresol, which is produced by gut microbial fermentation of dietary tyrosine. p-Cresol has adverse metabolic effects via depletion of the hepatic sulfur pool, which impacts metabolism of drugs, endogenous metabolites, and xenobiotics. Moreover, p-cresol reshapes gut microbial community structure by facilitating survival of species such as clostridia and inhibition of butyrate producers. Spaceflight may also impact the genes responsible for the metabolism of p-cresol (e.g. SULT) and for the safe metabolism of common drugs used in space, such as acetaminophen (e.g. SULT, CYP4502E1, GST). Understanding p-cresol production and its related molecular networks in astronauts may lead to precision medicine advances that enhance astronaut safety and performance on long-duration missions.