Systemic elevation of gut derived p-cresol during one year in space: implications for brain, heart, bone, liver and microbiome in astronauts

Introduction We observed the elevation of p -cresol in the untargeted metabolome of the multiomics portion of the NASA Twins Study of One Year in Space. p -Cresol is a uremic and neurotoxin that is produced via the metabolism of dietary tyrosine by gut bacteria. Intestinally produced p -cresol is absorbed into systemic circulation where it exerts its adverse metabolic effects and drives phenotypic changes relevant to astronauts, including the brain, heart, bone, liver, kidney, and colon. Methods A pair of monozygotic twins were studied for 25 months, during which one subject spent 340 days aboard the International Space Station (ISS), while his identical twin remained on Earth. Molecular analyses included genome, epigenome, transcriptome, proteome, metabolome, immunome, and microbiome. Our metabolite feature extraction was focused on plasma p -cresol ( p -cresyl sulfate [pCS] and p -cresol glucuronide [pCG]), along with associated biological dynamics that govern p -cresol production and metabolism. Results Significance was observed for pCG when comparing Post-flight vs. Inflight (adj p = 0.016). pCS values were significantly altered Post-flight vs. Inflight (adj p = 0.002) and Post-flight vs. Late-flight (adj p = 0.037). pCS values for Early-flight vs. Pre-flight approached significance (adj p = 0.08). In alignment with elevated plasma p -cresol values at certain stages of spaceflight, we found an increase in count-normalized abundance (raw reads) for the major p -cresol producer Clostridioides difficile in TW (Flight) vs. HR (Ground) for Post-flight, Inflight, and Overall (adj p = 0.014, adj p = 0.0006, and adj p = 2.02x10¯ 5 , respectively). Concomitantly, we observed a significant increase in count-normalized abundance for another of the major p -cresol producers Olsenella uli in TW vs. HR for Post-flight, Inflight, and Overall (adj p = 0.0045, adj p = 0.00043, adj p = 0.0016, respectively), including Interaction for Inflight vs. Pre-flight (adj p = 0.028). Discussion We observed an elevation of p -cresol during one year in space, which may have significant implications for astronaut health and performance. Molecular findings and p -cresol countermeasure candidates are discussed. We also explore the process from untargeted molecular feature extraction to description of biological meaning, to new hypothesis generation, to plausible countermeasure development for human spaceflight.