Short-term sleep restriction in humans alters diurnal circulating metabolite profiles, including those of microbial origin

BACKGROUNDGut microbes and their metabolites contribute to the host circulating metabolome and exhibit diurnal variation influenced by sleep-wake cycles and meal timing. Sleep deprivation alters the rhythmic circulating metabolome, but its impact on microbial metabolites remains unclear. We tested whether 24-hour circulating metabolite profiles, including those of microbial origin, differ under normal (habitual) versus short-term restricted sleep. METHODSIn a randomized crossover design, 9 healthy adults completed 2 in-lab 24-hour blood sampling sessions (q120): one following 3 nights of normal sleep (8. 5 hours/night), the other following 3 nights of sleep restriction (4. 5 hours/night). Meal timing and caloric intake were held constant. Serum metabolites were characterized using untargeted reverse-phase liquid chromatography-mass spectrometry and rhythmicity was assessed using empirical JTKCYCLE analysis. RESULTSWe identified 90 metabolites, including 14 of microbial origin or derived from host metabolism of microbial products, e. g. , butyrate and tryptophan derivatives. Sleep restriction significantly altered serum metabolite composition compared with normal sleep. While many compounds maintained rhythmicity across conditions, sleep restriction disrupted rhythms of several key compounds, including microbe-derived metabolites. Notably, butyrate and indole-3-propionic acid lost rhythmicity, whereas new rhythms emerged in the tryptophan catabolite, kynurenine, and lipid metabolism intermediates. CONCLUSIONWe provide evidence that microbial metabolites are detectable in human blood and exhibit sleep-dependent rhythmicity. Sleep restriction alters diurnal circulating microbial and host-derived metabolite rhythms even under constant meal timing, composition, and calories. These findings support links between host sleep patterns and gut microbial metabolism and suggest microbial metabolites as potential biomarkers or mediators of sleep loss-associated health risks. TRIAL REGISTRATIONNCT00989976. FUNDINGNIH/NCRR KL2RR025000; R56DK102872-01A1, P30DK020595; P30DK042086; K01DK111785; F31DK122714; DOD W81XWH-07-2-0071.