More than 20% of the global workforce engages in night shiftwork, a schedule that forces the body to be awake and eat when the internal circadian clock signals rest. The metabolic toll is well documented: higher rates of obesity, type 2 diabetes, and cardiovascular disease have all been linked to shiftwork. But the biochemical chain of events has remained poorly understood. A new study from the University of Colorado Boulder (published in Journal of Biological Rhythms) provides the most detailed metabolomic map yet of what goes wrong inside shiftworkers’ cells, pinpointing two specific metabolites, uridine and glycoursodeoxycholic acid, whose misalignment predicts impaired glucose tolerance and reduced energy expenditure.
The researchers placed 14 healthy adults (8 women, mean age 26.4 years) in a controlled laboratory setting for a 6-day simulated night-shift protocol. Every 4 hours around the clock, they drew blood for untargeted metabolomic profiling, measuring hundreds of circulating metabolites. Whole-room calorimetry tracked energy expenditure, and standardized test meals measured glucose and insulin responses. By modeling the 24-hour rhythms of each metabolite against the imposed sleep-wake and feeding schedule, the team could distinguish metabolites driven by the internal circadian clock from those driven by behavior alone, and quantify exactly how far each drifted from alignment.
The pyrimidine pathway: uridine as a metabolic signal
Among the hundreds of metabolites surveyed, uridine stood out. A nucleoside central to pyrimidine metabolism, uridine showed a dramatic acrophase shift during simulated night shiftwork: its peak timing drifted away from its normal circadian phase. More importantly, the magnitude of uridine’s misalignment correlated directly with worse glucose tolerance (p < 0.05). Participants whose uridine rhythm was most disrupted also showed the largest spike in blood glucose after a test meal. Circulating uridine concentrations were additionally linked to lower energy expenditure.
Uridine is known to influence insulin signaling and hepatic glucose production, but this is the first study to demonstrate that its circadian rhythm, not just its total level, is a predictor of metabolic health during simulated shiftwork.
Bile acid-microbiome signaling: glycoursodeoxycholic acid as a gut-brain clock relay
The second key metabolite was glycoursodeoxycholic acid (GUDCA), a conjugated bile acid produced by microbial metabolism in the gut and recycled through the enterohepatic circulation. GUDCA’s rhythm also became internally misaligned during the night-shift protocol, and this misalignment was similarly associated with impaired glucose tolerance and reduced energy expenditure.
Bile acids serve dual roles as digestive detergents and as signaling molecules that activate nuclear receptors (FXR, TGR5) involved in glucose and lipid homeostasis. The circadian disruption of GUDCA suggests that the gut microbiome’s metabolic output is itself clock-controlled and that shiftwork decouples this signaling axis from the rest of the body’s metabolic program.
Widespread metabolic disruption
Beyond these 2 specific pathways, the metabolomic profiling revealed widespread alterations across lipid metabolism and additional unannotated pathways. On the whole-body level, the night-shift protocol produced significant increases in both glucose area-under-the-curve and insulin area-under-the-curve (p < 0.05 for each), while energy expenditure as measured by whole-room calorimetry decreased (p < 0.05). These functional changes confirm that the metabolomic shifts are not epiphenomena; they translate directly into measurable metabolic impairment.
Why it matters
Current occupational health guidelines for shiftworkers focus on behavioral advice: strategic napping, caffeine timing and light exposure management. This study opens the door to a complementary approach. Measuring and potentially correcting the specific metabolic pathways that circadian misalignment disrupts could become part of shiftworker health monitoring. Uridine and bile acid metabolism could serve as biomarkers for assessing individual vulnerability to shiftwork, or even as targets for nutritional or pharmacological interventions.
The study is small (n = 14) and conducted under tightly controlled laboratory conditions. This was a necessary step for precision metabolomics, but results may not fully capture the complexity of real-world shiftwork with its variable schedules, diet and light exposure. The associations between metabolite misalignment and metabolic outcomes are correlational; causal testing will require follow-up studies that manipulate uridine or bile acid signaling directly.
Bottom line
Night shiftwork disrupts the 24-hour rhythms of specific metabolites, particularly uridine (pyrimidine metabolism) and glycoursodeoxycholic acid (bile acid-microbiome signaling), and the degree of disruption predicts how badly glucose tolerance and energy expenditure suffer. These findings identify metabolomic pathways that could explain why shiftworkers face elevated cardiometabolic risk and point toward personalized monitoring strategies.
Source: Kubicki M, McHill AW, Melanson EL, Reisdorph N, Wright KP Jr, Depner CM. Internal Circadian Misalignment of the Human Metabolome Links Night Shiftwork to Metabolic Impairment. Journal of Biological Rhythms. Published online July 13, 2026. DOI: 10.1177/07487304261459478. PMID: 42438369.