A Summary of the article “Steroid hormone biosynthesis and dietary related metabolites associated with excessive daytime sleepiness”
Background
The article by Faquih et al, published in eBioMedicine in September 2025, addresses the biological profile of Excessive Daytime Sleepiness (EDS), a complex sleep problem affecting approximately 33% of the United States population. While EDS is often associated with insufficient sleep or other sleep disorders, unique genetic markers and metabolic pathways underlie the condition. Given the strong links between EDS and cardiometabolic disorders such as obesity and cardiovascular disease, the study aimed to use metabolomics to gain etiological insights into EDS in multi-ethnic populations.
Methods
The primary analysis utilized metabolomics data from 6,071 individuals in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) cohort, assessing 877 metabolites. EDS was measured using the continuous score from the Epworth Sleepiness Scale (ESS) questionnaire. Linear regression models were implemented, adjusted for demographic, lifestyle, and physiological factors, and repeated in sex-specific groups. To understand the metabolic context, Gaussian Graphical Modelling (GGM) coupled with pathway and enrichment analyses was performed to create a holistic interactive network of associations. Replication analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA), the UK Biobank (UKB), and the Health2000 study. Furthermore, Mendelian Randomisation (MR) analysis was used to assess the potential directionality and causal associations between EDS and key metabolites.
Key Findings and Interpretations
The central finding was that the metabolomic profile of EDS is characterized by metabolites within the steroid hormone biosynthesis pathway, indicating that endogenous and dietary metabolites are involved, with some pathways exhibiting sex differences.
Steroid Hormones and Cortisol Metabolism: The primary model identified seven associated metabolites, including two specific pregnenolone steroids: pregnenediol sulphate and tetrahydrocortisol glucuronide. Both were associated with less sleepiness (negative association with ESS score). The GSMR analysis further supported the association with pregnenediol sulphate, suggesting a potentially causal link. These findings suggest that the protective association of these adrenal steroids with EDS may stem from an immunosuppressive role of adrenocortical activation, consistent with the anti-inflammatory effects of glucocorticoids. The network analysis confirmed that the steroid hormone biosynthesis pathway was central, linking these metabolites to cortisol and melatonin metabolism.
Dietary Metabolites and Sex Differences: The study also identified associations with dietary metabolites:
- Long-chain fatty acids (LC-PUFAs): Dihomo-linoleate (20:2n6) and docosadienoate (22:2n6), derived primarily from diet, were associated with reduced EDS. Dihomo-linoleate was also linked to increased sleep duration and higher sleep efficiency via actigraphy, suggesting a higher sleep propensity subtype. Replication studies in UKB and Health2000 using proxy fatty acid measures supported the negative association with ESS.
- Sphingomyelin: Sphingomyelin (d18:2/16:0, d18:1/16:1) was associated with reduced EDS and linked to increased sleep propensity. Sphingolipids are important for regulating steroid hormones and cortisol biosynthesis in the adrenal cortex.
- Male-Specific Findings: While no significant associations were found exclusively in females, males exhibited three additional associated metabolites: two glycerophospholipids (GPCs) and tyramine O-sulphate. Tyramine O-sulphate, a metabolite derived from dietary monoamines (e.g., fermented foods), was associated with higher EDS, delayed sleep midpoint, and lower sleep efficiency. The network analysis showed tyramine reactions shared enzymatic groups with melatonin metabolism, suggesting a role in sleep regulation, potentially via the TAAR1 receptor—a target for sleep disorder treatments.
Conclusion
The findings elucidate the metabolomic profile of EDS, highlighting the central role of steroid hormone biosynthesis and specific dietary-related metabolites. The identification of these pathways provides insights for future research aimed at developing targets for the prevention, prediction, and treatment of EDS and related sleep disorders. The sex-specific differences, particularly the association of tyramine O-sulphate in men, underscore the need for further studies tailored to different population groups.
References
Faquih, T., Potts, K. S., Nagarajan, P., Yu, B., Kaplan, R., Isasi, C. R., Qi, Q., Taylor, K. D., Liu, P. Y., Strausz, S. J., Ollila, H. M., Huang, T., Tracy, R. P., Johnson, C., Rich, S. S., Clish, C. B., Rotter, J. I., Redline, S., Sofer, T., & Wang, H. (2025). Steroid hormone biosynthesis and dietary related metabolites associated with excessive daytime sleepiness. eBioMedicine, 119. https://doi.org/10.1016/j.ebiom.2025.105881
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