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Metabolites found in common foods are associated with the risk of excessive daytime sleepiness (EDS), a new study showed, suggesting diet may play a role in the sleep disorder. 

Omega fatty acids, typically found in Mediterranean diets, were associated with decreased EDS risk, investigators found. Tyramine, present in aged or fermented foods, was associated with higher risk, especially in men.

Although EDS affects one in three Americans and is linked to higher risk of cardiovascular disease, among other negative health outcomes, it's often overlooked and remains poorly understood, lead author Tariq Faquih, PhD, a research fellow at the Sleep Medicine Epidemiology Division at Brigham and Women's Hospital in Boston, told Medscape Medical News. 

Adding information about these newly identified blood biomarkers to previous findings on the genetic underpinnings of EDS creates a clearer picture of the disorder, the researchers noted in a press release.

"As we learn what's happening biologically, we are beginning to understand how and why EDS occurs, the early signs that someone might have it, and what we can do to help patients," Faquih said in the statement.

The study was published online on August 19 in The Lancet eBioMedicine.

'A Serious Health Concern'

As previously reported by Medscape Medical News, the American Academy of Sleep Medicine (AASM) has dubbed EDS a serious health concern and called for more research into associated biomarkers. In March, AASM issued new guidelines to help clinicians treat sleep disorders that cause excessive sleepiness.

But sleep disorders like sleep apnea are only one potential cause of EDS. Prior research suggests genetics and metabolism may also play a role. 

To better understand the underlying biology of EDS, researchers conducted a metabolomic analysis using blood and urine samples collected from participants in the ongoing Hispanic Community Health Study/Study of Latinos (HCHS/SOL). 

Researchers measured the levels of 877 metabolites in samples from 6071 individuals (mean age 48 years, 60% women, 32.5% of Mexican descent). 

The investigators then used linear regression and other models to determine which metabolites were associated with Epworth Sleepiness Scale (ESS) scores indicating high or low risk for EDS. 

Identifying Blood Biomarkers

Researchers identified seven metabolites in the blood that were associated with EDS (P < .00013). The association held even after adjusting for age, sex, BMI, Hispanic background, smoking, alcohol use, and exercise. 

Five of the metabolites were lipid-based, and the remaining two were unannotated. A male-specific analysis revealed three more metabolites associated with EDS. 

The metabolites associated with EDS were mainly obtained from dietary sources and were involved in steroid hormone biosynthesis, including cortisol production, researchers noted. Two steroid metabolites, tetrahydrocortisol glucuronide and pregnenediol sulfate, were linked to reduced sleepiness.

"This is significant because cortisol is incredibly important for sleep and the regulation of our circadian clock. On top of that, both metabolites relating to progesterone are known to interact with the GABA-A receptors, which are major targets of sleep medications," Faquih said.

Tyramine-O-sulphate was linked to worse sleep quality and increased daytime sleepiness, and omega-3 and omega-6 fatty acids were associated with a lower risk of EDS, investigators found. 

While the researchers were able to replicate their findings in the UK Biobank and Finland Health 2000 studies, they were unable to do so in the Multi-Ethnic Study of Atherosclerosis (MESA) due to the small number of metabolites.

The findings align with previously identified genes linked to EDS, Faquih said, noting that the genes they mapped in earlier studies are also involved in the biosynthesis and metabolism of fatty acids and melatonin.

"Consuming a diet high with fatty acids can help with EDS, but also genetics can help in how well they are produced in the body and how efficiently they produce progesterone and tetrahydrocortisol glucuronide," he said.

More Work Needed

Future research could explore how sex differences can affect EDS at different times across life; for example, pre- and post-menopause, Faquih said.

Commenting on the findings for Medscape Medical News, James Rowley, MD, past president and current spokesperson for the American Academy of Sleep Medicine, noted that another potential issue is that the ESS sleep questionnaire can have flaws in its scoring. 

However, it is "the only real tool we have to be able to study thousands of people," he said.

This was an interesting exploratory study, but more work is needed to confirm and progress the findings, said Rowley, who also is program director of the Sleep Medicine Fellowship at Rush University Medical Center in Chicago and was not a part of the research. 

Often, treatment of sleep disorders is thought of in two ways, he said. 

"Either get more sleep or we treat the sleep disorder that you have. What we know though is that for a lot of people who have sleep disorders, the treatment does not necessarily bring them back to normal," Rowley said.

This highlights the need for more research into external factors like diet and diseases that might be at play, he added.

Faquih and Rowley declared no disclosures. The study was supported by grants from the National Institutes of Health and National Institute on Aging, among others.