The effect of obstructive sleep apnea on peripheral blood amino acid and biogenic amine metabolome at multiple time points overnight

Kiens, Ott; Taalberg, Egon; Иванова, В Л; Veeväli, Ketlin; Laurits, Triin; Tamm, Riin; Ottas, Aigar; Kilk, Kalle; Soomets, Ursel; Altraja, Alan

doi:10.1038/s41598-021-88409-y

Cited by 8 publications

(10 citation statements)

References 33 publications

(50 reference statements)

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“…In addition to IDO, other downstream enzymes in the KP—including TRP, KYN, KYNA and QA, were analyzed in the CUMS group. As expected, KYN/TRP was an indicator of IDO activity [ 40 ], we found the ratio of KYN to TRP was increased in the brain and serum (Fig. 5 A, E) ( p < 0.01 ), suggesting it has a significant value as a surrogate marker of IDO activation [ 32 , 41 ].…”

Section: Resultssupporting

confidence: 77%

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Chen

et al. 2022

BMC Neurosci

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Inflammation and glutamate (GLU) are widely thought to participate in the pathogenesis of depression, and current evidence suggests that the development of depression is associated with the activation of the kynurenine pathway (KP). However, the exact mechanism of KP among the inflammation, GLU and depression remain poorly understood. In this study, we examined the involvement of KP, inflammation and GLU in depressive phenotype induced by chronic unpredictable mild stress (CUMS) in C57B/6 J mice. Our results showed that CUMS caused depressive like-behavior in the sucrose preference test, tail suspension test and forced swimming test. From a molecular perspective, CUMS upregulated the peripheral and central inflammatory response and activated indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme of KP, which converts tryptophan (TRP) into kynurenine (KYN). KYN is a precursor for QA in microglia, which could activate the N-methyl-D-aspartate receptor (NMDAR), increasing the GLU release, mirrored by increased IDO activity, quinolinic acid and GLU levels in the hippocampus, prefrontal cortex and serum. However, intervention with IDO inhibitor 1-methyl-DL-tryptophan (50 mg/kg/s.c.) and 1-methyl-L-tryptophan (15 mg/kg/i.p.) reversed the depressive-like behaviors and adjusted central and peripheral KP’s metabolisms levels as well as GLU content, but the inflammation levels were not completely affected. These results provide certain evidence that KP may be a vital pathway mediated by IDO linking inflammation and glutamate, contributing to depression.

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Section: Resultssupporting

confidence: 77%

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Chen

et al. 2022

BMC Neurosci

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“…The association of increased serum L-ornithine and proline among asthma subjects with OSA remained significant after accounting for BMI. While an increase in serum proline was recently described in patients with mild-to-moderate OSA [ 16 ], this association has not previously been reported among asthma patients with OSA.…”

Section: Discussionmentioning

confidence: 75%

“…Like asthma, OSA is associated with dysregulation of the L-arginine metabolism. OSA patients have been shown to have decreased L-arginine bioavailability, increased arginase activity, increased proline and decreased NO in small cross-sectional studies [13][14][15][16]. These studies, however, did not include individuals with comorbid asthma.…”

Section: Introductionmentioning

confidence: 99%

Differences in l-arginine metabolism and asthma morbidity among asthma patients with and without obstructive sleep apnea

et al. 2022

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Background Imbalance in l-arginine and nitric oxide (NO) metabolism has been implicated in the pathophysiology of asthma and obstructive sleep apnea (OSA), and both diseases impact the other’s morbidity. We sought to determine whether l-arginine/NO metabolism differs between adults with asthma with or without comorbid OSA, and its association with asthma morbidity. Methods This is a cross-sectional study of 322 adults with asthma recruited in Denver, CO and New York City, NY. Data were collected on OSA status, spirometry, and metrics of asthma control and morbidity. l-Arginine metabolites were quantified in patient serum. Bivariate analyses and multiple regression were performed to determine differences between l-arginine metabolism, OSA and association with asthma morbidity. Results Among the 322 participants, 92 (28.5%) had OSA. The cohort was 81.6% female, 23.4% identified as Black and 30.6% as Latino. Patients with asthma and OSA had significantly higher serum concentrations of NO synthase inhibitor asymmetric dimethylarginine (ADMA) (p-value = 0.019), lower L-arginine to ornithine ratios (p-value = 0.003), and increased ornithine (p-value = 0.001) and proline levels (p-value < 0.001) compared to those without OSA. In adjusted models, OSA was associated with worse asthma control, adjusted mean difference in asthma control questionnaire of 0.36 (95% confidence interval [CI]: 0.06 to 0.65), and asthma quality of life questionnaire, adjusted mean difference: − 0.53 (95% CI: − 0.85 to − 0.21), after adjusting for relevant covariates including body mass index and L-arginine metabolites. Conclusions Adults with asthma and OSA had increased ADMA, an inhibitor of nitric oxide synthase, and greater metabolism of l-arginine via the arginase pathway compared to those with asthma alone, indicating a possible shared pathophysiological mechanism of these diseases.

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“…This is in line with our evidence: peripheral phenylalanine was elevated among individuals with moderate to severe OSA patients ( S3 Table ). A prior lab-based study that measured a few metabolites over the course of sleep reported that phenylalanine levels decreased less overnight among patients with OSA compared to controls (40). Phenylalanine levels were also reported to be elevated after sleep restriction (41).…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Metabolite Index for Obstructive Sleep Apnea across Race/Ethnicities

Zhang

Ngo

et al. 2022

Preprint

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BackgroundObstructive sleep apnea (OSA) is a common disorder characterized by recurrent episodes of upper airway obstruction during sleep resulting in oxygen desaturation and sleep fragmentation, and associated with increased risk of adverse health outcomes. Metabolites are being increasingly used for biomarker discovery and evaluation of disease processes and progression. Studying metabolomic associations with OSA in a diverse community-based cohort may provide insights into the pathophysiology of OSA. We aimed to develop and replicate a metabolite index for OSA and identify individual metabolites associated with OSA.Methods and FindingsWe studied 219 metabolites and their associations with the apnea hypopnea index (AHI) and with moderate-severe OSA (AHI≥15) in the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) (n=3507) using two methods: (1) association analysis of individual metabolites, and (2) least absolute shrinkage and selection operator (LASSO) regression to identify a subset of metabolites jointly associated with OSA, and develop a metabolite index for OSA. Results were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) (n=475). When assessing the associations with individual metabolites, we identified seven metabolites significantly positively associated with OSA in HCHS/SOL (FDR p<0.05), of which four associations - glutamate, oleoyl-linoleoyl-glycerol (18:1/18:2), linoleoyl-linoleoyl- glycerol (18:2/18:2) and phenylalanine, replicated in MESA (one sided-p <0.05). The OSA metabolite index, composed of 14 metabolites, was associated with 50% increase of risk for moderate-severe OSA (OR=1.50 [95% CI: 1.21-1.85] per 1 SD of OSA metabolite index, p<.001) in HCHS/SOL and 44% increased risk (OR=1.55 [95% CI: 1.10-2.20] per 1 SD of OSA metabolite index, p=0.013) in MESA, both adjusted for demographics, lifestyle, and comorbidities. Similar albeit less significant associations were observed for AHI.ConclusionsWe developed a metabolite index that replicated in an independent multi-ethnic dataset, demonstrating the robustness of metabolomic-based OSA index to population heterogeneity. Replicated metabolite associations may provide insights into OSA-related molecular and metabolic mechanisms.

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The effect of obstructive sleep apnea on peripheral blood amino acid and biogenic amine metabolome at multiple time points overnight

Cited by 8 publications

References 33 publications

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Involvement of kynurenine pathway between inflammation and glutamate in the underlying etiopathology of CUMS-induced depression mouse model

Differences in l-arginine metabolism and asthma morbidity among asthma patients with and without obstructive sleep apnea

Development and Validation of a Metabolite Index for Obstructive Sleep Apnea across Race/Ethnicities

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