The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
New Insights into Stress Metabolomics. Looking for new Diagnostic Biomarkers.
Open accessPreprint — published as 10.1038/s41598-025-29572-4 · Paper page
Abstract
Stress is associated with the onset of various neurological disorders such as depression, PTSD, and anxiety. Despite the extensive research performed, metabolic changes triggered in response to acute psychological stress remain unclear. This study evaluates acute stress biomarkers and its adverse effects in university students through psychometric, biochemical, and metabolomic analyses, implementing Machine Learning on statistical models. In the study, forty participants were subject to relaxation and stress induction using autogenic training and a modified Trier Social Stress Test (TSST-M). Psychometric questionnaires confirmed the achievement of these states, while saliva and blood were sampled for biochemical analyses. Additionally, blood samples were applied to untargeted metabolomic approaches. The results reveal that although most biomarkers showed changes under stress state, the machine learning predictive model successfully identified salivary α-amylase and State-Trait Anxiety Inventory-state (STAI-s) as prominent stress markers. Additionally, several metabolic pathways, including steroid hormone biosynthesis, glycerophospholipid metabolism, linoleic acid metabolism, tyrosine metabolism, and aminoacyl-tRNA biosynthesis, were affected. Alterations of this sort, we conclude, allow us to gain further understanding into the adverse effects systematically associated with stress. In this way, our findings highlight the significant impact of acute mental stress on multiple metabolic pathways directly implicated in stress-related disorders.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
The effects of psychosocial stress on dopaminergic function and the acute stress response
Bloomfield, M. A., McCutcheon, R. A., Kempton, M., Freeman, T. P., & Howes, O. (2019) · eLife · doi:10.7554/elife.46797 · Cited by 112
Flagged first, then by citations
Research works printed but not linked: 90
- Chrousos, G. P. Stress and disorders of the stress system. Nat. Rev. Endocrinol. 5, 374–381 (2009). · DOI · Paper page
- Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252 (1992). · DOI · Paper page
- Resick, P. A. Stress and Trauma In Stress and Trauma (Psychology, (2014). · DOI
- Su, C., Li, X., Yang, L. & Zeng, Y. Mechanism, measurement, and quantification of stress in decision process: a model based systematic-review protocol. Preprint at (2022). https://arxiv.org/abs/2203.10397 · arXiv
- Chovatiya, R., Medzhitov, R. & Stress Inflammation, and Defense of Homeostasis. Mol. Cell. 54, 281–288 (2014). · DOI · Paper page
- Xin, Y. et al. The relationship between personality and the response to acute psychological stress. Sci. Rep. 7, 16906 (2017). · DOI
- Iqbal, T. et al. A Review of Biophysiological and Biochemical Indicators of Stress for Connected and Preventive Healthcare. Diagnostics 11, 556 (2021). · DOI
- Lazarus, R. S. From Psychological Stress to the Emotions: A History of Changing Outlooks. Annu. Rev. Psychol. 44, 1–22 (1993). · DOI · Paper page
- Tamashiro, K. L., Sakai, R. R., Shively, C. A., Karatsoreos, I. N. & Reagan, L. P. Chronic stress, metabolism, and metabolic syndrome. Stress 14, 468–474 (2011). · DOI
- Pfeifer, L. S., Heyers, K., Ocklenburg, S. & Wolf, O. T. Stress research during the COVID-19 pandemic and beyond. Neurosci. Biobehav Rev. 131, 581 (2021). · DOI
- Santabárbara, J. et al. Prevalence of anxiety in the COVID-19 pandemic: An updated meta-analysis of community-based studies. Prog Neuropsychopharmacol. Biol. Psychiatry. 109, 110207 (2021). · DOI
- Van De Keus, M. et al. Preventing sickness absence among employees with common mental disorders or stress-related symptoms at work: a cluster randomised controlled trial of a problem-solving-based intervention conducted by the Occupational Health Services. Occup. Environ. Med. 77, 454–461 (2020). · DOI
- Bergström, G. et al. Preventing sickness absenteeism among employees with common mental disorders or stress-related symptoms at work: Design of a cluster randomized controlled trial of a problem-solving based intervention versus care-as-usual conducted at the Occupational Health Services. BMC Public. Health 17, (2017). · DOI
- Kim, E. J. & Kim, J. J. Neurocognitive effects of stress: a metaparadigm perspective. Mol. Psychiatry. 28, 2750–2763 (2023). · DOI
- Thompson, D. J. et al. Stress and Cortisol in Disaster Evacuees: An Exploratory Study on Associations with Social Protective Factors. Appl. Psychophysiol. Biofeedback. 40, 33–44 (2015). · DOI
- Goyal, A., Singh, S., Vir, D. & Pershad, D. Automation of Stress Recognition Using Subjective or Objective Measures. Psychol. Stud. (Mysore). 61, 348–364 (2016). · DOI
- Arza, A. et al. Measuring acute stress response through physiological signals: towards a quantitative assessment of stress. Med. Biol. Eng. Comput. 57, 271–287 (2019). · DOI · Paper page
- Khoulji, S. et al. Psychological and Physiological Profiles in Oncology Caregivers: A Multivariable Cross-Sectional Study. Trans. Mach. Learn. Artif. Intell. 5, (2017).
- Wester, V. L. & van Rossum, E. F. C. Clinical applications of cortisol measurements in hair. Eur. J. Endocrinol. 173, M1–M10 (2015). · DOI · Paper page
- Katan, M. & Christ-Crain, M. The stress hormone copeptin: a new prognostic biomarker in acute illness. Swiss Med. Wkly. 140, 11–15 (2010).
- Lorenzo-Tejedor, M. et al. Direct infussion Electrospray Mass Spectrometry as a new non-invasive tool for serum metabolomics in induced-stress subjects. Eur. J. Psychiatry. 29, 259–275 (2015). · DOI
- Shi, B. et al. A 1H-NMR plasma metabonomic study of acute and chronic stress models of depression in rats. Behav. Brain. Res. 241, 86–91 (2013). · DOI
- Fiehn, O. Metabolomics – the link between genotypes and phenotypes. Plant Mol. Biol. 48, 155–171 (2002). · DOI · Paper page
- García Villar, J. & Quintana-Domeque, C. Income and body mass index in Europe. Econ. Hum. Biol. 7, 73–83 (2009). · DOI
- Gromski, P. S. et al. A tutorial review: Metabolomics and partial least squares-discriminant analysis–a marriage of convenience or a shotgun wedding. Anal. Chim. Acta. 879, 10–23 (2015). · DOI
- Spanakis, E. K., Wand, G. S., Ji, N. & Golden, S. H. Association of HPA axis hormones with copeptin after psychological stress differs by sex. Psychoneuroendocrinology 63, 254–261 (2016). · DOI
- Siegenthaler, J., Walti, C., Urwyler, S. A., Schuetz, P. & Christ-Crain, M. Copeptin concentrations during psychological stress: the PsyCo study. Eur. J. Endocrinol. 171, 737–742 (2014). · DOI
- Noushad, S. et al. Physiological biomarkers of chronic stress: A systematic review. Int. J. Health Sci. (Qassim). 15, 46 (2021).
- Kudielka, B. M., Hellhammer, D. H. & Wüst, S. Why do we respond so differently? Reviewing determinants of human salivary cortisol responses to challenge. Psychoneuroendocrinology 34, 2–18 (2009). · DOI · Paper page
- Granger, D. A., Kivlighan, K. T., El-Sheikh, M., Gordis, E. B. & Stroud, L. R. Salivary α‐Amylase in Biobehavioral Research. Ann. N Y Acad. Sci. 1098, 122–144 (2007). · DOI · Paper page
- Viau, V. & Meaney, M. J. Testosterone-dependent variations in plasma and intrapituitary corticosteroid binding globulin and stress hypothalamic-pituitary-adrenal activity in the male rat. J. Endocrinol. 181, 223–231 (2004). · DOI
- Garzón Rey, J. M. et al. An approach to an acute emotional stress reference scale. Rev. Neurol. 64, 529 (2017).
- García Pagès, E. et al. Psychosomatic response to acute emotional stress in healthy students. Front. Physiol. 13, (2023). · DOI
- Ali, N. & Nater, U. M. Salivary Alpha-Amylase as a Biomarker of Stress in Behavioral Medicine. Int. J. Behav. Med. 27, 337–342 (2020). · DOI · Paper page
- Nater, U. M. & Rohleder, N. Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: Current state of research. Psychoneuroendocrinology 34, 486–496 (2009). · DOI · Paper page
- Singh, S. et al. Pre-clinical Investigations of Therapeutic Markers Associated with Acute and Chronic Restraint Stress: A Nuclear Magnetic Resonance Based Contrast Metabolic Approach. Nanotheranostics 7, 91–101 (2023). · DOI
- Morgan, L. et al. Saliva metabolome alterations after acute stress. Sci. Rep. 12, 1–10 (2022). · DOI
- Noerman, S. et al. Plasma lipid profile associates with the improvement of psychological well-being in individuals with perceived stress symptoms. Sci. Rep. 10, 1–13 (2020). · DOI
- Bozelli, J. C., Azher, S. & Epand, R. M. Plasmalogens and Chronic Inflammatory Diseases. Front. Physiol. 12, 730829 (2021). · DOI
- Denis, I., Potier, B., Vancassel, S., Heberden, C. & Lavialle, M. Omega-3 fatty acids and brain resistance to ageing and stress: Body of evidence and possible mechanisms. Ageing Res. Rev. 12, 579–594 (2013). · DOI · Paper page
- Hamazaki, K. et al. Effect of omega-3 fatty acid-containing phospholipids on blood catecholamine concentrations in healthy volunteers: a randomized, placebo-controlled, double-blind trial. Nutrition 21, 705–710 (2005). · DOI
- Lin, L. L. et al. cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–278 (1993). · DOI
- Dennis, E. A., Cao, J., Hsu, Y. H., Magrioti, V. & Kokotos, G. Phospholipase A2 enzymes: physical structure, biological function, disease implication, chemical inhibition, and therapeutic intervention. Chem. Rev. 111, 6130–6185 (2011). · DOI
- Liu, P. et al. The mechanisms of lysophosphatidylcholine in the development of diseases. Life Sci. 247, 117443 (2020). · DOI · Paper page
- Adams, P. B., Lawson, S., Sanigorski, A. & Sinclair, A. J. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 31, S157–S161 (1996). · DOI
- Choque, B., Catheline, D., Rioux, V. & Legrand, P. Linoleic acid: Between doubts and certainties. Biochimie 96, 14–21 (2014). · DOI
- Katan, M. B., Zock, P. L. & Mensink, R. P. Effects of fats and fatty acids on blood lipids in humans: An overview. Am. J. Clin. Nutr. 60, (1994). · DOI
- Wang, Q., Zhang, H., Jin, Q. & Wang, X. Effects of Dietary Linoleic Acid on Blood Lipid Profiles: A Systematic Review and Meta-Analysis of 40 Randomized Controlled Trials. Foods 12, 2129 (2023).
- Ramamoorthy, S., Cidlowski, J. A. & Corticosteroids Mechanisms of Action in Health and Disease. Rheum. Dis. Clin. North. Am. 42, 15–31 (2016).
- Church, D. D., Ferrando, A. A., Gwin, J. A., Wolfe, R. R. & Pasiakos, S. M. Mitigation of Muscle Loss in Stressed Physiology: Military Relevance. Nutrients 11, 1703 (2019). · DOI
- Kvetňanský, R., Pacák, K., Sabban, E. L., Kopin, I. J. & Goldstein, D. S. Stressor Specificity of Peripheral Catecholaminergic Activation. Adv. Pharmacol. 42, 556–560 (1997). · DOI
- Kvetnansky, R., Lu, X. & Ziegler, M. G. Stress-Triggered Changes in Peripheral Catecholaminergic Systems. Adv. Pharmacol. 68, 359–397 (2013). · DOI
- James, G. D. & Brown, D. E. The Biological Stress Response and Lifestyle: Catecholamines and Blood Pressure. Annu. Rev. Anthropol. 26, 313–335 (1997). · DOI
- Carter, J. R. & Goldstein, D. S. Sympathoneural and Adrenomedullary Responses to Mental Stress. Compr. Physiol. 5, 119 (2015). · DOI
- Channer, B. et al. Dopamine, Immunity, and Disease. Pharmacol. Rev. 75, 62–158 (2023). · DOI
- Moore, S. C., Vaz de Castro, P. A. S., Yaqub, D., Jose, P. A. & Armando, I. Anti-Inflammatory Effects of Peripheral Dopamine. Int. J. Mol. Sci. 24, (2023). · DOI
- Goldstein, D. S. Catecholamines and Stress. Endocr. Regul. 37, 69–80 (2003).
- Marinelli, M. Dopaminergic Reward Pathways and Effects of Stress in Stress and Addiction 41–83 (Elsevier, (2007). · DOI
- Baik, J. H. Stress and the dopaminergic reward system. Exp. Mol. Med. 52, 1879 (2020). · DOI
- Levine, S. & Muneyyirci-Delale, O. Stress-Induced Hyperprolactinemia: Pathophysiology and Clinical Approach. Obstet. Gynecol. Int. https://doi.org/10.1155/2018/9253083 (2018). · DOI
- Jaroenporn, S. et al. Physiological roles of prolactin in the adrenocortical response to acute restraint stress. Endocr. J. 54, 703–711 (2007). · DOI
- Faron-Górecka, A. et al. The Involvement of Prolactin in Stress-Related Disorders. Int. J. Environ. Res. Public Health. 20, 3257 (2023). · DOI
- Ruiz-Herrera, X. et al. Prolactin Promotes Adipose Tissue Fitness and Insulin Sensitivity in Obese Males. Endocrinology 158, 56–68 (2017).
- Ochoa-Amaya, J. E. et al. Acute and chronic stress and the inflammatory response in hyperprolactinemic rats. Neuroimmunomodulation 17, 386–395 (2010). · DOI
- Song, J. et al. Prolactin mediates effects of chronic psychological stress on induction of fibrofatty cells in the heart. Am. J. Transl Res. 8, 644 (2016).
- Dennerstein, L. et al. Progesterone and the premenstrual syndrome: a double blind crossover trial. Br. Med. J. (Clin Res. Ed). 290, 1617 (1985). · DOI
- Wirth, M. M., Meier, E. A., Fredrickson, B. L. & Schultheiss, O. C. Relationship between salivary cortisol and progesterone levels in humans. Biol. Psychol. 74, 104–107 (2007). · DOI
- Maes, M., Christophe, A., Bosmans, E., Lin, A. & Neels, H. In humans, serum polyunsaturated fatty acid levels predict the response of proinflammatory cytokines to psychologic stress. Biol. Psychiatry. 47, 910–920 (2000). · DOI · Paper page
- Zhang, X. S. et al. Caprylic Acid Improves Lipid Metabolism, Suppresses the Inflammatory Response and Activates the ABCA1/p-JAK2/p-STAT3 Signaling Pathway in C57BL/6J Mice and RAW264.7 Cells. Biomed. Environ. Sci. 35, 95–106 (2022).
- Azcoitia, I., Barreto, G. E. & Garcia-Segura, L. M. Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences. Front. Neuroendocrinol. 55, 100787 (2019). · DOI · Paper page
- Engler-Chiurazzi, E. B., Brown, C. M., Povroznik, J. M. & Simpkins, J. W. Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury. Prog Neurobiol. 157, 188–211 (2017). · DOI
- Aguiló, J. et al. Proyecto ES3: intentando la cuantificación y medida del nivel de estrés. Rev. Neurol. 61, 405 (2015). · DOI
- Kudielka, B. M., Schommer, N. C., Hellhammer, D. H. & Kirschbaum, C. Acute HPA axis responses, heart rate, and mood changes to psychosocial stress (TSST) in humans at different times of day. Psychoneuroendocrinology 29, 983–992 (2004). · DOI · Paper page
- Linden Wolfgang. The autogenic training method of JH Schultz. in Principles and Practice of Stress Management (eds. Lehrer, P. M., Woolfolk, R. L. & Sime, W. E.) 151–174 (The Guilford Press, (2007).
- Birkett, M. A. The Trier Social Stress Test protocol for inducing psychological stress. J. Vis. Exp. 56, 1–6. https://doi.org/10.3791/3238 (2011). · DOI
- Kirschbaum, C., Pirke, K. M. & Hellhammer, D. H. The ’Trier Social Stress Test’--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology 28, 76–81 (1993). · DOI · Paper page
- Richer, R. et al. Machine learning-based detection of acute psychosocial stress from body posture and movements. Sci. Rep. 14, 1–19 (2024). · DOI
- Pfeifer, L. S. et al. Using the online version of the Trier Social Stress Test to investigate the effect of acute stress on functional lateralization. Sci. Rep. 14, 1–15 (2024). · DOI
- Remor, E. Psychometric Properties of a European Spanish Version of the Perceived Stress Scale (PSS). Span. J. Psychol. 9, 86–93 (2006). · DOI · Paper page
- Guillén, A. & Buela, G. Estructura factorial del Cuestionario de Ansiedad Estado-Riesgo (STAI) para pacientes diagnosticados con depresión. Salud mental. 38, 293–298 (2015). · DOI
- Cohen, S., Kamarck, T. & Mermelstein, R. A global measure of perceived stress. J. Health Soc. Behav. 24, 385–396 (1983). · DOI · Paper page
- McCormack, H. M., de Horne, D. J., Sheather, S. & L. & Clinical applications of visual analogue scales: a critical review. Psychol. Med. 18, 1007–1019 (1988). · DOI
- Lesage, F. X. & Berjot, S. Validity of occupational stress assessment using a visual analogue scale. Occup. Med. (Chic Ill). 61, 434–436 (2011). · DOI
- Lesage, F. X., Berjot, S. & Deschamps, F. Clinical stress assessment using a visual analogue scale. Occup. Med. (Chic Ill). 62, 600–605 (2012). · DOI · Paper page
- Spielberger, C. D. State-Trait Anxiety Inventory. in The Corsini Encyclopedia of Psychology 1–1 (Wiley, (2010).
- Alfaro, E., Gáamez, M. & García, N. adabag: An R Package for Classification with Boosting and Bagging. J. Stat. Softw. 54, 1–35 (2013). · DOI
- González-Domínguez, R. & Sayago, A. Fernández-Recamales, Á. Direct infusion mass spectrometry for metabolomic phenotyping of diseases. Bioanalysis 9, 131–148 (2017). · DOI
- Pang, Z. et al. MetaboAnalyst 5.0: narrowing the gap between raw spectra and functional insights. Nucleic Acids Res. 49, W388–W396 (2021). · DOI
- Kanehisa, M., Furumichi, M., Sato, Y., Matsuura, Y. & Ishiguro-Watanabe, M. KEGG: Biological Systems Database As A Model Of The Real World. Nucleic Acids Res. 53, D672–D677 (2025). · DOI
- Kanehisa, M. & Goto, S. K. E. G. G. Kyoto Encyclopedia Of Genes And Genomes. Nucleic Acids Res. 28, 27–30 (2000). · DOI · Paper page
Metadata
- Authors
- Frempong, G. A., Goni, G., Lorenzo-Tejedor, M., Cámara, C. D. L., Lázaro, J., Rasia, E. M., Aguiló, J., Bailon, R., & Bernal, M. L.
- Affiliations
- Universidad de Zaragoza (ES)
- University of Zaragoza
- Aragon Institute of Health Research (IIS Aragon)
- National Scientific and Technical Research Council
- Universitat Autònoma de Barcelona (ES)
- Venue
- Scientific Reports
- Published
- 2025-06-11
- Volume
- 16
- Issue
- 1
- Pages
- 1567-1567
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC12800245
- OpenAlex
- W7119575705
- Cited by
- 3
- References
- 1
- Citations by year
- 2026: 3
- FWCI
- 13.66
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Scientific Reports (publishedVersion, cc-by-nc-nd)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Zaguan (Universidad de Zaragoza) (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministerio de Ciencia e Innovación (TED2021, TED2021-131106B-I00)
- Gobierno de Aragón (T39_23R)
- Universitat Politècnica de València
- European Social Fund
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Physical Sciences › Computer Science › Artificial Intelligence › Emotion and Mood Recognition
- Keywords
- acute psychological stress, stress response, young adults, university students, salivary amylase, stress biomarkers, untargeted metabolomics, metabolic pathways, steroidogenesis, glycerophospholipid metabolism, linoleic acid metabolism, tyrosine metabolism, aminoacyl-tRNA biosynthesis, Trier Social Stress Test, stress-related disorders
- MeSH terms
- Machine Learning, Adolescent, Adult, Anxiety, Female, Humans, Male, Psychometrics, Saliva, Stress, Psychological, Biomarkers, Salivary alpha-Amylases, Metabolomics, Young Adult
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review