Stressful life events impact individual's functionality and contribute to disease outcomes, yet the biological pathways underlying life stress remain unclear. We characterized the metabolomic profiles of stressful life events using data from 3,264 participants (5,163 observations) of the Dutch NESDA cohort. 98 metabolites were identified, with upregulated metabolites overrepresented in phosphatidylethanolamine and downregulated metabolites overrepresented in fatty acid metabolism. 92 of these metabolites were available in the Dutch NEO cohort (N=599): 11 were significantly replicated including six lipids (e.g., three bile acids (glycochenodeoxycholate 3-sulfate)), one carbohydrate, and one xenobiotic. 21 overlapping metabolites were additionally available in the Chinese GBCS cohort (N=200): 10-undecenoate (11:1n1) (fatty acid) and glycochenodeoxycholate 3-sulfate (bile acid) showed consistent associations across both Dutch and Chinese cohorts. Stressful life events are associated with metabolic dysregulation, particularly involving fatty acid and bile acid pathways, highlighting promising biological targets to reduce the impact of stress on mental and somatic health.

The authors declare the following competing interests. Matthias Arnold and Gabi Kastenmuller named co-inventor on one patent: U.S. Patent No. 7,906,283: Methods to Identify Patients at Risk of Developing Adverse Events During Treatment with Antidepressant Medication, Inventors: McMahon FJ, Laje G, Manji H, Rush AJ, Paddock S. Arnold M, and Kastenmuller G, are co-inventors (through Duke University/Helmholtz Zentrum Munchen) on patents on applications of metabolomics in diseases of the central nervous system and hold equity in Chymia LLC and IP in PsyProtix and Atai that are exploring the potential for therapeutic applications targeting mitochondrial metabolism in depression. Rima Kaddurah-Daouk is an inventor on a series of patents on use of metabolomics for the diagnosis and treatment of central nervous system diseases and holds equity in Metabolon Inc., Chymia, and Metabosensor. The funders listed above had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the paper; and decision to submit the paper for publication. All the other authors declare no conflict of interest.

Metabolomics data was generated by the Alzheimer Gut Microbiome Project (AGMP) and the Alzheimer Disease Metabolomics Consortium (ADMC). The AGMP and ADMC were funded wholly or in part by the following grants and supplements awarded to Rima Kaddurah-Daouk at Duke University in partnership with a large number of academic institutions: R01AG046171, RF1AG051550, RF1AG057452, R01AG059093, U19AG063744, 3U19AG063744-04S1, RF1AG058942, 1U01AG088562, U01AG061359, R01AG081322). As such, the investigators within the AGMP and the ADMC, not listed specifically in this author list, provided analysis-ready data, but did not participate in designing the study, conducting the analyses or writing of this manuscript. Matthias Arnold and Gabi Kastenmuller received funding (through their institutions) from the National Institutes of Health/National Institute on Aging through grants RF1AG058942, RF1AG059093, U01AG061359, U19AG063744, and R01AG069901. Rick Jansen received funding from ZonMw: The Netherlands Organization for Health Research and Development (project number: 636310017, research program GGZ). Brenda Penninx is supported by the research project "Stress in Action" which is financially supported by the Dutch Research Council and the Dutch Ministry of Education, Culture and Science (NWO gravitation grant number 024.005.010). The infrastructure for the NESDA study is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (VU University Medical Center, GGZ inGeest, Leiden University Medical Center, Leiden University, GGZ Rivierduinen, University Medical Center Groningen, University of Groningen, Lentis, GGZ Friesland, GGZ Drenthe, Rob Giel Onderzoekscentrum). The NEO study is funded by the participating departments, the Division and the Board of Directors of the Leiden University Medical Centre, and by the Leiden University, Research Profile Area "Vascular and Regenerative Medicine". The GBCS is funded by the University of Hong Kong Foundation for Educational Development and Research (SN/1f/HKUF-DC; C2040028505200), the Health Medical Research Fund (HMRF/13143241) in Hong Kong, the Guangzhou Public Health Bureau (201102A211004011), the Natural Science Foundation of Guangdong (2018A 030313140), Guangzhou Twelfth People Hospital, the University of Birmingham, UK, School of Public Health, the University of Hong Kong and Greater Bay Area Public Health Research Collaboration. Metabolomics data of the GBCS was supported by the Natural Science Foundation of Guangdong (2025A1515011659) and the fundamental research funds for the central universities, Sun Yat-Sen university (24qnpy211).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Netherlands Study of Anxiety and Depression (NESDA) was approved centrally by the Ethical Review Board of the VU University Medical Centre and subsequently by local review boards of each participating center (METC number 2003-183). All participants provided written informed consent. The present study used de-identified NESDA data.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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All data produced in the present study are available upon reasonable request to the authors.