Understanding stress through metabolomic and psychosocial lenses: Pathways to biomarker discovery

Identifying reliable biomarkers of trauma-related psychological stress is critical for accurate diagnosis and appropriate intervention. Metabolomic profiling offers a promising approach to uncover biochemical correlates of stress. This study investigated salivary metabolomic signatures of traumatic stress in Syrian refugee women resettled in Jordan, with Jordanian women serving as a comparison group. We conducted a cross-sectional study to assess mental distress among Syrian refugee (n = 48) and Jordanian women (n = 52) living in northern Jordan. Saliva samples were collected and processed from all participants, of which 25 (11 Syrian refugee and 14 Jordanian women) yielded sufficiently detectable metabolomic profiles and were included in the exploratory metabolomic analysis. Psychometric assessments included validated measures of perceived stress and mental distress. Saliva samples were analyzed using global quantitative metabolomics via high-resolution TIMS-TOF mass spectrometry to identify metabolites associated with stress. While Syrian refugee women reported higher perceived stress compared with Jordanian women (mean ± SD: 30.72 ± 9.2 vs. 27.19 ± 7.7; p = 0.040), both Jordanian and Syrian women exhibited high scores in Self Reporting Questionnaire (mean score ± SD: Syrian refugees = 11.59 ± 4.5, Jordanian women = 10.60 ± 4.7; p = 0.285). Syrian refugee women exhibited elevated salivary metabolites linked to oxido-inflammatory and stress-response pathways including purine metabolism, glutathione metabolism, pyrimidine metabolism, and plasmalogen synthesis. Our findings point to salivary metabolites involved in oxido-inflammatory cascades as potential biomarkers of psychological stress, which in the future may provide objective, noninvasive indicators of stress, complementing psychometric assessments and offering new avenues for evaluating mental health risk in vulnerable populations such as refugees. Findings should be interpreted as associations rather than evidence of causality.