Psychological stress during medical internship is associated with inflammatory signatures linked to mental health.

Psychosocial stress is a major risk factor for mental disorders and affects peripheral physiology, including immune function. However, it remains unclear how stress exposure in otherwise healthy individuals alters circulating immune markers in relation to common mental health symptoms. We investigated this question in otherwise healthy medical students (N = 82) during their first medical internship, a naturalistic stressor. In hypothesis-driven analyses, we tested whether longitudinal changes in three predefined inflammatory markers, matrix metalloproteinase-8 (MMP-8), tumor necrosis factor- (TNF)-α, and interleukin-6 (IL-6), were associated with changes in General Health Questionnaire-28 (GHQ) total and subscale scores. We additionally performed exploratory analyses of a broader circulating immune-protein panel to identify other candidate markers associated with symptom change. GHQ scores and circulating immune markers were assessed before the internship and again after three months. The internship period was associated with increased GHQ scores. Greater increases in circulating MMP-8 were associated with greater worsening of GHQ scores, driven primarily by the Anxiety/Insomnia subscale. In contrast, changes in TNF-α and IL-6 were not significantly associated with GHQ total or subscale scores. Exploratory analyses identified several nominal associations with GHQ total scores, but none survived multiple-testing correction and these findings should be considered hypothesis-generating. These findings suggest that MMP-8 may be a relevant immune correlate of stress-related symptom worsening during a naturalistic stressor. Future studies should clarify temporal directionality and determine whether interventions targeting neuroimmune and inflammatory pathways can reduce stress-related mental health symptoms.