Psychosocial stress is associated with lipidomic gut microbial and brain connectivity differences relevant to cardiometabolic vulnerability

Discrimination-related chronic psychosocial stress is associated with cardiovascular disease (CVD) risk through multisystem dysregulation. Stress-associated differences in gut microbial ecology, lipid metabolism, and intrinsic brain connectivity may contribute to cardiometabolic vulnerability, but integrated multiomic evidence remains limited. We studied 117 premenopausal women recruited from Los Angeles and stratified by Everyday Discrimination Scale (EDS) scores into higher (> 6, n = 64) and lower (≤ 6, n = 53) exposure groups.

Participants completed clinical and psychological assessments, fasting blood and stool collection, and neuroimaging via MRI. Microbiome profiling targeted the V4 region of 16S rDNA; lipidomics was performed using LC–MS. Analyses included covariate-adjusted group models, exploratory cross-domain correlations, single-mediator mediation models, and moderation models.

Participants with higher EDS scores exhibited higher anxiety, depression, perceived stress, and gastrointestinal-specific anxiety, together with lower mental and physical health scores. Lipidomic profiling identified lower Phosphatidylethanolamine and altered Phosphatidylcholine, fatty acids, Lysophosphatidylcholine, and Plasmenyl‑phosphatidylethanolamine species; total Phosphatidylserine was directionally lower but not significant in the group-level general linear model. Microbiome analyses identified higher Mollicutes RF39 and Ruminococcaceae UCG.009, whereas Prevotella 2 and Candidatus Stoquefichus showed directional but non-significant differences in this subset.

Resting-state fMRI identified higher connectivity primarily among parieto-occipital/occipital region of interest (ROI) pairs and one supramarginal-insular connection. Mediation, moderation, and cross-domain correlation analyses yielded hypothesis-generating indirect-effect, interaction, and association signals involving selected microbial, lipidomic, and connectivity features. Because these analyses were exploratory and cross-sectional, they do not establish temporal ordering, biological pathways, or mechanistic mediation.

Higher discrimination-related psychosocial stress was associated with psychological symptoms and selected microbial, lipidomic, and resting-state connectivity differences in premenopausal women. Larger longitudinal studies are needed to establish the reproducibility and temporal relationships of these findings. We thank the Clinical and Database Core (Cathy Liu and Arthur Dunn) and the Neuroimaging Core (Priten Vora, Ming Wei Hung, Lisa Kilpatrick) from the Goodman-Luskin Microbiome Center.

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This research was supported by grants from the National Institutes of Health to AC [grant numbers R03 DK121025, K23 DK106528, R01 MD0159040], and by a UCLA CURE Pilot and Feasibility Study award. The funding agencies had no role in the design of the study; in the collection, analysis, or interpretation of data; in the writing of the manuscript; or in the decision to submit the article for publication.