The interactions between psychological stress, gut microbiota, and fecal metabolites: A longitudinal multi-omics study in Chinese adolescents.

Objectives: This study investigated the bidirectional associations between psychological stress, gut microbiota, and fecal metabolites in a cohort of Chinese adolescents using a multi-omics approach. Methods: Baseline fecal samples from 124 adolescents were subjected to 16S rRNA gene amplicon sequencing, with 51 participants providing samples for metagenomic sequencing and untargeted metabolomics at baseline and follow-up. Psychological stress was assessed via the Adolescent Self-Rating Life Events Checklist. Results: After covariates adjustment, baseline total stress was associated with depleted alpha- and beta-diversity and abundances of the genera Lachnospiraceae NK4A136 group and unclassified Muribaculaceae.In longitudinal analyses, with the same covariates, baseline total stress was associated with six follow-up microbial species (Pfdr < 0.1; Actinomyces spp. HMSC035G02, Actinomyces sp. ICM58, Actinomyces sp. oral taxon 172, Schaalia odontolytica, Blautia sp. AF17-9LB, and Blautia sp. AM47-4) and 83 metabolites, predominantly lipids. These metabolites were primarily enriched in Kyoto Encyclopedia of Genes and Genomes pathways of lipid metabolism. Schaalia odontolytica, Actinomyces sp. ICM58, and Actinomyces spp. HMSC035G02 mediated associations between the total stress score and five lipids, with Schaalia odontolytica demonstrating the strongest effect (26.3 % mediated). Seven baseline metabolites but no microbial species were predictive of follow-up total stress. These metabolites exhibited an area under the curve of 0.72 for differentiating adolescents with high versus low stress, with 5-oxo-eicosatetraenoic acid being the strongest predictor. Conclusions: This study suggests that psychological stress is associated with specific gut microbes and lipid metabolites change, and in turn, specific metabolites contribute to psychological stress change. These findings provide insights into bidirectional interactions between psychological stress and gut microbiota in adolescents.