Integrated gut microbiota and metabolome analyses link anger to metabolic dysregulation in patients with type 2 diabetes mellitus

Abstract

Objective This exploratory pilot study aimed to investigate the associations of anger-related irritability symptoms with gut microbiota and circulating metabolites in patients with type 2 diabetes mellitus (T2DM) using multi-omics analysis. Methods We conducted a cross-sectional study, in which T2DM patients were categorized into a self-reported irritable T2DM group (IDM, n = 29) and a self-reported non-irritable DM group (NIDM, n = 28) based on Visual Analog Scale (VAS) scores, with a healthy control group (HC, n = 30) also established. Fecal 16S rRNA gene sequencing and UPLC-MS/MS-based untargeted metabolomic profiling of blood samples were performed. Differences in microbial community structure between groups were analyzed using alpha and beta diversity metrics and linear discriminant analysis effect size (LEfSe) analysis. Differentially abundant genera were identified by MaAsLin2 with adjustment for confounders. Exploratory metabolite markers were screened based on thresholds for p < 0.05, variable importance in projection (VIP) > 1, |log2 fold change (FC)| > 1. Associations between differentially abundant genera and exploratory metabolite markers were explored using Spearman correlation analysis. Functional prediction was conducted based on differentially represented KEGG orthology (KO) and clusters of orthologous groups (COG) entries to identify altered metabolic pathways. Results Both beta diversity and LEfSe analyses revealed differences in gut microbial community structure and potential discriminatory taxa among the three groups. Five differentially abundant genera and twelve exploratory metabolite markers were identified between IDM and NIDM. A combined model incorporating microbial and metabolomic markers demonstrated superior diagnostic performance (AUC = 0.872) compared with models using either type of marker alone. Twelve statistically significant microbiota–metabolite associations were found in Spearman analysis. Functional prediction analysis indicated enrichment of bile acid and tryptophan metabolism pathways. Conclusion VAS-defined irritability symptoms were associated with specific gut microbial and metabolomic alterations in T2DM, providing exploratory evidence for future studies on emotion-related metabolic dysregulation.