Document resource
Background Patients with type 2 diabetes mellitus (T2DM) are at markedly increased risk of atherosclerotic plaque instability and subsequent acute cardiovascular events. Current risk stratification strategies mainly rely on traditional metabolic parameters and imaging findings, which fail to fully explain the heterogeneity of plaque vulnerability among T2DM patients. Growing evidence suggests that gut microbiota dysbiosis contributes to insulin resistance and systemic inflammation; however, clinically relevant microbial signatures and metabolites associated with plaque instability in T2DM remain insufficiently characterized.Methods This observational clinical study enrolled patients with T2DM and angiographically confirmed atherosclerosis. Gut microbiota composition was analyzed using metagenomic sequencing of fecal samples. Circulating microbial-derived metabolites, including 4-methylcatechol (4MC), were quantified by targeted metabolomics. Insulin resistance was assessed using the homeostasis model assessment (HOMA-IR). Plaque stability was evaluated based on vascular imaging parameters and histopathological features when available. Associations between microbial alterations and plaque vulnerability were assessed using correlation analyses and multivariate logistic regression models.Results Compared with non-diabetic controls, T2DM patients exhibited significant gut microbiota dysbiosis, characterized by a marked reduction in Bacteroides vulgatus abundance (~45%, P<0.01) and decreased circulating 4MC levels. Lower 4MC concentrations were significantly correlated with increased insulin resistance (HOMA-IR; r = −0.42, P<0.01) and reduced fibrous cap thickness (r = 0.38, P=0.02). Patients in the lowest tertile of circulating 4MC levels showed a significantly higher prevalence of vulnerable plaque features compared with those in the highest tertile (58% vs. 29%, P<0.01). In multivariate logistic regression analysis adjusting for age, sex, lipid profiles, glycemic control, and other conventional cardiovascular risk factors, low circulating 4MC levels were independently associated with plaque vulnerability (odds ratio [OR] = 2.31, 95% confidence interval [CI]: 1.32–4.05, P=0.003).Conclusions Gut microbiota dysbiosis and reduced levels of the microbial-derived metabolite 4MC are independently associated with insulin resistance and atherosclerotic plaque vulnerability in patients with T2DM. Bacteroides vulgatus–derived 4MC may serve as a clinically relevant biomarker for identifying high-risk individuals and improving cardiovascular risk stratification in diabetes.