Gut Microbial Dysbiosis in Type 2 Diabetes Patients with Concurrent Atherosclerosis

The association of the gut microbiome with T2DM has been conflicting due to the disease's inherent complexity-a challenge that is further exacerbated in T2DM-related atherosclerotic cardiovascular diseases (ASCVD). Even when individual microbial species are associated with T2DM or ASCVD, mechanisms remain elusive-highlighting a pressing need for gut microbiota profiling in T2DM-related ASCVD. This perspective review examines gut microbial dysbiosis in T2DM with atherosclerosis (T2DM-AS), focusing on population-specific profiles from southern China and microbial biomarkers to predict disease progression.

T2DM-AS patients exhibit reduced Firmicutes-to-Bacteriodota ratio, with reduced Clostridia, Oscillospirales, Ruminococcaceae, and Faecalibacterium. Dysbiosis includes increased pro-inflammatory Enterobacteriaceae, Enterococcaceae, and Streptococcaceae, with higher abundances of Escherichia-Shigella, Klebsiella, Streptococcus, and Alloprevotella. Beneficial butyrate-producing genera Faecalibacterium, Dialister, and Butyricicoccus are markedly depleted. Enterobacteriaceae/Escherichia-Shigella abundance strongly correlates with the Gensini score, serum zonulin (a gut permeability marker), cholesterol, triglyceride, and alanine aminotransferase. Mechanistically, the bacterial type III secretion system primarily drives a pathogenic cascade involving: (1) ferroptosis-mediated intestinal damage, (2) gut barrier disruption, (3) abnormal glycerophospholipid metabolism with phosphatidylcholine upregulation, and (4) macrophage activation and systemic inflammation that aggravates atherosclerosis. Pathogenic gut microbial signatures-enrichment of type III secretion system-harboring Enterobacteriaceae and depletion of butyrate-producing taxa-represent potential biomarkers for T2DM-AS progression. The type III secretion system-ferroptosis-lipid metabolism axis critically links gut dysbiosis to accelerated atherosclerosis, suggesting interventions targeting gut barrier integrity or lipid metabolism as therapeutic avenues. Population-specific profiling is essential for microbiome-based approaches to T2DM-AS management.