Circulating Bacterial DNA as a Novel Blood-Based Biomarker in Type 2 Diabetes Mellitus (DM2): Results from the PROMOTERA Study

Blood bacterial DNA (BB-DNA) has been identified as a novel biomarker for metabolic dysfunction, yet its relationship with epigenetic features in type 2 diabetes mellitus (DM2) patients remains largely unexplored. This study investigated the relationship between BB-DNA and epigenetic, inflammatory, and aging-related markers in 285 elderly both with and without DM2. BB-DNA levels were higher in DM2 patients than in non-diabetic subjects, with the highest levels in those with severe renal impairment. BB-DNA showed a positive association with plasma IL-1β, linking bacterial DNA to systemic inflammation. Epigenetic analysis revealed a negative correlation between BB-DNA and DNA methylation-based leukocyte telomere length, suggesting accelerated aging in DM2. Additionally, BB-DNA was positively associated with DNAm-based biological age estimators, particularly DNAmPhenoAge and DNAmAge Skin Blood Clock. BB-DNA also correlated with DNAmVEGFA and DNAmCystatin C, key markers of diabetic nephropathy and vascular dysfunction. Furthermore, BB-DNA levels were associated with hypomethylation of genes involved in inflammation (e.g., IL1β, TNFα, IFNγ), cellular senescence (p16, p21, TP53), and metabolic regulation (e.g., IGF1, SREBF1, ABCG1, PDK4). These associations suggest that increased BB-DNA may reflect and potentially promote a pro-inflammatory and pro-senescent epigenetic profile in DM2. Importantly, many of these associations remained significant after adjusting for diabetes status, supporting BB-DNA as a robust biomarker across clinical subgroups. These findings provide new insights into the relationship between BB-DNA, inflammation, and epigenetic aging in DM2, highlighting BB-DNA as a potential biomarker for disease progression and complications, particularly in relation to renal dysfunction and systemic inflammation.