Circulating microbiome and its clinical implications in diabetes mellitus: Mechanistic insights and therapeutic perspectives

Abstract

The circulating microbiome, comprised of microbial DNA, metabolites, and cell-derived fragments, has emerged as a potential contributor to the pathophysiology of diabetes mellitus. This review summarizes current evidence on how microbial translocation and blood-borne microbial components influence metabolic and immune dysfunction in type 1 and type 2 diabetes. Quantitative studies report elevated circulating lipopolysaccharide levels (often > 2-fold higher in diabetic cohorts), increased trimethylamine-N-oxide, and reduced short-chain fatty acids, all of which correlate with systemic inflammation, insulin resistance, and glycemic variability. Mechanistic data indicate that microbial products activate Toll-like receptors (TLRs), particularly TLR4 and TLR2, amplifying cytokine release and impairing β-cell function. Distinct microbial DNA signatures identified through metagenomics further link the circulating microbiome to complications, such as nephropathy, cardiovascular dysfunction, and impaired wound healing. Emerging therapeutic approaches, including microbiome-directed diets, prebiotics, probiotics, and strategies that reduce microbial translocation, show promise in modulating these systemic effects. Despite rapid advances, major gaps remain in establishing causality, standardizing detection methods, and defining clinically actionable microbial biomarkers. Addressing these challenges will be essential for translating circulating microbiome research into diagnostic tools and personalized interventions for diabetes management.

Keywords: Diabetes mellitus; Circulating microbiome; Blood microbiome; Microbial components; Toll-like receptors; Trimethylamine N-oxide; Short chain fatty acids

Core Tip: The circulating microbiome, encompassing microbial DNA, products, and microbial components detected in blood, links gut barrier dysfunction to chronic, low-grade inflammation in diabetes. Quantifying blood microbial signatures (16S rDNA/cell free DNA, endotoxin activity, metabolites) may enable early risk stratification for insulin resistance and prediction of micro- and macrovascular complications. Integrating longitudinal cell-free microbiome profiling with glycemic and inflammatory indices could refine diagnosis, personalize therapy, and monitor responses to interventions (dietary fiber, pre/probiotics, postbiotics, barrier-restoring strategies, and microbiome-informed pharmacotherapy, such as metformin). Standardized sampling, contamination control, and causal studies are critical to translate these insights into routine diabetes care.