The gut-brain-mitochondria axis in type 2 diabetes-associated cognitive decline: mechanistic convergence, biomarkers, and therapeutic opportunities.

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a major risk factor for cognitive impairment and dementia, extending beyond its traditional metabolic complications. Emerging evidence suggests that cognitive decline in T2DM arises from a complex interplay among gut dysbiosis, chronic inflammation, impaired insulin signaling, blood-brain barrier dysfunction, and mitochondrial abnormalities. The gut-brain-mitochondria (GBM) axis has recently emerged as an integrated mechanistic framework linking peripheral metabolic disturbances to central neurodegenerative processes. Within this axis, alterations in gut microbial composition and function promote intestinal barrier disruption, endotoxemia, and aberrant production of microbial metabolites, which collectively contribute to systemic inflammation, neuroinflammation, and neuronal insulin resistance. Mitochondria occupy a central position in this network by regulating cellular bioenergetics, redox homeostasis, calcium signaling, and neuronal survival. Mitochondrial dysfunction amplifies oxidative stress, impairs synaptic plasticity, disrupts adult hippocampal neurogenesis, and accelerates neurodegenerative signaling pathways associated with cognitive decline. Furthermore, bidirectional communication between gut-derived metabolites and mitochondrial pathways influences neuronal resilience and disease progression. This review synthesizes current evidence describing the mechanistic convergence of gut dysbiosis, mitochondrial dysfunction, and neuroinflammation in T2DM-associated cognitive impairment. We also discuss emerging biomarkers, including mitochondrial DNA copy number, circulating lactate, lipopolysaccharide, zonulin, and microbial metabolite signatures, that may facilitate early disease detection and patient stratification. Finally, we critically evaluate therapeutic strategies targeting the GBM axis, including microbiota-directed interventions, mitochondrial-targeted antioxidants, metabolic modulators, and lifestyle-based approaches. Understanding the integrated role of the GBM axis may provide novel opportunities for precision-based interventions to prevent or slow diabetes-associated cognitive decline.