The Mitochondria-Microbiome Crosstalk: A Bidirectional Dialogue in Health and Disease

The intricate bidirectional communication between mitochondria and the gut microbiota – termed mitochondria-microbiome crosstalk – plays a pivotal role in regulating host metabolism, immune responses, and overall physiological homeostasis. Emerging evidence highlights how microbial-derived metabolites, such as short-chain fatty acids, secondary bile acids, and lipopolysaccharides, directly modulate mitochondrial function by influencing energy production (ATP synthesis), oxidative stress (ROS balance), and inflammatory signaling (e.g., NLRP3 inflammasome activation). Conversely, mitochondrial health shapes the gut microbial ecosystem through oxygen tension regulation, immune-mediated selection of commensal bacteria, and metabolic byproduct secretion (e.g., succinate, lactate). Dysregulation of this crosstalk is implicated in a spectrum of diseases, including metabolic disorders (obesity, type 2 diabetes, NAFLD), neurodegenerative conditions (Parkinson’s and Alzheimer’s diseases), and chronic inflammatory states (inflammatory bowel disease, autoimmune diseases). Therapeutic strategies targeting this axis – such as probiotics, dietary interventions (high-fiber/ketogenic diets), and mitochondrial boosters (NAD+ precursors, antioxidants) – hold promise for restoring homeostasis. This review synthesizes current knowledge on the molecular mechanisms underlying mitochondria-microbiome interactions, their pathophysiological consequences, and potential clinical applications, while addressing challenges in translating preclinical findings to personalized medicine. Unraveling this complex dialogue may open new avenues for treating diseases rooted in metabolic and microbial dysbiosis.