Molecular Dialogues in the Mitochondria–Microbiome Crosstalk: Metabolites, Signaling, and Immunity

The bidirectional dialogue between mitochondria and the human microbiota-the mitochondria-microbiome axis-plays a pivotal role in regulating host metabolism, immune signaling, and overall physiological homeostasis. Growing evidence underscores the role of microbial metabolites-including short-chain fatty acids, secondary bile acids, and lipopolysaccharides-as direct modulators of mitochondrial bioenergetics, redox balance, and inflammatory cascades. Conversely, mitochondrial integrity governs the microbial landscape by regulating local oxygen tension, modulating immune-mediated selection, and secreting metabolic byproducts that shape commensal populations. Disruptions to this bidirectional crosstalk are linked to a diverse pathological spectrum. These include metabolic syndromes like obesity, type 2 diabetes, and NAFLD; neurodegenerative disorders such as Parkinson's and Alzheimer's; and systemic inflammatory conditions, notably inflammatory bowel disease and various autoimmune pathologies. Therapeutic interventions designed to modulate this axis-ranging from targeted probiotics, dietary interventions, and mitochondrial boosters-offer significant potential for reinstating physiological homeostasis. This review explores the molecular foundations of mitochondria-microbiome crosstalk, its role in disease pathogenesis, and the potential for microbiome-targeted therapies to restore mitochondrial health. Unraveling this complex dialogue may open new avenues for treating diseases rooted in metabolic and microbial dysbiosis. On the basis of a wide-ranging literature survey, the frontiers of the molecular dialogues involved in the mitochondria-microbiome communications are evaluated. By analyzing publication trends, we identify nascent perspectives and transformative concepts, mapping the mitochondria-microbiome axis research, aiming to bridge the gap between basic science and translational applications. This synthesis offers a fresh lens for treating diseases rooted in this intricate biological interplay.