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Growing evidence underscores the role of microbial metabolites\u2014including short\u2010chain fatty acids, secondary bile acids, and lipopolysaccharides\u2014as direct modulators of mitochondrial bioenergetics, redox balance, and inflammatory cascades. Conversely, mitochondrial integrity governs the microbial landscape by regulating local oxygen tension, modulating immune\u2010mediated 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\u2014ranging from targeted probiotics, dietary interventions, and mitochondrial boosters\u2014offer significant potential for reinstating physiological homeostasis. This review explores the molecular foundations of mitochondria\u2013microbiome crosstalk, its role in disease pathogenesis, and the potential for microbiome\u2010targeted 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\u2010ranging literature survey, the frontiers of the molecular dialogues involved in the mitochondria\u2013microbiome communications are evaluated. By analyzing publication trends, we identify nascent perspectives and transformative concepts, mapping the mitochondria\u2013microbiome axis research, aiming to bridge the gap between basic science and translational applications. 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