Emerging microbiome–mitochondria crosstalk in host defense and infectious diseases: mechanistic insights into NLRP3 inflammasome activation and mtDNA-mediated immunomodulation

Abstract

Recent studies highlight a complex interaction between the gut microbiome and host mitochondrial dynamics in the modulation of immune responses as well as susceptibility to infectious and inflammatory pathologies. Recent empirical studies elucidate that metabolites derived from microbiota, encompassing short-chain fatty acids, trimethylamine, and indole derivatives, orchestrate mitochondrial functionality and the production of reactive oxygen species, which subsequently affect NLRP3 inflammasome activation. Dysbiosis within the gut microbiota has been documented to aggravate mitochondrial stress in host intestinal epithelial cells and other tissue-resident cells, facilitate the release of mitochondrial DNA (mtDNA), and initiate inflammatory pathways across a spectrum of conditions, including colitis, neurodegeneration, cardiovascular disorders, and sepsis. In contrast, the application of probiotics, postbiotics, and phytochemicals may restore microbial equilibrium, bolster mitochondrial integrity through mitophagy and PINK1/Parkin pathways, and mitigate NLRP3 inflammasome-mediated pyroptosis. Furthermore, experimental findings suggest that mtDNA functions as a damage-associated molecular pattern, activating cGAS-STING and NLRP3 signaling pathways, thereby establishing a connection between alterations in microbiota and systemic inflammation. The microbiome–mitochondria axis has been further associated with organ-specific immune responses, encompassing interactions among the gut-lung, gut-brain, gut-kidney, and gut-liver systems. Notably, the liver serves as a primary intermediary hub, receiving gut-derived metabolites and inflammatory mediators through the portal circulation and thereby linking intestinal microbial signals to peripheral immune and metabolic responses. Collectively, these investigations emphasize the emerging mechanistic significance of microbiota-induced modulation of mitochondrial function in host defense mechanisms, thereby illuminating potential therapeutic approaches that focus on microbial composition, mitochondrial dynamics, and inflammasome signaling to alleviate infectious and inflammatory pathologies. This review integrates contemporary understandings of the interactions between microbiota, mitochondria, and NLRP3 inflammasome activation, thereby establishing a framework for prospective translational research.