Gut microbiota–mitochondria–barrier–multiorgan axis: a network-based hypothesis for systemic injury

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Intestinal barrier failure is considered a driver of multiple organ dysfunction syndrome (MODS) in critical illness; however, the precise molecular mechanisms linking altered gut microbes to systemic injury remain unclear. Here we propose a testable hypothesis: mitochondrial dysfunction within intestinal epithelial cells (IECs) acts as a mechanistic hub connecting microbial dysbiosis to barrier breakdown and eventual multiorgan damage. This system is not a unidirectional chain but a highly network-based process with bidirectional feedback loops, context-dependent interactions, and hypothetical cross-talk that require experimental validation. We review evidence that microbial metabolites-short-chain fatty acids, hydrogen sulfide, secondary bile acids-directly modulate mitochondrial respiration, membrane potential, and reactive oxygen species (ROS) production in the gut lining. Once mitochondrial quality control falters, the cell suffers adenosine triphosphate (ATP) depletion, excessive ROS, calcium-driven calpain activation, and leakage of mitochondrial damage-associated molecular patterns (mtDAMPs) like mitochondrial DNA (mtDNA) into the cytoplasm. These mtDAMPs ignite the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway and the NLR family pyrin domain containing 3 (NLRP3) inflammasome, disrupting tight junctions and converting the intestinal barrier into an active inflammatory broadcaster. Critically, the inflammatory response is amplified by immune intermediary layers, including neutrophil extracellular trap (NET) formation, monocyte/macrophage metabolic reprogramming, endothelial activation, and complement activation, which bridge local barrier disruption to systemic organ injury. When mtDAMPs reach the circulation, they trigger sterile inflammation in distant organs through shared innate immune sensors (Toll-like receptor 9 [TLR9] and NLRP3) in liver, lung, and brain. A word of caution: circulating mtDNA originates from multiple tissues (e.g., immune cells, skeletal muscle, liver) and therefore represents a systemic DAMP, not a gut-specific signal; its interpretation requires contextual information on tissue origin and temporal dynamics. Human evidence still lacks clear answers on temporal order, directionality, epigenetic mediation, and quantitative thresholds. We discuss how circulating metabolites and mtDNA could serve as candidate monitoring biomarkers to turn this conceptual network into a testable, quantitative model. Finally, we outline a multi-dimensional research framework (metabolite replenishment, mitophagy enhancement, epigenetic tuning) while stressing that any clinical application must await prospective validation. For now, the "microbiota-mitochondria-barrier-multiorgan" axis should be seen as a well-grounded hypothesis, not an established fact.

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