Aug 2026· Frontiers in Immunology· Vol 17· 0 citations· 43 references
TL;DR
It is discussed how circulating metabolites and mtDNA could serve as candidate monitoring biomarkers to turn this conceptual network into a testable, quantitative model and a multi-dimensional research framework while stressing that any clinical application must await prospective validation.
Abstract
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.
Aging is a progressive degenerative process of cellular and systemic homeostasis in organisms, with mitochondrial dysfunction and altered intercellular communication as core hallmarks of this process. During aging, the gut microbiome and mitochondria exhibit a highly synchronized degenerative trajectory: this is characterized by decreased microbial diversity, reduced abundance of beneficial short-chain fatty acid (SCFA)-producing bacteria, and expansion of pro-inflammatory pathobionts in the gut, alongside impaired oxidative phosphorylation efficiency, excessive reactive oxygen species (ROS) production, and compromised quality control in mitochondria. Built on the evolutionary cornerstone of endosymbiotic theory, this review establishes a theoretical framework for the Microbiome-Mitochondria Axis (MMA) and proposes that the ancient molecular homology between mitochondria and modern gut bacteria has preserved a sensitive cross-species signal crosstalk mechanism. This review systematically dissects the bidirectional communication mechanisms of the MMA. First, microbial metabolites—including SCFAs, tryptophan-derived indole metabolites, and secondary bile acids—regulate mitochondrial energy metabolism, oxidative stress responses, and dynamic homeostasis via key signaling pathways such as AMPK-PGC-1α, AhR-Nrf2, and FXR/TGR5. Conversely, dysfunctional mitochondria actively reshape the gut microenvironment and propagate sterile inflammation through multiple pathways: mitochondrial ROS (mtROS)-mediated intestinal barrier disruption, metabolic reprogramming of immune cells toward a pro-inflammatory phenotype, and activation of the cGAS-STING innate immune pathway triggered by mitochondrial DNA (mtDNA) release. Here, we propose a unified theoretical framework centered on the MMA as a self-reinforcing pathological loop. In this model, gut dysbiosis drives depletion of beneficial microbial metabolites, which triggers mitochondrial quality control failure, mtDNA leakage, and inflammaging; in turn, inflammaging exacerbates gut dysbiosis by remodeling the intestinal microenvironment, thus forming a closed, self-amplifying vicious cycle. The MMA links multiple hallmarks of aging, including epigenetic alterations, immunosenescence, and stem cell exhaustion, providing a unifying pathological basis for age-related disorders such as neurodegenerative diseases, cardiovascular diseases, sarcopenia, and osteoarthritis. It also offers a systematic entry point for anti-aging interventions targeting the bidirectional metabolic-immune crosstalk between the microbiome and mitochondria.
Enshuo Liu, Jianbo Jia, Qi Liu et al.· Frontiers in Microbiology· 0 citations
This review elucidates the core mechanisms underpinning this dysfunction, including reactive oxygen species (ROS)-induced redox imbalance, mitochondrial DNA (mtDNA) damage accumulation, impaired mitophagy, and metabolic reprogramming, and critically examines how mitochondria act as signaling hubs for inter-organ crosstalk.
C. Han, Zilian Zhang, Yafeng Song· Gerontology· 0 citations
Metabolic dysfunction-associated steatotic liver disease (MASLD) is closely related to liver mitochondrial dysfunction, which is driven not as an isolated event but by a self-amplifying injury loop involving impaired intrinsic quality control, aberrant organelle crosstalk, and dysregulated gut-liver signaling. This review summarizes findings in three interconnected regulatory layers: (1) intrinsic mitochondrial quality control (MQC) (PINK1/Parkin- and BNIP3/NIX-mediated mitophagy, Drp1/Mfn-driven dynamics, and chaperone/protease-maintained proteostasis); (2) organelle interactions (ER-mitochondria contacts, lipid droplet tethering, and lysosome crosstalk); and (3) extrinsic modulation via the gut-derived metabolites. We highlight that dysregulated mitophagy and mitochondrial fragmentation promote lipid accumulation and inflammation, whereas the abnormal formation of mitochondria-associated membranes (MAMs) exacerbates calcium overload and oxidative stress. Furthermore, short-chain fatty acids and bile acids derived from the gut differentially modulate mitochondrial bioenergetics. Preclinical evidence indicates that restoring MQC or targeting organelle interactions can improve MASLD symptoms. Given the multifactorial nature of MASLD, single-target interventions are insufficient; multi-target strategies and tissue-specific delivery are essential for clinical translation.
Jingwen Liu, Kewei Li, Yinggui Deng et al.· Pharmacological Research· 0 citations
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.
Xinxing Lu, Wenbin Sun, Daowei Zhang et al.· Frontiers in Cellular and In...· 0 citations
: The gut microbiota, oxidative stress, and extracellular vesicles (EVs) form an interdependent triad essential for gastrointestinal homeostasis and systemic health. This narrative review summarizes the molecular crosstalk among these components in inflammation and disease. Literature was retrieved from PubMed and Scopus using relevant keywords and reference screening. Gut microbes regulate redox balance through metabolites such as short-chain fatty acids and modulation of host reactive oxygen species (ROS) production via mitochondrial pathways and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Dysbiosis has been associated with excessive ROS generation, impaired antioxidant defenses, and activation of redox-sensitive signaling pathways, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κ B), NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, and mitogen-activated protein kinase (MAPK), contributing to inflammatory and metabolic diseases. EVs act as mediators of host-microbe communication by transferring bioactive cargo that may influence oxidative stress, immune responses, and epithelial integrity. Host-derived EVs, shaped by redox status, may further contribute to systemic inflammation associated with chronic diseases. Therapeutic strategies include microbiota modulation, antioxidants, nuclear factor erythroid 2-related factor 2 (Nrf2) activators, NADPH oxidase inhibitors, and EV-based interventions. Integrated multi-omics and standardized EV profiling are needed for precision medicine approaches.
Hassan Ali, T. Velikova, P. Marinova· Biocell (Mendoza)· 0 citations
Chronic kidney disease (CKD) is increasingly recognised as a systemic disorder driven by interconnected disturbances in gut microbial balance, metabolic regulation and renal cellular stress responses rather than by isolated renal dysfunction alone. Current therapies mainly slow disease progression but do not fully address the molecular networks responsible for renal inflammation, fibrosis and cardiovascular complications. This review summarises evidence showing that CKD is associated with gut dysbiosis marked by depletion of short-chain fatty acids (SCFAs) producing bacteria and enrichment of proteolytic, uremic toxin-generating microbial populations. These alterations increase the production and systemic accumulation of gut-derived metabolites such as indoxyl sulphate (IS), p-cresyl sulphate (pCS) and trimethylamine-N-oxide (TMAO) while reducing protective metabolites such as SCFAs and secondary bile acids. Accumulated uremic toxins contribute to oxidative stress, endothelial dysfunction, nuclear factor kappa B (NF-κB) and NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation, mitochondrial injury and renal fibrotic remodelling. Autophagy is discussed as a central regulatory mechanism connecting microbial metabolites with renal cell injury. Dysregulation of AMPK-mTOR signalling, ULK1-Beclin-1 complex activity and PINK1-Parkin-dependent mitophagy impairs mitochondrial quality control, promotes redox imbalance and supports progressive tubular damage, podocyte injury and interstitial fibrosis. Metabolomics further provides a systems-level approach for identifying CKD associated metabolic signatures including amino acid imbalance, lipid dysregulation, mitochondrial energy defects and accumulation of gut-derived uremic solutes. By integrating these findings, this review proposes the microbiota-autophagy-metabolomics triad as a useful framework for understanding CKD progression. This model highlights how gut dysbiosis alters systemic metabolite profiles, how these metabolites regulate renal autophagic activity, and how impaired autophagy further promotes metabolic and inflammatory reprogramming. Targeting gut microbiota, microbial metabolites and autophagy-related pathways may therefore facilitate future biomarker development and precision-based therapeutic strategies for CKD management.
Khemender Lidoo, Rupinder Kaur, Ravinder Singh et al.· International Immunopharmaco...· 0 citations