{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T13:28:25Z","timestamp":1787232505421,"version":"build-2736575974"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T00:00:00Z","timestamp":1787184000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>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\u2014short-chain fatty acids, hydrogen sulfide, secondary bile acids\u2014directly 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 \u201cmicrobiota\u2013mitochondria\u2013barrier\u2013multiorgan\u201d axis should be seen as a well-grounded hypothesis, not an established fact.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1885379","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T13:00:15Z","timestamp":1787230815000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Gut microbiota\u2013mitochondria\u2013barrier\u2013multiorgan axis: a network-based hypothesis for systemic injury"],"prefix":"10.3389","volume":"17","author":[{"given":"Yachao","family":"Li","sequence":"first","affiliation":[{"name":"Sichuan Academy of Medical Sciences, University of Electronic Science and Technology of China, and Sichuan Provincial People\u2019s Hospital Operating Room","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaijue","family":"Qiu","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanling","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Surgery, Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qin","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Operating Room, Sichuan Academy of Medical Sciences & Sichuan Provincial People\u2019s Hospital, University of Electronic Science and Technology of China","place":["Chengdu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"45368","DOI":"10.1038\/s41598-025-28987-3","article-title":"Braden score for early mortality risk assessment in critically ill intensive care patients with multiple organ dysfunction syndrome","volume":"15","author":"Deng","year":"2025","journal-title":"Sci Rep"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.6026\/973206300212262","article-title":"Evaluation of MODS and survival outcome in infectious diseases using SOFA and SAPS scores","volume":"21","author":"Ghanghoria","year":"2025","journal-title":"Bioinformation"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccc.2015.11.004","article-title":"The gut as the motor of multiple organ dysfunction in critical illness","volume":"32","author":"Klingensmith","year":"2016","journal-title":"Crit Care Clin"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1007\/s15010-018-1178-5","article-title":"Gut-origin sepsis in the critically ill patient: pathophysiology and treatment","volume":"46","author":"Assimakopoulos","year":"2018","journal-title":"Infection"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2020.110770","article-title":"Intestinal barrier damage, systemic inflammatory response syndrome, and acute lung injury: a troublesome trio for acute pancreatitis","volume":"132","author":"Ge","year":"2020","journal-title":"BioMed Pharmacother"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-022724-100847","article-title":"Pharmaeecology: how the gut microbiome contributes to variations in drug response","volume":"65","author":"Trepka","year":"2025","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"595","DOI":"10.3390\/cells14080595","article-title":"Phenotyping the chemical communications of the intestinal microbiota and the host: secondary bile acids as postbiotics","volume":"14","author":"Urbani","year":"2025","journal-title":"Cells"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-024-00931-2","article-title":"Mitochondrial function and gastrointestinal diseases","volume":"21","author":"Haque","year":"2024","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1428242","article-title":"The interplay between mitochondria, the gut microbiome and metabolites and their therapeutic potential in primary mitochondrial disease","volume":"15","author":"Zachos","year":"2024","journal-title":"Front Pharmacol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"742","DOI":"10.1038\/s41598-018-36941-9","article-title":"Prominent action of butyrate over \u03b2-hydroxybutyrate as histone deacetylase inhibitor, transcriptional modulator and anti-inflammatory molecule","volume":"9","author":"Chriett","year":"2019","journal-title":"Sci Rep"},{"key":"B11","doi-asserted-by":"publisher","first-page":"559","DOI":"10.3390\/life14050559","article-title":"Short-chain fatty acids and human health: from metabolic pathways to current therapeutic implications","volume":"14","author":"Facchin","year":"2024","journal-title":"Life (Basel)"},{"key":"B12","doi-asserted-by":"publisher","first-page":"1480","DOI":"10.3390\/ph17111480","article-title":"Hydrogen sulfide and gut microbiota: their synergistic role in modulating sirtuin activity and potential therapeutic implications for neurodegenerative diseases","volume":"17","author":"Munteanu","year":"2024","journal-title":"Pharm (Basel)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"587","DOI":"10.3390\/antiox12030587","article-title":"GYY4137-derived hydrogen sulfide donates electrons to the mitochondrial electron transport chain via sulfide:quinone oxidoreductase in endothelial cells","volume":"12","author":"Star","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2024.107434","article-title":"The potential role of mitochondria in the microbiota-gut-brain axis: implications for brain health","volume":"209","author":"Qiao","year":"2024","journal-title":"Pharmacol Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-025-03072-w","article-title":"Microbiota, mitochondria, and epigenetics in health and disease: converging pathways to solve the puzzle","volume":"477","author":"Rukavina Mikusic","year":"2025","journal-title":"Pflugers Arch"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2025.177562","article-title":"The mitochondria-gut microbiota crosstalk - a novel frontier in cardiovascular diseases","volume":"998","author":"Kulkarni","year":"2025","journal-title":"Eur J Pharmacol"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1347","DOI":"10.1101\/2023.07.27.549844","article-title":"Mitochondrial perturbation in the intestine causes microbiota-dependent injury and gene signatures discriminative of inflammatory disease","volume":"32","author":"Urbauer","year":"2024","journal-title":"Cell Host Microbe"},{"key":"B18","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1186\/s40168-023-01686-9","article-title":"Interplay of gut microbiota and host epithelial mitochondrial dysfunction is necessary for the development of spontaneous intestinal inflammation in mice","volume":"11","author":"Alula","year":"2023","journal-title":"Microbiome"},{"key":"B19","doi-asserted-by":"publisher","first-page":"7770","DOI":"10.3390\/ijms25147770","article-title":"From molecular mechanisms to clinical therapy: understanding sepsis-induced multiple organ dysfunction","volume":"25","author":"Srdi\u0107","year":"2024","journal-title":"Int J Mol Sci"},{"key":"B20","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1152\/physrev.00029.2002","article-title":"The calpain system","volume":"83","author":"Goll","year":"2003","journal-title":"Physiol Rev"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1152\/ajpgi.00405.2015","article-title":"Cellular zinc is required for intestinal epithelial barrier maintenance via the regulation of claudin-3 and occludin expression","volume":"311","author":"Miyoshi","year":"2016","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpj.2014.11.029","article-title":"Mitochondrial DNA stress primes the antiviral innate immune response","volume":"520","author":"West","year":"2015","journal-title":"Nature"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/ni.1980","article-title":"Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome","volume":"12","author":"Nakahira","year":"2011","journal-title":"Nat Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.105","article-title":"Neutrophil extracellular traps in immunity and disease","volume":"18","author":"Papayannopoulos","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.1735","article-title":"Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation","volume":"11","author":"Lewis","year":"2015","journal-title":"Nat Chem Biol"},{"key":"B26","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.it.2017.03.001","article-title":"Macrophage immunometabolism: where are we (going)","volume":"38","author":"Van den Bossche","year":"2017","journal-title":"Trends Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1097\/01.ccm.0000057847.32590.c1","article-title":"Endothelial cell heterogeneity","volume":"2","author":"Aird","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1038\/nature08780","article-title":"Circulating mitochondrial DAMPs cause inflammatory responses to injury","volume":"464","author":"Zhang","year":"2010","journal-title":"Nature"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.14715\/cmb\/2024.70.2.25","article-title":"Mitochondria-targeted reactive oxygen species blocker SS-31 blocks hepatic stellate cell activation and alleviates hepatic fibrosis by regulating NLRP3 inflammasomes","volume":"70","author":"Liu","year":"2024","journal-title":"Cell Mol Biol (Noisy-le-grand)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.7150\/thno.29620","article-title":"p66Shc contributes to liver fibrosis through the regulation of mitochondrial reactive oxygen species","volume":"9","author":"Zhao","year":"2019","journal-title":"Theranostics"},{"key":"B31","doi-asserted-by":"publisher","first-page":"e136496","DOI":"10.1172\/jci.insight.136496","article-title":"Chronic-plus-binge alcohol intake induces production of proinflammatory mtDNA-enriched extracellular vesicles and steatohepatitis via ASK1\/p38MAPK\u03b1-dependent mechanisms","volume":"5","author":"Ma","year":"2020","journal-title":"JCI Insight"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v22.i31.6965","article-title":"Mitochondrial DNA from hepatocytes as a ligand for TLR9: drivers of nonalcoholic steatohepatitis","volume":"22","author":"Handa","year":"2016","journal-title":"World J Gastroenterol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2022.09.017","article-title":"Gut-liver axis: pathophysiological concepts and clinical implications","volume":"34","author":"Tilg","year":"2022","journal-title":"Cell Metab"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2025.02.007","article-title":"The microbial metabolite \u03b4-valerobetaine strengthens the gut epithelial barrier","volume":"195","author":"Askew","year":"2025","journal-title":"Am J Pathol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1186\/s13613-024-01377-0","article-title":"Organ crosstalk and dysfunction in sepsis","volume":"14","author":"Borges","year":"2024","journal-title":"Ann Intensive Care"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1097\/ta.0000000000002169","article-title":"Inhibition of histone deacetylase 6 attenuates intestinal inflammation and apoptosis in a rodent model of hemorrhagic shock","volume":"86","author":"Chang","year":"2019","journal-title":"J Trauma Acute Care Surg"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1155\/2020\/3276148","article-title":"MitoQ modulates lipopolysaccharide-induced intestinal barrier dysfunction via regulating Nrf2 signaling","volume":"2020","author":"Zhang","year":"2020","journal-title":"Mediators Inflammation"},{"key":"B38","doi-asserted-by":"publisher","first-page":"403","DOI":"10.1038\/s41419-018-0436-x","article-title":"The mitochondrially targeted antioxidant MitoQ protects the intestinal barrier by ameliorating mitochondrial DNA damage via the Nrf2\/ARE signaling pathway","volume":"9","author":"Hu","year":"2018","journal-title":"Cell Death Dis"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/jcsm.70041","article-title":"Sepsis induces long-term muscle and mitochondrial dysfunction due to autophagy disruption amenable by urolithin A","volume":"16","author":"Pierre","year":"2025","journal-title":"J Cachexia Sarcopenia Muscle"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.mito.2025.102047","article-title":"Urolithin-A supplementation alleviates sepsis-induced acute lung injury by reducing mitochondrial dysfunction and modulating macrophage polarization","volume":"84","author":"Mohsin","year":"2025","journal-title":"Mitochondrion"},{"key":"B41","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s40662-023-00362-1","article-title":"Homocysteine and mitochondrial quality control in diabetic retinopathy","volume":"11","author":"Malaviya","year":"2024","journal-title":"Eye Vis (Lond)"},{"key":"B42","doi-asserted-by":"publisher","first-page":"55","DOI":"10.3349\/ymj.2023.0131","article-title":"Beneficial effects of low-grade mitochondrial stress on metabolic diseases and aging","volume":"65","author":"Min","year":"2024","journal-title":"Yonsei Med J"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.5492\/wjccm.v10.i6.355","article-title":"Sequential organ failure assessment score is superior to other prognostic indices in acute pancreatitis","volume":"10","author":"Teng","year":"2021","journal-title":"World J Crit Care Med"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1885379\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T13:00:16Z","timestamp":1787230816000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1885379\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,20]]},"references-count":43,"alternative-id":["10.3389\/fimmu.2026.1885379"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1885379","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,20]]},"article-number":"1885379"}}