{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T17:12:36Z","timestamp":1793293956037,"version":"4.5.0"},"reference-count":102,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T00:00:00Z","timestamp":1779926400000},"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. Med."],"abstract":"<jats:p>Sepsis-associated gastrointestinal dysfunction (SAGD) is a frequent complication in critically ill patients, marked by impaired motility, feeding intolerance, and disruption of the intestinal barrier, and is linked to poor clinical outcomes. Growing evidence indicates that SAGD arises from the interaction between systemic inflammation and neuroimmune dysregulation. Pro-inflammatory cytokines such as tumor necrosis factor, interleukin-1\u03b2, and interleukin-6 promote epithelial injury, disturb tight junction integrity, and impair neuromuscular function, while microcirculatory disturbances further aggravate tissue hypoxia and barrier breakdown. At the same time, alterations in the gut\u2013brain axis and autonomic imbalance compromise gastrointestinal motility and disrupt the cholinergic anti-inflammatory pathway, suggesting that SAGD represents a coordinated inflammatory\u2013barrier\u2013neuroimmune disorder. Current management remains mainly supportive and does not target these underlying processes. As a central element of the gut\u2013brain axis, the vagus nerve plays a key role in regulating both immune responses and gastrointestinal function. Neuromodulation approaches aimed at vagal pathways\u2014especially transcutaneous auricular vagus nerve stimulation (taVNS)\u2014have therefore attracted attention as non-invasive strategies to influence inflammation and autonomic balance. Although direct clinical evidence in SAGD is still limited, the biological rationale supports further exploration.<\/jats:p>","DOI":"10.3389\/fmed.2026.1841517","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:16:25Z","timestamp":1779948985000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Sepsis-associated gastrointestinal dysfunction: neuroimmune mechanisms, gut\u2013brain axis disruption, and therapeutic potential of vagus nerve\u2013targeted neuromodulation"],"prefix":"10.3389","volume":"13","author":[{"given":"Zhiyang","family":"Wu","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian","place":["Liaoning, China"]},{"name":"Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Qilu Hospital (Qingdao), Cheeloo College of Medicine, Shandong University, Qingdao","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, The Second Affiliated Hospital of Dalian Medical University, Dalian","place":["Liaoning, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The third international consensus definitions for sepsis and septic shock (Sepsis-3).","volume":"315","author":"Singer","year":"2016","journal-title":"JAMA."},{"key":"B2","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990\u20132017: analysis for the Global Burden of Disease Study.","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e1063","DOI":"10.1097\/CCM.0000000000005337","article-title":"Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021.","volume":"49","author":"Evans","year":"2021","journal-title":"Crit Care Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1007\/s00134-011-2459-y","article-title":"Gastrointestinal function in intensive care patients: terminology, definitions and management. Recommendations of the ESICM Working Group on Abdominal Problems.","volume":"38","author":"Reintam Blaser","year":"2012","journal-title":"Intens Care Med."},{"key":"B5","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1097\/CCM.0000000000004712","article-title":"Incidence, risk factors, and clinical consequence of enteral feeding intolerance in the mechanically ventilated critically Ill: an analysis of a multicenter, multiyear database.","volume":"49","author":"Heyland","year":"2021","journal-title":"Crit Care Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s40560-023-00674-3","article-title":"Different definitions of feeding intolerance and their associations with outcomes of critically ill adults receiving enteral nutrition: a systematic review and meta-analysis.","volume":"11","author":"Li","year":"2023","journal-title":"J Intens Care."},{"key":"B7","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1177\/0148607115621863","article-title":"Guidelines for the provision and assessment of nutrition support therapy in the adult critically Ill patient: society of Critical Care Medicine (SCCM) and American Society for Parenteral and Enteral Nutrition (A.S.P.E.N.).","volume":"40","author":"McClave","year":"2016","journal-title":"JPEN J Parenter Enteral Nutr."},{"key":"B8","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.clnu.2018.08.037","article-title":"ESPEN guideline on clinical nutrition in the intensive care unit.","volume":"38","author":"Singer","year":"2019","journal-title":"Clin Nutr."},{"key":"B9","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1042\/CS20220777","article-title":"The leaky gut and the gut microbiome in sepsis - targets in research and treatment.","volume":"137","author":"Chancharoenthana","year":"2023","journal-title":"Clin Sci."},{"key":"B10","doi-asserted-by":"publisher","first-page":"tkab036","DOI":"10.1093\/burnst\/tkab036","article-title":"Crosstalk between gut microbiota and sepsis.","volume":"9","author":"Niu","year":"2021","journal-title":"Burns Trauma."},{"key":"B11","doi-asserted-by":"publisher","first-page":"555","DOI":"10.1038\/s41385-020-00368-1","article-title":"The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes.","volume":"14","author":"Jacobson","year":"2021","journal-title":"Mucosal Immunol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"604179","DOI":"10.3389\/fimmu.2020.604179","article-title":"The gut-brain axis: how microbiota and host inflammasome influence brain physiology and pathology.","volume":"11","author":"Rutsch","year":"2020","journal-title":"Front Immunol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"e0203487","DOI":"10.1371\/journal.pone.0203487","article-title":"Heart rate variability as predictor of mortality in sepsis: a systematic review.","volume":"13","author":"de Castilho","year":"2018","journal-title":"PLoS One."},{"key":"B14","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1038\/nature01321","article-title":"The inflammatory reflex.","volume":"420","author":"Tracey","year":"2002","journal-title":"Nature."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1214","DOI":"10.1136\/gutjnl-2012-302550","article-title":"The vagal innervation of the gut and immune homeostasis.","volume":"62","author":"Matteoli","year":"2013","journal-title":"Gut."},{"key":"B16","doi-asserted-by":"publisher","first-page":"458","DOI":"10.1038\/35013070","article-title":"Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.","volume":"405","author":"Borovikova","year":"2000","journal-title":"Nature."},{"key":"B17","doi-asserted-by":"publisher","first-page":"3627","DOI":"10.1016\/j.neuron.2022.09.003","article-title":"Bioelectronic medicine: preclinical insights and clinical advances.","volume":"110","author":"Pavlov","year":"2022","journal-title":"Neuron."},{"key":"B18","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1007\/s12264-020-00619-y","article-title":"Transcutaneous auricular vagus nerve stimulation: from concept to application.","volume":"37","author":"Wang","year":"2021","journal-title":"Neurosci Bull."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1126","DOI":"10.1016\/j.brs.2021.06.006","article-title":"Transcutaneous auricular vagus nerve stimulation influences gastric motility: a randomized, double-blind trial in healthy individuals.","volume":"14","author":"Steidel","year":"2021","journal-title":"Brain Stimul."},{"key":"B20","doi-asserted-by":"publisher","first-page":"1620965","DOI":"10.3389\/fimmu.2025.1620965","article-title":"Intestinal injury signaling pathway in sepsis.","volume":"16","author":"Liu","year":"2025","journal-title":"Front Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41385-021-00443-1","article-title":"Enteric neuroimmune interactions coordinate intestinal responses in health and disease.","volume":"15","author":"Wang","year":"2022","journal-title":"Mucosal Immunol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s13613-021-00869-7","article-title":"The autonomic nervous system in septic shock and its role as a future therapeutic target: a narrative review.","volume":"11","author":"Carrara","year":"2021","journal-title":"Ann Intensive Care."},{"key":"B23","doi-asserted-by":"publisher","first-page":"767456","DOI":"10.3389\/fimmu.2021.767456","article-title":"IL-1beta and the intestinal epithelial tight junction barrier.","volume":"12","author":"Kaminsky","year":"2021","journal-title":"Front Immunol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"G367","DOI":"10.1152\/ajpgi.00173.2003","article-title":"TNF-alpha-induced increase in intestinal epithelial tight junction permeability requires NF-kappa B activation.","volume":"286","author":"Ma","year":"2004","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"key":"B25","doi-asserted-by":"publisher","first-page":"31263","DOI":"10.1074\/jbc.M111.238147","article-title":"Interleukin-6 (IL-6) regulates claudin-2 expression and tight junction permeability in intestinal epithelium.","volume":"286","author":"Suzuki","year":"2011","journal-title":"J Biol Chem."},{"key":"B26","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1016\/S0002-9440(10)62264-x","article-title":"Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression.","volume":"166","author":"Wang","year":"2005","journal-title":"Am J Pathol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"e85345","DOI":"10.1371\/journal.pone.0085345","article-title":"Interleukin-6 modulation of intestinal epithelial tight junction permeability is mediated by JNK pathway activation of claudin-2 gene.","volume":"9","author":"Al-Sadi","year":"2014","journal-title":"PLoS One."},{"key":"B28","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/s10020-022-00597-z","article-title":"PLK1 protects intestinal barrier function during sepsis by targeting mitochondrial dynamics through TANK-NF-\u03baB signalling.","volume":"28","author":"Cao","year":"2022","journal-title":"Mol Med."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1831","DOI":"10.1007\/s12031-022-02044-4","article-title":"Effect of reactive EGCs on intestinal motility and enteric neurons during endotoxemia.","volume":"72","author":"Li","year":"2022","journal-title":"J Mol Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"137395","DOI":"10.1016\/j.neulet.2023.137395","article-title":"Mini-review: enteric glial cell reactions to inflammation and potential therapeutic implications for GI diseases, motility disorders, and abdominal pain.","volume":"812","author":"Linan-Rico","year":"2023","journal-title":"Neurosci Lett."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1475729","DOI":"10.1155\/2019\/1475729","article-title":"Targeting IL-17A improves the dysmotility of the small intestine and alleviates the injury of the interstitial cells of cajal during sepsis.","volume":"2019","author":"Li","year":"2019","journal-title":"Oxid Med Cell Longev."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1540\/jsmr.59.1","article-title":"Interstitial cells of Cajal in gastrointestinal inflammatory diseases.","volume":"59","author":"Kaji","year":"2023","journal-title":"J Smooth Muscle Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"384","DOI":"10.1038\/nature01339","article-title":"Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.","volume":"421","author":"Wang","year":"2003","journal-title":"Nature."},{"key":"B34","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12974-023-03001-7","article-title":"Cholinergic signaling via the \u03b17 nicotinic acetylcholine receptor regulates the migration of monocyte-derived macrophages during acute inflammation.","volume":"21","author":"Keever","year":"2024","journal-title":"J Neuroinflamm."},{"key":"B35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s12276-018-0126-x","article-title":"Mechanisms regulating intestinal barrier integrity and its pathological implications.","volume":"50","author":"Chelakkot","year":"2018","journal-title":"Exp Mol Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"891","DOI":"10.3389\/fimmu.2019.00891","article-title":"Challenge to the intestinal mucosa during sepsis.","volume":"10","author":"Haussner","year":"2019","journal-title":"Front Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2574","DOI":"10.1016\/j.bbadis.2017.03.005","article-title":"The intestinal microenvironment in sepsis.","volume":"1863","author":"Fay","year":"2017","journal-title":"Biochim Biophys Acta (BBA) - Mol Basis Dis."},{"key":"B38","doi-asserted-by":"publisher","first-page":"2844","DOI":"10.1242\/jcs.065581","article-title":"Occludin is required for cytokine-induced regulation of tight junction barriers.","volume":"123","author":"Van Itallie","year":"2010","journal-title":"J Cell Sci."},{"key":"B39","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1093\/ibd\/izae232","article-title":"Intestinal epithelial tight junction barrier regulation by novel pathways.","volume":"31","author":"Arumugam","year":"2025","journal-title":"Inflamm Bowel Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"155","DOI":"10.2119\/molmed.2016.00256","article-title":"Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.","volume":"23","author":"Lorentz","year":"2017","journal-title":"Mol Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"C1378","DOI":"10.1152\/ajpcell.1997.273.4.C1378","article-title":"Physiological regulation of epithelial tight junctions is associated with myosin light-chain phosphorylation.","volume":"273","author":"Turner","year":"1997","journal-title":"Am J Physiol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1242\/jcs.02915","article-title":"Myosin light chain phosphorylation regulates barrier function by remodeling tight junction structure.","volume":"119","author":"Shen","year":"2006","journal-title":"J Cell Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"111","DOI":"10.1083\/jcb.200902153","article-title":"Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo.","volume":"189","author":"Marchiando","year":"2010","journal-title":"J Cell Biol."},{"key":"B44","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1038\/s41385-022-00514-x","article-title":"Intestinal epithelial cell metabolism at the interface of microbial dysbiosis and tissue injury.","volume":"15","author":"Rath","year":"2022","journal-title":"Mucosal Immunol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"343","DOI":"10.5847\/wjem.j.1920-8642.2022.031","article-title":"Intestinal microcirculation dysfunction in sepsis: pathophysiology, clinical monitoring, and therapeutic interventions.","volume":"13","author":"Tang","year":"2022","journal-title":"World J Emerg Med."},{"key":"B46","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1177\/1751143716678638","article-title":"The microcirculation and its measurement in sepsis.","volume":"18","author":"Charlton","year":"2017","journal-title":"J Intens Care Soc."},{"key":"B47","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1089\/ars.2021.0027","article-title":"Oxidative stress and endothelial dysfunction in sepsis and acute inflammation.","volume":"35","author":"Joffre","year":"2021","journal-title":"Antioxid Redox Signal."},{"key":"B48","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1007\/s11033-025-10894-5","article-title":"Mitochondrial function in intestinal ischemia-reperfusion injury: mechanisms and therapeutic perspectives.","volume":"52","author":"Han","year":"2025","journal-title":"Mol Biol Rep."},{"key":"B49","doi-asserted-by":"publisher","first-page":"97","DOI":"10.1186\/s13054-024-04875-6","article-title":"Vascular leak in sepsis: physiological basis and potential therapeutic advances.","volume":"28","author":"McMullan","year":"2024","journal-title":"Crit Care."},{"key":"B50","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1111\/j.1553-2712.2008.00109.x","article-title":"Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials.","volume":"15","author":"Trzeciak","year":"2008","journal-title":"Acad Emerg Med."},{"key":"B51","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.jcrc.2019.05.002","article-title":"Influence of systemic hemodynamics on microcirculation during sepsis.","volume":"52","author":"Collet","year":"2019","journal-title":"J Crit Care."},{"key":"B52","doi-asserted-by":"publisher","first-page":"17562848221094214","DOI":"10.1177\/17562848221094214","article-title":"The role of bacterial translocation in sepsis: a new target for therapy.","volume":"15","author":"Potruch","year":"2022","journal-title":"Ther Adv Gastroenterol."},{"key":"B53","doi-asserted-by":"publisher","first-page":"1452","DOI":"10.3389\/fimmu.2017.01452","article-title":"The vagus nerve in the neuro-immune axis: implications in the pathology of the gastrointestinal tract.","volume":"8","author":"Bonaz","year":"2017","journal-title":"Front Immunol."},{"key":"B54","doi-asserted-by":"publisher","first-page":"e0053322","DOI":"10.1128\/msystems.00533-22","article-title":"The microbiota-gut-brain axis in sepsis-associated encephalopathy.","volume":"7","author":"Gareau","year":"2022","journal-title":"MSystems."},{"key":"B55","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/s41575-019-0157-3","article-title":"The role of short-chain fatty acids in microbiota-gut-brain communication.","volume":"16","author":"Dalile","year":"2019","journal-title":"Nat Rev Gastroenterol Hepatol."},{"key":"B56","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/S2468-1253(16)30119-4","article-title":"The role of the gut microbiota in sepsis.","volume":"2","author":"Haak","year":"2017","journal-title":"Lancet Gastroenterol Hepatol."},{"key":"B57","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1172\/JCI30555","article-title":"Physiology and immunology of the cholinergic antiinflammatory pathway.","volume":"117","author":"Tracey","year":"2007","journal-title":"J Clin Invest."},{"key":"B58","doi-asserted-by":"publisher","first-page":"8284","DOI":"10.1073\/pnas.1605635113","article-title":"Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis.","volume":"113","author":"Koopman","year":"2016","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B59","doi-asserted-by":"publisher","first-page":"e0180060","DOI":"10.1371\/journal.pone.0180060","article-title":"Heart rate variability as predictor of mortality in sepsis: a prospective cohort study.","volume":"12","author":"de Castilho","year":"2017","journal-title":"PLoS One."},{"key":"B60","doi-asserted-by":"publisher","first-page":"103116","DOI":"10.1016\/j.autneu.2023.103116","article-title":"Heart rate variability as a marker and predictor of inflammation, nosocomial infection, and sepsis - a systematic review.","volume":"249","author":"Adam","year":"2023","journal-title":"Auton Neurosci."},{"key":"B61","doi-asserted-by":"publisher","first-page":"104622","DOI":"10.1016\/j.neubiorev.2022.104622","article-title":"The cholinergic anti-inflammatory pathway in humans: state-of-the-art review and future directions.","volume":"136","author":"Alen","year":"2022","journal-title":"Neurosci Biobehav Rev."},{"key":"B62","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/S0140-6736(18)30696-2","article-title":"Sepsis and septic shock.","volume":"392","author":"Cecconi","year":"2018","journal-title":"Lancet."},{"key":"B63","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1186\/s40560-025-00786-y","article-title":"Gut integrity in intensive care: alterations in host permeability and the microbiome as potential therapeutic targets.","volume":"13","author":"Oami","year":"2025","journal-title":"J Intensive Care."},{"key":"B64","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1007\/s00134-016-4665-0","article-title":"Early enteral nutrition in critically ill patients: ESICM clinical practice guidelines.","volume":"43","author":"Reintam Blaser","year":"2017","journal-title":"Intensive Care Med."},{"key":"B65","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.1097\/00003246-199508000-00008","article-title":"Effect of erythromycin on gastric motility in mechanically ventilated critically ill patients: a double-blind, randomized, placebo-controlled study.","volume":"23","author":"Dive","year":"1995","journal-title":"Crit Care Med."},{"key":"B66","doi-asserted-by":"publisher","first-page":"412","DOI":"10.1177\/0148607108319803","article-title":"Erythromycin vs metoclopramide for facilitating gastric emptying and tolerance to intragastric nutrition in critically ill patients.","volume":"32","author":"MacLaren","year":"2008","journal-title":"JPEN J Parenter Enteral Nutr."},{"key":"B67","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1097\/00003246-200109000-00015","article-title":"Delayed gastric emptying in ventilated critically ill patients: measurement by 13 C-octanoic acid breath test.","volume":"29","author":"Ritz","year":"2001","journal-title":"Crit Care Med."},{"key":"B68","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.3748\/wjg.v13.i29.3909","article-title":"Mechanisms underlying feed intolerance in the critically ill: implications for treatment.","volume":"13","author":"Deane","year":"2007","journal-title":"World J Gastroenterol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"820","DOI":"10.1056\/NEJMcp062614","article-title":"Clinical practice. diabetic gastroparesis.","volume":"356","author":"Camilleri","year":"2007","journal-title":"N Engl J Med."},{"key":"B70","doi-asserted-by":"publisher","first-page":"1197","DOI":"10.14309\/ajg.0000000000001874","article-title":"ACG clinical guideline: gastroparesis.","volume":"117","author":"Camilleri","year":"2022","journal-title":"Am J Gastroenterol."},{"key":"B71","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s11894-024-00954-4","article-title":"The gut in critical illness.","volume":"27","author":"Patel","year":"2025","journal-title":"Curr Gastroenterol Rep."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1337","DOI":"10.1038\/s41430-021-00860-2","article-title":"Gastric-tube versus post-pyloric feeding in critical patients: a systematic review and meta-analysis of pulmonary aspiration- and nutrition-related outcomes.","volume":"75","author":"Liu","year":"2021","journal-title":"Eur J Clin Nutr."},{"key":"B73","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.clnesp.2022.04.014","article-title":"A systematic review of the definitions and prevalence of feeding intolerance in critically ill adults.","volume":"49","author":"Jenkins","year":"2022","journal-title":"Clin Nutr ESPEN."},{"key":"B74","doi-asserted-by":"publisher","first-page":"CD008875","DOI":"10.1002\/14651858.CD008875.pub2","article-title":"Post-pyloric versus gastric tube feeding for preventing pneumonia and improving nutritional outcomes in critically ill adults.","volume":"8","author":"Alkhawaja","year":"2015","journal-title":"Cochrane Database Syst Rev."},{"key":"B75","doi-asserted-by":"publisher","first-page":"73","DOI":"10.4161\/viru.26482","article-title":"Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock.","volume":"5","author":"De Backer","year":"2014","journal-title":"Virulence."},{"key":"B76","doi-asserted-by":"publisher","first-page":"1628","DOI":"10.1007\/s10620-015-4011-3","article-title":"Metagenomic analysis reveals dynamic changes of whole gut microbiota in the acute phase of intensive care unit patients.","volume":"61","author":"Ojima","year":"2016","journal-title":"Dig Dis Sci."},{"key":"B77","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1186\/s13054-016-1434-y","article-title":"Probiotic and synbiotic therapy in critical illness: a systematic review and meta-analysis.","volume":"19","author":"Manzanares","year":"2016","journal-title":"Crit Care."},{"key":"B78","doi-asserted-by":"publisher","first-page":"e1","DOI":"10.1093\/cid\/cix1085","article-title":"Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA).","volume":"66","author":"McDonald","year":"2018","journal-title":"Clin Infect Dis."},{"key":"B79","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1016\/S0140-6736(08)60207-X","article-title":"Probiotic prophylaxis in predicted severe acute pancreatitis: a randomised, double-blind, placebo-controlled trial.","volume":"371","author":"Besselink","year":"2008","journal-title":"Lancet."},{"key":"B80","doi-asserted-by":"publisher","first-page":"2450","DOI":"10.1016\/j.immuni.2021.10.012","article-title":"The immunology of sepsis.","volume":"54","author":"van der Poll","year":"2021","journal-title":"Immunity."},{"key":"B81","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3389\/fpsyt.2018.00044","article-title":"Vagus nerve as modulator of the brain-gut axis in psychiatric and inflammatory disorders.","volume":"9","author":"Breit","year":"2018","journal-title":"Front Psychiatry."},{"key":"B82","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1016\/j.conb.2020.03.006","article-title":"Vagal sensory neurons and gut-brain signaling.","volume":"62","author":"Yu","year":"2020","journal-title":"Curr Opin Neurobiol."},{"key":"B83","doi-asserted-by":"publisher","first-page":"49","DOI":"10.3389\/fnins.2018.00049","article-title":"The vagus nerve at the interface of the microbiota-gut-brain axis.","volume":"12","author":"Bonaz","year":"2018","journal-title":"Front Neurosci."},{"key":"B84","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1007\/s11033-025-10288-7","article-title":"Targeting the cholinergic anti-inflammatory pathway: an innovative strategy for treating diseases.","volume":"52","author":"Li","year":"2025","journal-title":"Mol Biol Rep."},{"key":"B85","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.bbi.2005.03.015","article-title":"The cholinergic anti-inflammatory pathway.","volume":"19","author":"Pavlov","year":"2005","journal-title":"Brain Behav Immun."},{"key":"B86","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1186\/s12974-023-02768-z","article-title":"\u03b17 nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect.","volume":"20","author":"Liu","year":"2023","journal-title":"J Neuroinflamm."},{"key":"B87","doi-asserted-by":"publisher","first-page":"98","DOI":"10.1126\/science.1209985","article-title":"Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit.","volume":"334","author":"Rosas-Ballina","year":"2011","journal-title":"Science."},{"key":"B88","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1038\/nrendo.2012.189","article-title":"The vagus nerve and the inflammatory reflex\u2013linking immunity and metabolism.","volume":"8","author":"Pavlov","year":"2012","journal-title":"Nat Rev Endocrinol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"e14842","DOI":"10.1111\/nmo.14842","article-title":"Enteric neuropathy and the vagus nerve: therapeutic implications.","volume":"37","author":"Bonaz","year":"2025","journal-title":"Neurogastroenterol Motil."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1623","DOI":"10.1084\/jem.20052362","article-title":"Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis.","volume":"203","author":"Huston","year":"2006","journal-title":"J Exp Med."},{"key":"B91","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1016\/j.brs.2023.02.008","article-title":"Transcutaneous auricular vagus nerve stimulation reduces cytokine production in sepsis: an open double-blind, sham-controlled, pilot study.","volume":"16","author":"Wu","year":"2023","journal-title":"Brain Stimul."},{"key":"B92","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s10286-023-00938-w","article-title":"A systematic review of the effects of transcutaneous auricular vagus nerve stimulation on baroreflex sensitivity and heart rate variability in healthy subjects.","volume":"33","author":"Soltani","year":"2023","journal-title":"Clin Auton Res."},{"key":"B93","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/s42234-019-0020-4","article-title":"Investigational treatment of rheumatoid arthritis with a vibrotactile device applied to the external ear.","volume":"5","author":"Addorisio","year":"2019","journal-title":"Bioelectron Med."},{"key":"B94","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1186\/s42234-023-00124-3","article-title":"Transcutaneous auricular vagus nerve stimulation attenuates inflammatory bowel disease in children: a proof-of-concept clinical trial.","volume":"9","author":"Sahn","year":"2023","journal-title":"Bioelectron Med."},{"key":"B95","doi-asserted-by":"publisher","first-page":"632697","DOI":"10.3389\/fnins.2021.632697","article-title":"Brain-heart interaction during transcutaneous auricular vagus nerve stimulation.","volume":"15","author":"Machetanz","year":"2021","journal-title":"Front Neurosci."},{"key":"B96","doi-asserted-by":"publisher","first-page":"e0263833","DOI":"10.1371\/journal.pone.0263833","article-title":"The effect of transcutaneous auricular vagus nerve stimulation on HRV in healthy young people.","volume":"17","author":"Geng","year":"2022","journal-title":"PLoS One."},{"key":"B97","doi-asserted-by":"publisher","first-page":"e150052","DOI":"10.1172\/jci.insight.150052","article-title":"Ameliorating effects and mechanisms of transcutaneous auricular vagal nerve stimulation on abdominal pain and constipation.","volume":"6","author":"Shi","year":"2021","journal-title":"JCI Insight."},{"key":"B98","doi-asserted-by":"publisher","first-page":"G700","DOI":"10.1152\/ajpgi.00426.2020","article-title":"Transcutaneous auricular vagal nerve stimulation improves functional dyspepsia by enhancing vagal efferent activity.","volume":"320","author":"Zhu","year":"2021","journal-title":"Am J Physiol Gastrointest Liver Physiol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"854","DOI":"10.3389\/fnins.2019.00854","article-title":"Current directions in the auricular vagus nerve stimulation I - a physiological perspective.","volume":"13","author":"Kaniusas","year":"2019","journal-title":"Front Neurosci."},{"key":"B100","doi-asserted-by":"publisher","first-page":"284","DOI":"10.3389\/fnins.2020.00284","article-title":"Critical review of transcutaneous vagus nerve stimulation: challenges for translation to clinical practice.","volume":"14","author":"Yap","year":"2020","journal-title":"Front Neurosci."},{"key":"B101","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/s40635-017-0146-1","article-title":"Heart rate variability in critical care medicine: a systematic review.","volume":"5","author":"Karmali","year":"2017","journal-title":"Intensive Care Med Exp."},{"key":"B102","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1007\/s10877-025-01296-w","article-title":"Heart rate variability as a marker of multiple organ dysfunction syndromes: a systematic review.","volume":"39","author":"Wojtanowski","year":"2025","journal-title":"J Clin Monit Comput."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1841517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T06:16:31Z","timestamp":1779948991000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2026.1841517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,28]]},"references-count":102,"alternative-id":["10.3389\/fmed.2026.1841517"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2026.1841517","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,28]]},"article-number":"1841517"}}