{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:07:17Z","timestamp":1793412437836,"version":"4.5.0"},"reference-count":54,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T00:00:00Z","timestamp":1769904000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T00:00:00Z","timestamp":1769040000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pharmacology"],"published-print":{"date-parts":[[2026,2]]},"DOI":"10.1016\/j.ejphar.2026.178594","type":"journal-article","created":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T16:56:51Z","timestamp":1769101011000},"page":"178594","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":3,"special_numbering":"C","title":["Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives"],"prefix":"10.1016","volume":"1015","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-7663-9052","authenticated-orcid":false,"given":"Nicola","family":"Benvenuto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo","family":"Mearelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianni","family":"Biolo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Filippo Giorgio","family":"Di Girolamo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"Roman-Pognuz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abbas","family":"Yadegar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annalisa","family":"Serio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saveria Lory","family":"Croc\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro","family":"Giuffr\u00e8","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"De Cristofaro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Grasselli Kmet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Vittoria","family":"Micioni Di Bonaventura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Verena","family":"Zerbato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6121-7009","authenticated-orcid":false,"given":"Stefano","family":"Di Bella","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"78","reference":[{"key":"10.1016\/j.ejphar.2026.178594_bib1","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1038\/s41575-023-00890-0","article-title":"Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis","volume":"21","author":"Aburto","year":"2024","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"issue":"1","key":"10.1016\/j.ejphar.2026.178594_bib2","first-page":"39","article-title":"Association between beta-hydroxybutyrate levels and survival in sepsis patients","volume":"5","author":"Acar","year":"2021","journal-title":"Eurasian J. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib3","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1042\/BJ20082222","article-title":"The regulation of intestinal mucin MUC2 expression by short-chain fatty acids: implications for epithelial protection","volume":"420","author":"Burger-van Paassen","year":"2009","journal-title":"Biochem. J."},{"key":"10.1016\/j.ejphar.2026.178594_bib4","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1038\/nm0417-402","article-title":"A curious connection: teasing apart the link between gut microbes and lung disease","volume":"23","author":"Chakradhar","year":"2017","journal-title":"Nat. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib5","doi-asserted-by":"crossref","first-page":"1450","DOI":"10.1093\/ibd\/izz046","article-title":"Microbiota metabolite butyrate differentially regulates Th1 and Th17 cells' differentiation and function in induction of colitis","volume":"25","author":"Chen","year":"2019","journal-title":"Inflamm. Bowel Dis."},{"key":"10.1016\/j.ejphar.2026.178594_bib6","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1038\/s41385-019-0160-6","article-title":"Microbes, metabolites, and the gut-lung axis","volume":"12","author":"Dang","year":"2019","journal-title":"Mucosal Immunol."},{"key":"10.1016\/j.ejphar.2026.178594_bib7","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1016\/S2213-2600(15)00427-0","article-title":"The microbiome and critical illness","volume":"4","author":"Dickson","year":"2016","journal-title":"Lancet Respir. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib8","doi-asserted-by":"crossref","DOI":"10.1128\/iai.00200-24","article-title":"The impact of butyrate on group B Streptococcus-induced intestinal barrier disruption","volume":"92","author":"Dominguez","year":"2024","journal-title":"Infect. Immun."},{"key":"10.1016\/j.ejphar.2026.178594_bib9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1556\/1886.2021.00001","article-title":"A literature survey on antimicrobial and immune-modulatory effects of butyrate revealing non-antibiotic approaches to tackle bacterial infections","volume":"11","author":"Du","year":"2021","journal-title":"Eur. J. Microbiol. Immunol. (Bp.)"},{"key":"10.1016\/j.ejphar.2026.178594_bib10","doi-asserted-by":"crossref","first-page":"1806","DOI":"10.4049\/jimmunol.1300835","article-title":"Hydrogen sulfide [corrected] increases survival during sepsis: protective effect of CHOP inhibition","volume":"192","author":"Ferlito","year":"2014","journal-title":"J. Immunol."},{"key":"10.1016\/j.ejphar.2026.178594_bib11","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1007\/s10753-019-00987-2","article-title":"Sodium butyrate ameliorates intestinal injury and improves survival in a rat model of cecal ligation and puncture-induced sepsis","volume":"42","author":"Fu","year":"2019","journal-title":"Inflammation"},{"key":"10.1016\/j.ejphar.2026.178594_bib12","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1186\/1472-6793-7-8","article-title":"Decrease in oxidative phosphorylation yield in presence of butyrate in perfused liver isolated from fed rats","volume":"7","author":"Gallis","year":"2007","journal-title":"BMC Physiol."},{"key":"10.1016\/j.ejphar.2026.178594_bib13","doi-asserted-by":"crossref","first-page":"G889","DOI":"10.1152\/ajpgi.00161.2019","article-title":"A story of liver and gut microbes: how does the intestinal flora affect liver disease? A review of the literature","volume":"318","author":"Giuffr\u00e8","year":"2020","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"10.1016\/j.ejphar.2026.178594_bib14","doi-asserted-by":"crossref","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":"10.1016\/j.ejphar.2026.178594_bib15","article-title":"Sepsis-pathophysiology and therapeutic concepts","volume":"8","author":"Jarczak","year":"2021","journal-title":"Front. Med. (Lausanne)"},{"key":"10.1016\/j.ejphar.2026.178594_bib16","doi-asserted-by":"crossref","DOI":"10.1155\/2022\/2513837","article-title":"Ketone body \u03b2-hydroxybutyrate prevents myocardial oxidative stress in septic cardiomyopathy","volume":"2022","author":"Ji","year":"2022","journal-title":"Oxid. Med. Cell. Longev."},{"key":"10.1016\/j.ejphar.2026.178594_bib17","doi-asserted-by":"crossref","first-page":"8915","DOI":"10.1007\/s11033-023-08713-w","article-title":"\u0392-hydroxybutyrate ameliorates sepsis-induced acute kidney injury","volume":"50","author":"Kim","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"10.1016\/j.ejphar.2026.178594_bib18","doi-asserted-by":"crossref","first-page":"1332","DOI":"10.1016\/j.cell.2016.05.041","article-title":"From dietary fiber to host physiology: short-chain fatty acids as key bacterial metabolites","volume":"165","author":"Koh","year":"2016","journal-title":"Cell"},{"key":"10.1016\/j.ejphar.2026.178594_bib19","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/S2213-2600(24)00257-1","article-title":"Empirical antibiotic therapy for sepsis: save the anaerobic microbiota","volume":"13","author":"Kullberg","year":"2025","journal-title":"Lancet Respir. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib20","article-title":"Sodium butyrate reduces endoplasmic reticulum stress by modulating CHOP and empowers favorable anti-inflammatory adipose tissue immune-metabolism in HFD fed mice model of obesity","volume":"4","author":"Kushwaha","year":"2022","journal-title":"Food Chem. (Oxf.)"},{"key":"10.1016\/j.ejphar.2026.178594_bib21","doi-asserted-by":"crossref","DOI":"10.53520\/jen2025.103189","article-title":"A pharmacokinetic comparison of three butyrate products","author":"La Monica","year":"2025","journal-title":"J. Exerc. Nutr."},{"key":"10.1016\/j.ejphar.2026.178594_bib22","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1097\/01.CCM.0000050454.01978.3B","article-title":"2001 SCCM\/ESICM\/ACCP\/ATS\/SIS international sepsis definitions conference","volume":"31","author":"Levy","year":"2003","journal-title":"Crit. Care Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib23","doi-asserted-by":"crossref","first-page":"3993","DOI":"10.1182\/blood-2024-205102","article-title":"Gut microbial metabolite butyrate alleviates the susceptibility to septic DIC by suppressing caspase-11\/gsdmd-dependent macrophage pyroptosis","volume":"144","author":"Li","year":"2024","journal-title":"Blood"},{"key":"10.1016\/j.ejphar.2026.178594_bib24","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1146\/annurev-immunol-071219-125715","article-title":"Microbiota metabolites in health and disease","volume":"38","author":"McCarville","year":"2020","journal-title":"Annu. Rev. Immunol."},{"key":"10.1016\/j.ejphar.2026.178594_bib25","doi-asserted-by":"crossref","first-page":"2133","DOI":"10.1056\/NEJMra2403213","article-title":"Sepsis and septic shock","volume":"391","author":"Meyer","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib26","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.clnu.2010.09.012","article-title":"Oral administration of tributyrin increases concentration of butyrate in the portal vein and prevents lipopolysaccharide-induced liver injury in rats","volume":"30","author":"Miyoshi","year":"2011","journal-title":"Clin. Nutr."},{"key":"10.1016\/j.ejphar.2026.178594_bib27","first-page":"E129","article-title":"Effect of oral tributyrin treatment on lipid mediator profiles in endotoxin-induced hepatic injury","volume":"66","author":"Miyoshi","year":"2020","journal-title":"Kobe J. Med. Sci."},{"key":"10.1016\/j.ejphar.2026.178594_bib28","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1113\/expphysiol.2014.077982","article-title":"Characterization of butyrate transport across the luminal membranes of equine large intestine: equine intestinal butyrate transport","volume":"99","author":"Nedjadi","year":"2014","journal-title":"Exp. Physiol."},{"key":"10.1016\/j.ejphar.2026.178594_bib29","doi-asserted-by":"crossref","first-page":"e16","DOI":"10.1017\/gmb.2023.14","article-title":"The butyrate-producing and spore-forming bacterial genus coprococcus as a potential biomarker for neurological disorders","volume":"4","author":"Notting","year":"2023","journal-title":"Gut Microbiome (Camb.)"},{"key":"10.1016\/j.ejphar.2026.178594_bib30","doi-asserted-by":"crossref","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":"10.1016\/j.ejphar.2026.178594_bib31","doi-asserted-by":"crossref","first-page":"1619","DOI":"10.3945\/jn.109.104638","article-title":"Butyrate enhances the intestinal barrier by facilitating tight junction assembly via activation of AMP-activated protein kinase in Caco-2 cell monolayers","volume":"139","author":"Peng","year":"2009","journal-title":"J. Nutr."},{"key":"10.1016\/j.ejphar.2026.178594_bib32","first-page":"2034","article-title":"Butyrate supplementation exacerbates myocardial and immune cell mitochondrial dysfunction in a rat model of faecal peritonitis","volume":"12","author":"Peters","year":"2022","journal-title":"Life (Basel)"},{"key":"10.1016\/j.ejphar.2026.178594_bib33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1124\/jpet.120.000187","article-title":"Acetate, a short-chain fatty acid, acutely lowers heart rate and cardiac contractility along with blood pressure","volume":"377","author":"Poll","year":"2021","journal-title":"J. Pharmacol. Exp. Therapeut."},{"key":"10.1016\/j.ejphar.2026.178594_bib34","doi-asserted-by":"crossref","DOI":"10.3390\/nu15102275","article-title":"Gut microbial metabolite butyrate and its therapeutic role in inflammatory bowel disease: a literature review","volume":"15","author":"Recharla","year":"2023","journal-title":"Nutrients"},{"key":"10.1016\/j.ejphar.2026.178594_bib35","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nri.2016.42","article-title":"Gut microbiota, metabolites and host immunity","volume":"16","author":"Rooks","year":"2016","journal-title":"Nat. Rev. Immunol."},{"key":"10.1016\/j.ejphar.2026.178594_bib36","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/S0140-6736(19)32989-7","article-title":"Global, regional, and national sepsis incidence and mortality, 1990-2017: analysis for the global burden of disease study","volume":"395","author":"Rudd","year":"2020","journal-title":"Lancet"},{"key":"10.1016\/j.ejphar.2026.178594_bib37","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1136\/gut.47.3.397","article-title":"Butyrate inhibits inflammatory responses through NF\u03baB inhibition: implications for Crohn's disease","volume":"47","author":"Segain","year":"2000","journal-title":"Gut"},{"key":"10.1016\/j.ejphar.2026.178594_bib38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1016\/j.cell.2016.01.013","article-title":"Are we really vastly outnumbered? Revisiting the ratio of bacterial to host cells in humans","volume":"164","author":"Sender","year":"2016","journal-title":"Cell"},{"key":"10.1016\/j.ejphar.2026.178594_bib39","series-title":"WHO","year":"2023"},{"key":"10.1016\/j.ejphar.2026.178594_bib40","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1186\/s13054-018-2167-x","article-title":"Synbiotics modulate gut microbiota and reduce enteritis and ventilator-associated pneumonia in patients with sepsis: a randomized controlled trial","volume":"22","author":"Shimizu","year":"2018","journal-title":"Crit. Care"},{"key":"10.1016\/j.ejphar.2026.178594_bib41","doi-asserted-by":"crossref","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":"10.1016\/j.ejphar.2026.178594_bib42","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1186\/s13054-023-04655-8","article-title":"The spectrum of sepsis-associated encephalopathy: a clinical perspective","volume":"27","author":"Sonneville","year":"2023","journal-title":"Crit. Care"},{"key":"10.1016\/j.ejphar.2026.178594_bib43","article-title":"Acute lung injury caused by sepsis: how does it happen?","volume":"10","author":"Sun","year":"2023","journal-title":"Front. Med. (Lausanne)"},{"key":"10.1016\/j.ejphar.2026.178594_bib44","article-title":"Lipopolysaccharide is cleared from the circulation by hepatocytes via the low density lipoprotein receptor","volume":"11","author":"Topchiy","year":"2016","journal-title":"PLoS One"},{"key":"10.1016\/j.ejphar.2026.178594_bib45","doi-asserted-by":"crossref","first-page":"2124","DOI":"10.1161\/HYPERTENSIONAHA.123.22437","article-title":"Effects of oral butyrate on blood pressure in patients with hypertension: a randomized, placebo-controlled trial","volume":"81","author":"Verhaar","year":"2024","journal-title":"Hypertension"},{"key":"10.1016\/j.ejphar.2026.178594_bib46","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.ajem.2016.11.022","article-title":"Butyrate pretreatment attenuates heart depression in a mice model of endotoxin-induced sepsis via anti-inflammation and anti-oxidation","volume":"35","author":"Wang","year":"2017","journal-title":"Am. J. Emerg. Med."},{"key":"10.1016\/j.ejphar.2026.178594_bib47","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1111\/sji.12515","article-title":"The inflammation induced by lipopolysaccharide can be mitigated by short-chain fatty acid, butyrate, through upregulation of IL-10 in septic shock","volume":"85","author":"Wang","year":"2017","journal-title":"Scand. J. Immunol."},{"key":"10.1016\/j.ejphar.2026.178594_bib48","doi-asserted-by":"crossref","first-page":"3917","DOI":"10.1007\/s00018-019-03190-6","article-title":"Bridging intestinal immunity and gut microbiota by metabolites","volume":"76","author":"Wang","year":"2019","journal-title":"Cell. Mol. Life Sci."},{"key":"10.1016\/j.ejphar.2026.178594_bib49","doi-asserted-by":"crossref","DOI":"10.1016\/j.ejphar.2023.176219","article-title":"Sodium butyrate ameliorates sepsis-associated lung injury by enhancing gut and lung barrier function in combination with modulation of CD4+Foxp3+ regulatory T cells","volume":"963","author":"Wei","year":"2024","journal-title":"Eur. J. Pharmacol."},{"key":"10.1016\/j.ejphar.2026.178594_bib50","article-title":"Assessment of spatial memory using the radial arm maze and Morris water maze","volume":"8","author":"Wenk","year":"2004","journal-title":"Curr. Protoc. Neurosci. Chapter"},{"key":"10.1016\/j.ejphar.2026.178594_bib51","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01361-14","article-title":"Membership and behavior of ultra-low-diversity pathogen communities present in the gut of humans during prolonged critical illness","volume":"5","author":"Zaborin","year":"2014","journal-title":"mBio"},{"key":"10.1016\/j.ejphar.2026.178594_bib52","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1038\/s41581-023-00683-3","article-title":"Sepsis-associated acute kidney injury: consensus report of the 28th acute disease quality Initiative workgroup","volume":"19","author":"Zarbock","year":"2023","journal-title":"Nat. Rev. Nephrol."},{"key":"10.1016\/j.ejphar.2026.178594_bib53","doi-asserted-by":"crossref","first-page":"2103","DOI":"10.2147\/JIR.S350566","article-title":"Gut microbiota mediates the susceptibility of mice to sepsis-associated encephalopathy by butyric acid","volume":"15","author":"Zhang","year":"2022","journal-title":"J. Inflamm. Res."},{"key":"10.1016\/j.ejphar.2026.178594_bib54","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1097\/SHK.0b013e31802e3f4c","article-title":"Sodium butyrate prevents lethality of severe sepsis in rats","volume":"27","author":"Zhang","year":"2007","journal-title":"Shock"}],"container-title":["European Journal of Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299926000762?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0014299926000762?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2026,2,3]],"date-time":"2026-02-03T13:05:13Z","timestamp":1770123913000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0014299926000762"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2]]},"references-count":54,"alternative-id":["S0014299926000762"],"URL":"https:\/\/doi.org\/10.1016\/j.ejphar.2026.178594","relation":{},"ISSN":["0014-2999"],"issn-type":[{"value":"0014-2999","type":"print"}],"subject":[],"published":{"date-parts":[[2026,2]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Therapeutic potential of butyrate supplementation in sepsis: a review of preclinical evidence and translational perspectives","name":"articletitle","label":"Article Title"},{"value":"European Journal of Pharmacology","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.ejphar.2026.178594","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2026 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}],"article-number":"178594"}}