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Supplementation during an acute ethanol challenge with or without tributyrin, a butyrate prodrug, was delivered to C57BL\/6 mice. A separate group of mice received 3 days of clindamycin prior to the acute ethanol challenge. Upon euthanasia, blood endotoxin, cecal bacteria, jejunal barrier integrity, and small intestinal lamina propria dendritic cells were assessed. HIMECs were tested for activation following exposure to ethanol \u00b1 lipopolysaccharide (LPS) and sodium butyrate. Tributyrin supplementation protected a butyrate-generating microbe during ethanol and antibiotic exposure. Tributyrin rescued ethanol-induced disruption in jejunal epithelial barrier, elevated plasma endotoxin, and increased mucosal vascular addressin cell-adhesion molecule-1 (MAdCAM-1) expression in intestinal microvascular endothelium. These protective effects of tributyrin coincided with a tolerogenic dendritic response in the intestinal lamina propria. Lastly, sodium butyrate pre- and co-treatment attenuated the direct effects of ethanol and LPS on MAdCAM-1 induction in the HIMECs from a patient with ulcerative colitis. Tributyrin supplementation protects small intestinal epithelial and microvascular barrier integrity and modulates microvascular endothelial activation and dendritic tolerizing function during a state of gut dysbiosis and acute ethanol challenge.<\/jats:p>","DOI":"10.3390\/ijms25031665","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T12:25:01Z","timestamp":1706531101000},"page":"1665","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["The Postbiotic Butyrate Mitigates Gut Mucosal Disruption Caused by Acute Ethanol Exposure"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0778-2319","authenticated-orcid":false,"given":"Mohamed Tausif","family":"Siddiqui","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingchun","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8667-8861","authenticated-orcid":false,"given":"David","family":"Shapiro","sequence":"additional","affiliation":[{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gail","family":"West","sequence":"additional","affiliation":[{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudio","family":"Fiocchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5717-7099","authenticated-orcid":false,"given":"Gail A. M.","family":"Cresci","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Hepatology and Nutrition, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Department of Inflammation & Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"},{"name":"Division of Pediatric Gastroenterology, Hepatology and Nutrition, Cleveland Clinic Children\u2019s Hospital, Cleveland, OH 44195, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/s41392-022-00974-4","article-title":"Microbiota in health and diseases","volume":"7","author":"Hou","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1042\/CS20171055","article-title":"Intestinal dysbiosis and permeability: The yin and yang in alcohol dependence and alcoholic liver disease","volume":"132","author":"Leclercq","year":"2018","journal-title":"Clin. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.3390\/biom5042573","article-title":"Alcohol and the intestine","volume":"5","author":"Patel","year":"2015","journal-title":"Biomolecules"},{"key":"ref_4","first-page":"49","article-title":"Role of the endothelium in inflammatory bowel diseases","volume":"33","author":"Cromer","year":"2005","journal-title":"Biologicals"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Knudsen, K.E.B., L\u00e6rke, H.N., Hedemann, M.S., Nielsen, T.S., Ingerslev, A.K., Nielsen, D.S.G., Theil, P.K., Purup, S., Hald, S., and Schioldan, A.G. (2018). Impact of diet-modulated butyrate production on intestinal barrier function and inflammation. Nutrients, 10.","DOI":"10.3390\/nu10101499"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/hep.31178","article-title":"Fecal microbiome distinguishes alcohol consumption from alcoholic hepatitis but does not discriminate disease severity","volume":"71","author":"Smirnova","year":"2020","journal-title":"Hepatology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"3297","DOI":"10.1021\/pr400362z","article-title":"Chronic ethanol consumption alters mammalian gastrointestinal content metabolites","volume":"12","author":"Xie","year":"2013","journal-title":"J. Proteome Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Roychowdhury, S., Glueck, B., Han, Y., Mohammad, M., and Cresci, G. (2019). A Designer Synbiotic Attenuates Chronic-Binge Ethanol-Induced Gut-Liver Injury in Mice. Nutrients, 11.","DOI":"10.3390\/nu11010097"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/j.immuni.2017.04.004","article-title":"Regionalized development and maintenance of the intestinal adaptive immune landscape","volume":"46","author":"Agace","year":"2017","journal-title":"Immunity"},{"key":"ref_10","first-page":"221","article-title":"Alcohol use in patients with Inflammatory Bowel Disease","volume":"17","author":"Ramos","year":"2021","journal-title":"Gastroenterol. Hepatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1002\/hep.1840080604","article-title":"Microvascular abnormalities of the portal hypertensive gastric mucosa","volume":"8","author":"Tarnawski","year":"1988","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1093\/toxsci\/kfs087","article-title":"Ethanol disrupts vascular endothelial barrier: Implication in cancer metastasis","volume":"127","author":"Xu","year":"2012","journal-title":"Toxicol. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s00280-003-0580-5","article-title":"Clinical and pharmacologic study of tributyrin: An oral butyrate prodrug","volume":"51","author":"Edelman","year":"2003","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3118","DOI":"10.3390\/cimb44070215","article-title":"Probiotic potential of Clostridium spp.","volume":"44","author":"Grenda","year":"2022","journal-title":"Advantages and doubts. Curr. Issues Mol. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1166","DOI":"10.3389\/fimmu.2017.01166","article-title":"Human gut symbiont Roseburia hominis promotes and regulates innate immunity","volume":"8","author":"Patterson","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1587","DOI":"10.1111\/jgh.13731","article-title":"Prophylactic tributyrin treatment mitigates chronic-binge ethanol-induced intestinal barrier and liver injury","volume":"32","author":"Cresci","year":"2017","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Andre, P., Laugerette, F., and Feart, C. (2019). Metabolic endotoxemia: A potential underlying mechanism of the relationship between dietary fat intake and risk for congnitive impairments in humans?. Nutrients, 11.","DOI":"10.3390\/nu11081887"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1242\/jcs.082271","article-title":"Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity","volume":"124","author":"Privratsky","year":"2011","journal-title":"J. Cell Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1369\/jhc.4A6514.2005","article-title":"Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues","volume":"54","author":"Pusztaszeri","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"836","DOI":"10.2174\/156652409789105525","article-title":"Role of \u03b27 integrins in intestinal lymphocyte homing and retention","volume":"9","author":"Gorfu","year":"2009","journal-title":"Curr. Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1038\/s41467-018-03318-5","article-title":"Fc\u03b1RI co-stimulation converts human intestinal CD103+ dendritic cells into pro-inflammatory cells through glycolytic reprogramming","volume":"9","author":"Hansen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1111\/acer.12428","article-title":"Tributyrin supplementation protects mice from acute ethanol-induced gut injury. Alcoholism: Clinical and Experimental Research","volume":"38","author":"Cresci","year":"2014","journal-title":"Alcohol. Clin. Exp. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"763","DOI":"10.1177\/0148607113486809","article-title":"Lactobacillus GG and Tributyrin Supplementation Reduce Antibiotic-Induced Intestinal Injury","volume":"37","author":"Cresci","year":"2013","journal-title":"JPEN J. Parenter. Enter. Nutr."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.3389\/fimmu.2017.01429","article-title":"Butyrte conditions human dendritic cells to prime type 1 regulatory T cells via both histone deacetylase inhibition and G protein-coupled receptor 109A signaling","volume":"8","author":"Kaisar","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2883","DOI":"10.3389\/fimmu.2018.02883","article-title":"Intestinal dendritic cells in health and gut inflammation","volume":"9","author":"Stagg","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"6025","DOI":"10.2147\/JIR.S300989","article-title":"The Immunomodulatory Functions of Butyrate","volume":"14","author":"Siddiqui","year":"2021","journal-title":"J. Inflamm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1479","DOI":"10.1136\/gut.2003.024828","article-title":"Influence of dietary factors on the clinical course of ulcerative colitis: A prospective cohort study","volume":"53","author":"Jowett","year":"2004","journal-title":"Gut"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1002\/JLB.4MA1217-506R","article-title":"Alcohol enhances symptoms and propensity for infection in inflammatory bowel disease patients and a murine model of DSS-induced colitis","volume":"104","author":"Cannon","year":"2018","journal-title":"J. Leukoc. Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1215","DOI":"10.1056\/NEJMoa1905725","article-title":"Vedolizumab versus adalimumab for moderate-to-severe ulcerative colitis","volume":"381","author":"Sands","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41467-018-07841-3","article-title":"Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanism underlying disease severity and treatment response","volume":"10","author":"Haberman","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2107866","DOI":"10.1080\/19490976.2022.2107866","article-title":"Novel technologies to characterize and engineer the microbiome in inflammatory bowel disease","volume":"14","author":"Monaco","year":"2022","journal-title":"Gut Microbes"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1159\/000512952","article-title":"The effect of sodium butyrate enemas compared with placebo on disease activity, endoscopic scores, and histological and inflammatory parameters in inflammatory bowel diseases: A systematic review of randomized controlled trials","volume":"28","author":"Jamka","year":"2021","journal-title":"Complement. Med. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/ygh2.425","article-title":"Diversion colitis: Aetiology, diagnosis and treatment. A systematic revie","volume":"2","author":"Dilke","year":"2020","journal-title":"GastroHep"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Recharla, N., Geesala, R., and Shi, X.Z. (2023). Gut microbial metabolite butyrate and its therapeutic role in Inflammatory Bowel Disease: A literature review. Nutrients, 15.","DOI":"10.20944\/preprints202304.0501.v1"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1023\/A:1005537411244","article-title":"Combined oral sodium butyrate and mesalazine treatment compared to oral mesalazine alone in ulcerative colitis","volume":"45","author":"Vernia","year":"2000","journal-title":"Dig. Dis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Vernero, M., De Blasio, F., Ribaldone, D.G., Bugianesi, E., Pellicano, R., Saracco, G.M., Astegiano, M., and Caviglia, G.P. (2020). The usefulness of microencapsulated sodium butyrate add-on therapy in maintaining remission in patients with Ulcerative Colitis: A prospective observational study. J. Clin. Med., 9.","DOI":"10.3390\/jcm9123941"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/nprot.2013.032","article-title":"Mouse model of chronic and binge ethanol feeding (the NIAAA model)","volume":"8","author":"Bertola","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1156","DOI":"10.1002\/jpen.1053","article-title":"Faecalibacterium prausnitzii and a prebiotic protect intestinal health in a mouse model of antibiotic and Clostridium difficile exposure","volume":"42","author":"Roychowdhury","year":"2018","journal-title":"JPEN J. Parenter. Enteral. Nutr."},{"key":"ref_39","first-page":"57281","article-title":"Isolating lymphocytes from the mouse small intestinal immune system","volume":"132","author":"Qiu","year":"2018","journal-title":"JOVE J. Vis. Exp."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1895","DOI":"10.1053\/gast.1997.v112.pm9178682","article-title":"Enhanced leukocyte binding by intestinal microvascular endothelial cells in inflammatory bowel disease","volume":"112","author":"Binion","year":"1997","journal-title":"Gastroenterology"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1665\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:51:24Z","timestamp":1760104284000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/3\/1665"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,29]]},"references-count":40,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25031665"],"URL":"https:\/\/doi.org\/10.3390\/ijms25031665","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,29]]}}}