{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T01:45:09Z","timestamp":1788140709783,"version":"build-2803163510"},"posted":{"date-parts":[[2025,12,17]]},"group-title":"Molecular Biology","reference-count":72,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"National Institute of Health\/National Institute of Neurological Disorders and Stroke","award":["R01NS125437"],"award-info":[{"award-number":["R01NS125437"]}]},{"name":"National Institute of Health","award":["DK114007"],"award-info":[{"award-number":["DK114007"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,12,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>Over the past decade, cerebrovascular inflammation has been increasingly recognized as a contributor to the progression of neurodegenerative diseases, particularly Alzheimer\u2019s disease (AD). One of the molecular hallmarks of cerebrovascular inflammation is the increased expression of vascular cell adhesion molecule (VCAM)-1 on blood-brain barrier (BBB) endothelial cells. Exposure to amyloid beta (A\u03b2) peptides, one of the primary hallmarks of AD, and pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-\u03b1) induces VCAM-1 expression on the BBB endothelium, which facilitates extravasation of leukocytes into the brain thereby promoting an inflammatory response. Therefore, it is crucial to explore therapeutic agents that can inhibit VCAM-1 expression induced by A\u03b2 and TNF-\u03b1. Short-chain fatty acids, such as butyrate, produced by the gut microbiota as byproducts of dietary fiber metabolism, are recognized for their anti-inflammatory properties. In this study, we successfully tested the hypothesis that butyrate mitigates A\u03b2 and TNF-\u03b1-induced VCAM-1 expression in polarized human cerebral microvascular endothelial cell monolayers, a widely used BBB in vitro model. Our findings indicated that pre-treatment with butyrate significantly reduced A\u03b242 and TNF-\u03b1 mediated upregulation of VCAM-1. Furthermore, we have shown STAT3\/GATA6 axis as a key mediator of anti-inflammatory effects of butyrate. These findings provide mechanistic insight into butyrate\u2019s protective role and highlight its potential to mitigate A\u03b2 and TNF-\u03b1-induced cerebrovascular inflammation in AD.<\/jats:p>","DOI":"10.64898\/2025.12.15.694447","type":"posted-content","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T05:45:30Z","timestamp":1766036730000},"source":"Crossref","is-referenced-by-count":2,"title":["Molecular Mechanisms Underlying the Regulation of VCAM-1 Expression by the Short-Chain Fatty Acid Butyrate"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4335-9307","authenticated-orcid":false,"given":"Vrishali S.","family":"Salian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vaishnavi","family":"Veerareddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojia","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna R.","family":"Kalari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purna C.","family":"Kashyap","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karunya K.","family":"Kandimalla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025122004350896000_2025.12.15.694447v1.1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70299-6"},{"key":"2025122004350896000_2025.12.15.694447v1.2","doi-asserted-by":"publisher","DOI":"10.1007\/bf02334602"},{"key":"2025122004350896000_2025.12.15.694447v1.3","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.121.032613"},{"key":"2025122004350896000_2025.12.15.694447v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.neurobiolaging.2012.02.023"},{"key":"2025122004350896000_2025.12.15.694447v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms11934"},{"issue":"2","key":"2025122004350896000_2025.12.15.694447v1.6","doi-asserted-by":"crossref","first-page":"42","DOI":"10.33696\/Neurol.5.087","article-title":"Cerebrovascular Dysfunction in Alzheimer\u2019s Disease and Transgenic Rodent Models","volume":"5","year":"2024","journal-title":"J Exp Neurol"},{"key":"2025122004350896000_2025.12.15.694447v1.7","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awad317"},{"issue":"1","key":"2025122004350896000_2025.12.15.694447v1.8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1186\/s40478-021-01176-9","article-title":"Brain insulin signaling and cerebrovascular disease in human postmortem brain","volume":"9","year":"2021","journal-title":"Acta Neuropathol Commun"},{"issue":"3","key":"2025122004350896000_2025.12.15.694447v1.9","doi-asserted-by":"crossref","first-page":"e0264390","DOI":"10.1371\/journal.pone.0264390","article-title":"Associations among cardiovascular and cerebrovascular diseases: Analysis of the nationwide claims-based JROAD-DPC dataset","volume":"17","year":"2022","journal-title":"PLoS One"},{"key":"2025122004350896000_2025.12.15.694447v1.10","doi-asserted-by":"publisher","DOI":"10.2147\/DNND.S19829"},{"key":"2025122004350896000_2025.12.15.694447v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2007.05.005"},{"issue":"1","key":"2025122004350896000_2025.12.15.694447v1.12","doi-asserted-by":"crossref","first-page":"26580","DOI":"10.1038\/s41598-024-78204-w","article-title":"Activation of glial cells induces proinflammatory properties in brain capillary endothelial cells in vitro","volume":"14","year":"2024","journal-title":"Sci Rep"},{"key":"2025122004350896000_2025.12.15.694447v1.13","doi-asserted-by":"publisher","DOI":"10.1186\/s12929-015-0165-8"},{"key":"2025122004350896000_2025.12.15.694447v1.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.01.005"},{"key":"2025122004350896000_2025.12.15.694447v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/374647a0"},{"key":"2025122004350896000_2025.12.15.694447v1.16","doi-asserted-by":"publisher","DOI":"10.3390\/nu3100858"},{"key":"2025122004350896000_2025.12.15.694447v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0157-3"},{"key":"2025122004350896000_2025.12.15.694447v1.18","doi-asserted-by":"publisher","DOI":"10.1126\/science.1223813"},{"issue":"1","key":"2025122004350896000_2025.12.15.694447v1.19","doi-asserted-by":"crossref","first-page":"91","DOI":"10.3233\/JAD-190120","article-title":"Sodium Butyrate Reduces Brain Amyloid-beta Levels and Improves Cognitive Memory Performance in an Alzheimer\u2019s Disease Transgenic Mouse Model at an Early Disease Stage","volume":"74","year":"2020","journal-title":"J Alzheimers Dis"},{"key":"2025122004350896000_2025.12.15.694447v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cbi.2021.109452"},{"key":"2025122004350896000_2025.12.15.694447v1.21","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0808567105"},{"key":"2025122004350896000_2025.12.15.694447v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s11010-011-0751-3"},{"key":"2025122004350896000_2025.12.15.694447v1.23","first-page":"712673","article-title":"and Alzheimer\u2019s Disease","volume":"12","year":"2021","journal-title":"Front Psychiatry"},{"issue":"3","key":"2025122004350896000_2025.12.15.694447v1.24","doi-asserted-by":"crossref","first-page":"e0282685","DOI":"10.1371\/journal.pone.0282685","article-title":"Butyrate suppresses atherosclerotic inflammation by regulating macrophages and polarization via GPR43\/HDAC-miRNAs axis in ApoE-\/-mice","volume":"18","year":"2023","journal-title":"PLoS One"},{"key":"2025122004350896000_2025.12.15.694447v1.25","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2018.00233"},{"key":"2025122004350896000_2025.12.15.694447v1.26","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.124.002280"},{"key":"2025122004350896000_2025.12.15.694447v1.27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.2000.279.6.C1772"},{"key":"2025122004350896000_2025.12.15.694447v1.28","doi-asserted-by":"publisher","DOI":"10.1006\/mvre.1995.1028"},{"key":"2025122004350896000_2025.12.15.694447v1.29","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.13.10.6283"},{"key":"2025122004350896000_2025.12.15.694447v1.30","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.175.1.531"},{"key":"2025122004350896000_2025.12.15.694447v1.31","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600823"},{"key":"2025122004350896000_2025.12.15.694447v1.32","doi-asserted-by":"crossref","unstructured":"L. Zhou , H. Ning , H. Wei , T. Xu , X. Zhao , A. Fu , Q. Qian , Z. Yang , X. Dou , S. Li , A Novel STAT3-Mediated GATA6 Pathway Contributes to tert-Butylhydroquinone-(tBHQ-) Protected TNFalpha-Activated Vascular Cell Adhesion Molecule 1 (VCAM-1) in Vascular Endothelium, Oxid Med Cell Longev 2020 (2020) 6584059.","DOI":"10.1155\/2020\/6584059"},{"key":"2025122004350896000_2025.12.15.694447v1.33","doi-asserted-by":"publisher","DOI":"10.1006\/bbrc.2000.2784"},{"key":"2025122004350896000_2025.12.15.694447v1.34","doi-asserted-by":"crossref","unstructured":"C.M. Davis , K. Lyon-Scott , E.V. Varlamov , W.H. Zhang , N.J. Alkayed , Role of Endothelial STAT3 in Cerebrovascular Function and Protection from Ischemic Brain Injury, Int J Mol Sci 23(20) (2022).","DOI":"10.3390\/ijms232012167"},{"key":"2025122004350896000_2025.12.15.694447v1.35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.173.3.2041"},{"key":"2025122004350896000_2025.12.15.694447v1.36","doi-asserted-by":"publisher","DOI":"10.1161\/01.ATV.21.6.917"},{"issue":"11","key":"2025122004350896000_2025.12.15.694447v1.37","doi-asserted-by":"crossref","first-page":"5605","DOI":"10.7150\/thno.55878","article-title":"HDAC1 and 2 regulate endothelial VCAM-1 expression and atherogenesis by suppressing methylation of the GATA6 promoter","volume":"11","year":"2021","journal-title":"Theranostics"},{"key":"2025122004350896000_2025.12.15.694447v1.38","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215650"},{"key":"2025122004350896000_2025.12.15.694447v1.39","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-020-02073-3"},{"issue":"1","key":"2025122004350896000_2025.12.15.694447v1.40","doi-asserted-by":"crossref","first-page":"25","DOI":"10.3233\/JAD-181143","article-title":"Associations Between Gut Microbiota and Alzheimer\u2019s Disease: Current Evidences and Future Therapeutic and Diagnostic Perspectives","volume":"68","year":"2019","journal-title":"J Alzheimers Dis"},{"key":"2025122004350896000_2025.12.15.694447v1.41","doi-asserted-by":"crossref","unstructured":"L. Wu , Y. Han , Z. Zheng , G. Peng , P. Liu , S. Yue , S. Zhu , J. Chen , H. Lv , L. Shao , Y. Sheng , Y. Wang , L. Li , L. Li , B. Wang , Altered Gut Microbial Metabolites in Amnestic Mild Cognitive Impairment and Alzheimer\u2019s Disease: Signals in Host-Microbe Interplay, Nutrients 13(1) (2021).","DOI":"10.3390\/nu13010228"},{"issue":"4","key":"2025122004350896000_2025.12.15.694447v1.42","doi-asserted-by":"crossref","first-page":"1337","DOI":"10.3233\/JAD-180176","article-title":"Gut Microbiota is Altered in Patients with Alzheimer\u2019s Disease","volume":"63","year":"2018","journal-title":"J Alzheimers Dis"},{"key":"2025122004350896000_2025.12.15.694447v1.43","doi-asserted-by":"crossref","unstructured":"A.V. Colombo , R.K. Sadler , G. Llovera , V. Singh , S. Roth , S. Heindl , L. Sebastian Monasor , A. Verhoeven , F. Peters , S. Parhizkar , F. Kamp , M. Gomez de Aguero , A.J. MacPherson , E. Winkler , J. Herms , C. Benakis , M. Dichgans , H. Steiner , M. Giera , C. Haass , S. Tahirovic , A. Liesz , Microbiota-derived short chain fatty acids modulate microglia and promote Abeta plaque deposition, Elife 10 (2021).","DOI":"10.7554\/eLife.59826"},{"key":"2025122004350896000_2025.12.15.694447v1.44","doi-asserted-by":"publisher","DOI":"10.1097\/00054725-200403000-00010"},{"issue":"2","key":"2025122004350896000_2025.12.15.694447v1.45","doi-asserted-by":"crossref","first-page":"813","DOI":"10.3233\/JAD-215400","article-title":"Markers of Cerebrovascular Injury, Inflammation, and Plasma Lipids Are Associated with Alzheimer\u2019s Disease Cerebrospinal Fluid Biomarkers in Cognitively Normal Persons","volume":"86","year":"2022","journal-title":"J Alzheimers Dis"},{"key":"2025122004350896000_2025.12.15.694447v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/S0197-4580(00)00124-X"},{"key":"2025122004350896000_2025.12.15.694447v1.47","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","year":"2018","journal-title":"Alzheimers Dement (N Y"},{"key":"2025122004350896000_2025.12.15.694447v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41380-021-01361-1"},{"issue":"4","key":"2025122004350896000_2025.12.15.694447v1.49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11357-022-00585-5","article-title":"Association of cerebral microvascular dysfunction and white matter injury in Alzheimer\u2019s disease","volume":"44","year":"2022","journal-title":"Geroscience"},{"issue":"1","key":"2025122004350896000_2025.12.15.694447v1.50","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/s13041-025-01179-w","article-title":"Sodium butyrate attenuates microglia-mediated neuroinflammation by modulating the TLR4\/MyD88\/NF-kappaB pathway and microbiome-gut-brain axis in cardiac arrest mice","volume":"18","year":"2025","journal-title":"Mol Brain"},{"key":"2025122004350896000_2025.12.15.694447v1.51","doi-asserted-by":"crossref","unstructured":"G. Cavaliere , A. Catapano , G. Trinchese , F. Cimmino , E. Penna , A. Pizzella , C. Cristiano , A. Lama , M. Crispino , M.P. Mollica , Butyrate Improves Neuroinflammation and Mitochondrial Impairment in Cerebral Cortex and Synaptic Fraction in an Animal Model of Diet-Induced Obesity, Antioxidants (Basel) 12(1) (2022).","DOI":"10.3390\/antiox12010004"},{"issue":"9","key":"2025122004350896000_2025.12.15.694447v1.52","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1007\/s11064-021-03369-z","article-title":"Neuroprotective Effects of Sodium Butyrate through Suppressing Neuroinflammation and Modulating Antioxidant Enzymes","volume":"46","year":"2021","journal-title":"Neurochem Res"},{"key":"2025122004350896000_2025.12.15.694447v1.53","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-019-0440-4"},{"key":"2025122004350896000_2025.12.15.694447v1.54","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.6A7171.2007"},{"key":"2025122004350896000_2025.12.15.694447v1.55","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-44098-2"},{"key":"2025122004350896000_2025.12.15.694447v1.56","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.3780164"},{"key":"2025122004350896000_2025.12.15.694447v1.57","doi-asserted-by":"publisher","DOI":"10.1016\/S0016-5085(99)70070-3"},{"key":"2025122004350896000_2025.12.15.694447v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2021.166170"},{"key":"2025122004350896000_2025.12.15.694447v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.jnutbio.2003.11.008"},{"issue":"3","key":"2025122004350896000_2025.12.15.694447v1.60","doi-asserted-by":"crossref","first-page":"1615","DOI":"10.1016\/S0022-3565(24)36955-1","article-title":"Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis","volume":"282","year":"1997","journal-title":"J Pharmacol Exp Ther"},{"key":"2025122004350896000_2025.12.15.694447v1.61","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.34.21096"},{"key":"2025122004350896000_2025.12.15.694447v1.62","doi-asserted-by":"publisher","DOI":"10.1084\/jem.176.6.1583"},{"key":"2025122004350896000_2025.12.15.694447v1.63","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.15.5.2558"},{"key":"2025122004350896000_2025.12.15.694447v1.64","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2012.09.017"},{"key":"2025122004350896000_2025.12.15.694447v1.65","doi-asserted-by":"publisher","DOI":"10.1021\/jf900856z"},{"key":"2025122004350896000_2025.12.15.694447v1.66","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1322269111"},{"key":"2025122004350896000_2025.12.15.694447v1.67","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn419"},{"key":"2025122004350896000_2025.12.15.694447v1.68","doi-asserted-by":"publisher","DOI":"10.1002\/stem.1609"},{"key":"2025122004350896000_2025.12.15.694447v1.69","doi-asserted-by":"publisher","DOI":"10.1016\/j.jneumeth.2012.10.001"},{"key":"2025122004350896000_2025.12.15.694447v1.70","doi-asserted-by":"publisher","DOI":"10.1021\/bi030029q"},{"key":"2025122004350896000_2025.12.15.694447v1.71","unstructured":"M.A.C. Center , Supercurve, 2015. https:\/\/bioinformatics.mdanderson.org\/public-software\/supercurve\/."},{"key":"2025122004350896000_2025.12.15.694447v1.72","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btm283"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2025.12.15.694447","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T12:35:20Z","timestamp":1766234120000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2025.12.15.694447"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":72,"URL":"https:\/\/doi.org\/10.64898\/2025.12.15.694447","relation":{},"subject":[],"published":{"date-parts":[[2025,12,17]]},"subtype":"preprint"}}