{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T14:57:56Z","timestamp":1791817076889,"version":"4.3.4"},"reference-count":202,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T00:00:00Z","timestamp":1763596800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The gut\u2013brain axis (GBA) is a critical area of research for understanding the pathogenesis of neuroinflammatory and neurodegenerative diseases. Metabolites produced by the gut microbiota, particularly short-chain fatty acids (SCFAs), act as key mediators in this bidirectional communication. While the roles of acetate, propionate, and butyrate are well-established, valeric acid (VA), a five-carbon SCFA, is poorly understood. This comprehensive review explores VA as a gut-derived physiological epigenetic modulator, examining its microbial biosynthesis and systemic effects. This review discusses how VA acts as a selective histone deacetylase inhibitor (HDACi), particularly targeting Class I HDACs, to modulate gene expression and exert neuroprotective and anti-inflammatory effects. The analysis compares VA with its pharmacological analog, valproic acid (VPA), a well-known but non-selective HDACi. This comparison highlights how VA\u2019s physiological nature may offer a more targeted and safer intervention. In conclusion, elucidating VA\u2019s role as a microbiome-derived epigenetic regulator would open promising avenues for therapeutic strategies that directly connect gut and CNS health within the GBA.<\/jats:p>","DOI":"10.3390\/cells14221823","type":"journal-article","created":{"date-parts":[[2025,11,20]],"date-time":"2025-11-20T09:44:53Z","timestamp":1763631893000},"page":"1823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Valeric Acid: A Gut-Derived Metabolite as a Potential Epigenetic Modulator of Neuroinflammation in the Gut\u2013Brain Axis"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4276-6991","authenticated-orcid":false,"given":"Chiara","family":"Paciolla","sequence":"first","affiliation":[{"name":"Department of Traslational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8219-0252","authenticated-orcid":false,"given":"Michele","family":"Manganelli","sequence":"additional","affiliation":[{"name":"Department of Traslational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2058-9479","authenticated-orcid":false,"given":"Mariagiovanna","family":"Di Chiano","sequence":"additional","affiliation":[{"name":"Department of Traslational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0857-7520","authenticated-orcid":false,"given":"Francesca","family":"Montenegro","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2252-9584","authenticated-orcid":false,"given":"Anna","family":"Gallone","sequence":"additional","affiliation":[{"name":"Department of Traslational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5132-6532","authenticated-orcid":false,"given":"Fabio","family":"Sallustio","sequence":"additional","affiliation":[{"name":"Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2345-2838","authenticated-orcid":false,"given":"Gabriella","family":"Guida","sequence":"additional","affiliation":[{"name":"Department of Traslational Biomedicine and Neuroscience (DiBraiN), University of Bari Aldo Moro, 70121 Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"987","DOI":"10.4081\/cp.2017.987","article-title":"Gut Microbiota\u2019s Effect on Mental Health: The Gut-Brain Axis","volume":"7","author":"Clapp","year":"2017","journal-title":"Clin. 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