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Ghrelin is a brain\u2010gut peptide that regulates the microbiota\u2010brain\u2010gut axis, facilitating communication between the GI tract and the central nervous system. This study aimed to investigate the role of ferulic acid (FA) in regulating Ghrelin to improve TBI and GI disorders (GID) induced by controlled cortical impact (CCI). This study used CCI as the in\u00a0vivo TBI model and scratch\u2010induced injury of primary astrocytes as the in\u00a0vitro TBI model. The role and mechanism of FA modulation of Ghrelin in ameliorating TBI and GID were explored using multi\u2010omics and network pharmacology analyses. In\u00a0vivo, results revealed that FA is the main active component of the Guanxin II compound and mimics its function. Significant improvement in GI hypomotility and brain injury was observed in the FA group compared to the CCI group. Concurrently, FA ameliorated intestinal barrier impairment triggered by CCI\u2010induced reduction in the expression of Ghrelin and reduces the inflammatory response. Furthermore, 16S rRNA results indicated that CCI\u2010induced TBI worsened gut microflora imbalance via the brain\u2010gut axis, while gut dysbiosis aggravated brain injury. FA improved the dysbiosis of <jats:italic>Bacteroidetes<\/jats:italic> and <jats:italic>Odoribacter<\/jats:italic> mainly by targeting the Ghrelin\u2010mediated inflammatory response. RNA\u2010seq and network pharmacology analyses revealed that FA mainly affects inflammation\u2010mediated pyroptosis pathways in the brain\u2010gut axis. Additionally, experimental evidence demonstrated that FA reversed CCI\u2010induced pyroptosis in rats and scratch injury\u2010induced pyroptosis in astrocytes by promoting the binding of Ghrelin to GHSR, which suppressed the TLR4\/NF\u2010\u03baB\/NLRP3 pathway. Conclusively, FA could alleviate TBI and GID by promoting Ghrelin to regulate the microbiota\u2010brain\u2010gut axis inflammation via the Ghrelin\/TLR4\/NLRP3 pathway.<\/jats:p>","DOI":"10.1002\/ptr.8450","type":"journal-article","created":{"date-parts":[[2025,3,28]],"date-time":"2025-03-28T04:35:10Z","timestamp":1743136510000},"page":"2291-2311","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Ferulic Acid Alleviates Traumatic Brain Injury and Gastrointestinal Disorders by Promoting Ghrelin to Regulate the Microbiota\u2010Brain\u2010Gut Axis Inflammation and Pyroptosis"],"prefix":"10.1002","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7042-1594","authenticated-orcid":false,"given":"Yawen","family":"Cai","sequence":"first","affiliation":[{"name":"Institute of TCM\u2010Related Comorbid Depression Nanjing University of Chinese Medicine  Nanjing 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