Ferulic Acid Alleviates Traumatic Brain Injury and Gastrointestinal Disorders by Promoting Ghrelin to Regulate the Microbiota‐Brain‐Gut Axis Inflammation and Pyroptosis

ABSTRACT Traumatic brain injury (TBI) is a severe condition with a high mortality rate, affecting multiple organs, including the gastrointestinal (GI) tract. Ghrelin is a brain‐gut peptide that regulates the microbiota‐brain‐gut 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 vivo TBI model and scratch‐induced injury of primary astrocytes as the in vitro TBI model. The role and mechanism of FA modulation of Ghrelin in ameliorating TBI and GID were explored using multi‐omics and network pharmacology analyses. In vivo, 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‐induced reduction in the expression of Ghrelin and reduces the inflammatory response. Furthermore, 16S rRNA results indicated that CCI‐induced TBI worsened gut microflora imbalance via the brain‐gut axis, while gut dysbiosis aggravated brain injury. FA improved the dysbiosis of Bacteroidetes and Odoribacter mainly by targeting the Ghrelin‐mediated inflammatory response. RNA‐seq and network pharmacology analyses revealed that FA mainly affects inflammation‐mediated pyroptosis pathways in the brain‐gut axis. Additionally, experimental evidence demonstrated that FA reversed CCI‐induced pyroptosis in rats and scratch injury‐induced pyroptosis in astrocytes by promoting the binding of Ghrelin to GHSR, which suppressed the TLR4/NF‐κB/NLRP3 pathway. Conclusively, FA could alleviate TBI and GID by promoting Ghrelin to regulate the microbiota‐brain‐gut axis inflammation via the Ghrelin/TLR4/NLRP3 pathway.