Gastrodin alleviates acute colitis with comorbid anxiety- and depression-like behaviours rather than cognitive dysfunction by modulating gut microbiota and suppressing inflammation.

Inflammatory bowel disease (IBD) patients frequently suffer from emotional disturbances, predominantly anxiety- and depression-like symptoms, and may also have cognitive dysfunction, but the mechanisms remain unclear, and no therapies targeting the gut or nervous system exist. Gastrodin (GAS), the primary active component of Gastrodia elata, has anti-inflammatory and neuroprotective effects. Whether GAS can alleviate acute colitis with comorbid anxiety- and depression-like behaviours or cognitive dysfunction via the gut-brain axis is unknown. Using a 3% dextran sulfate sodium (DSS)-induced mouse model, we administered GAS (240 mg/kg) by gavage for 7 days. The open field, elevated plus maze, tail suspension, and forced swimming tests showed that GAS improved behavioural abnormalities (including anxiety- and depression-like behaviours); it also restored colon length and reduced colonic histopathological injury. Metagenomic sequencing revealed that GAS reshaped the gut microbiota, increasing Sporosarcina and Nitrospirae while decreasing Clostridiaceae and Lachnospiraceae. Untargeted metabolomics indicated that GAS shifted the metabolic profile away from DSS and normalized taurine levels, and KEGG pathway analysis suggested that GAS may partially ameliorate DSS-induced metabolic disturbances by downregulating virulence-related pathways and upregulating energy metabolic pathways such as the TCA cycle and oxidative phosphorylation relative to DSS. Western blot confirmed that GAS restored the tight junction protein Occludin and decreased TNF-α. Quantitative proteomics demonstrated that GAS reversed the aberrant expression of 191 colonic proteins. These results demonstrate correlative associations between GAS treatment and the alleviation of acute colitis and behavioural abnormalities, alongside concurrent changes in gut microbiota composition, metabolite profiles, and intestinal barrier proteins. Whether these associations reflect a causal gut-brain axis mechanism requires direct experimental validation. GAS modulates the microbiota, partially restores metabolism, repairs the gut barrier, and suppresses local inflammation, suggesting a potential gut-brain axis mechanism. These findings position GAS as a promising candidate for further mechanistic and translational investigation in IBD-associated behavioural comorbidities.