Meranzin hydrate from Fructus Aurantii restores brain-gut homeostasis through a microbiota-dependent butyrate-ghrelin axis

Although gut microbiota-derived metabolites are increasingly implicated in host neuroendocrine regulation, it remains unresolved whether an orally delivered botanical can restore coordinated brain–gut homeostasis through a functionally supported microbiota-metabolite-endocrine pathway centered on a content-anchored, brain-accessible constituent. Here, using content-anchored pharmacometry in a chronic unpredictable mild stress (CUMS) model of depression with gastrointestinal (GI) hypomotility, we identified meranzin hydrate (MH) as the only absorbed prototype of Fructus Aurantii (FRA) detected in the brain and showed that, at its content-anchored dose, MH reproduced the major antidepressant-like and prokinetic effects observed with the parent botanical. Integrating 16S rRNA profiling, short-chain fatty acid (SCFA) quantification, plasma ghrelin, antagonist mapping, resting-state fMRI, serum-equivalent assays, and cross-tissue transcriptomics showed that MH reversed stress-disrupted microbial ecology, restored fermentative output, particularly butyrate, and re-established coupling between microbial metabolic function, circulating ghrelin, and synchronized brain-gut phenotypes. To directly test microbiota dependency, broad-spectrum antibiotic-mediated microbiota depletion was introduced, which markedly attenuated MH-associated recovery of SCFA output, plasma ghrelin levels, depressive-like behavior, and GI motility. Importantly, exogenous sodium butyrate did not restore bacterial biomass but partially rescued ghrelin levels and downstream phenotypes under microbiota-depleted conditions, supporting a microbiota-dependent butyrate-ghrelin mechanism rather than a purely correlative ecological association. Downstream, GHSR1a blockade disrupted this recovery hierarchy, whereas transcriptomic convergence analysis identified a shared contractile-immune host response program across the hippocampus and stomach. Collectively, these findings identify MH as a pharmacologically important, content-anchored contributor to FRA efficacy and provide functional perturbation-and-rescue evidence supporting a microbiota-dependent butyrate-ghrelin interface that contributes to coordinated brain-gut recovery under chronic stress.