BACKGROUND: Brain-gut interaction disorders, such as functional dyspepsia (FD) comorbid with depression, are highly prevalent and severely affect patients' quality of life; however, the underlying mechanisms remain incompletely understood, and effective therapeutic options are still limited. Zuojin Pill (ZJP), a classic Chinese herbal formula, has shown potential in treating both gastrointestinal disorders and depressive symptoms, but its role in FD-depression comorbidity and underlying mechanisms remain unclear.
PURPOSE: This investigation aimed to evaluate the therapeutic potential of ZJP and delineate its mechanistic pathways in alleviating comorbid depressive symptoms and Gastrointestinal (GI) impairments.
STUDY DESIGN: A combined clinical observational study and preclinical experimental study was conducted to integrate human and animal data for mechanistic validation.
METHODS: Baseline assessments were conducted in healthy controls and patients with functional dyspepsia (FD)-depression comorbidity, including evaluations of gut microbiota composition, metabolite profiles, inflammatory cytokines, gastrointestinal hormones, and serotonin (5-HT) levels. An animal model using mice was developed to assess the efficacy of ZJP in addressing depression-related phenotypes and GI functional deficits. Furthermore, Parabacteroides distasonis was used to induce pathological features in mice, and the intervention effects of ZJP were systematically assessed.
RESULTS: Patients with FD-depression comorbidity exhibited gut microbiota dysbiosis, characterized by a significant increase in P. distasonis abundance. Metabolomic analysis highlighted tryptophan metabolism as a key altered pathway. In model mice, ZJP administration alleviated depression-like behaviors and gastrointestinal dysfunction. Mechanistically, ZJP targeted P. distasonis, regulated tryptophan-derived metabolites, enhanced anti-inflammatory cytokine expression, improved synaptic plasticity, and restored intestinal mucosal barrier integrity.
CONCLUSIONS: ZJP ameliorates depression with gastrointestinal dysfunction by modulating P. distasonis and its associated tryptophan metabolic pathway, thereby restoring gut-brain axis homeostasis. These results establish a mechanistic foundation supporting the therapeutic use of ZJP in treating brain-gut interaction disorders.
