Zuojin Pill ameliorates depression with gastrointestinal dysfunction via Parabacteroides distasonis

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.

This investigation aimed to evaluate the therapeutic potential of ZJP and delineate its mechanistic pathways in alleviating comorbid depressive symptoms and Gastrointestinal (GI) impairments.

A combined clinical observational study and preclinical experimental study was conducted to integrate human and animal data for mechanistic validation.

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.

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.

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.