Shugan Tongbian Decoction ameliorates constipation and mental disorder by inhibiting UPR^mt via Wnt/Retromer axis

The Shugan Tongbian Decoction (SGTBD), a Traditional Chinese Medicine (TCM), has demonstrated potential efficacy in alleviating constipation with anxiety and depression; however, its pharmacological action on functional constipation (FC) with anxiety and depression has received little attention.

FC is increasing, and its course is positively correlated with emotional disorders, which affect the quality of life of patients. We studied brain and intestine protective effects of SGTBD and explored its underlying molecular mechanisms using network pharmacology analyses and experimental validation.

Network pharmacology analyses were performed. SGTBD composition was determined using analytical methods, and its main compounds were identified using high-performance liquid chromatography coupled with mass spectrometry (HPLC- MS). A rat model of FC with anxiety and depression was established using compound diphenoxylate combined with chronic unpredictable mild stress (CUMS) to evaluate SGTBD effects on constipation and behavioral indicators and pathological changes [hematoxylin and eosin (HE), alcian blue stain, periodic acid schiff (AB-PAS) and Nissl staining]. Neurotransmitter testing was performed using an enzyme linked immunosorbent assay (ELISA) for 5-HT. Mitochondrial damage was evaluated using western blotting (WB) and transmission electron microscopy. The impact of SGTBD on the Wnt/retromer pathway was evaluated using WB and quantitative real-time polymerase chain reaction (qRT-PCR).

SGTBD may have pharmacological effects, including the regulation of neurodevelopment and oxidative stress-induced cell apoptosis. SGTBD significantly improved behavioral indicators, reduced constipation, and mitigated pathological damage. It inhibited mitochondrial unfolded protein response (UPR^mt) and enhanced neurotransmitter. qRT-PCR, Transmission electron microscopy (TEM), and WB results revealed that SGTBD could inhibit mitochondrial damage by repairing mitochondrial structures, with the Wnt/Retromer signaling pathway playing a key role in this process.

SGTBD regulates the balance between brain and gut UPR^mt. It reduces mitochondrial damage and is associated with restoring the levels of the Wnt/Retromer pathway. This improved the mitochondrial structures of the brain-gut axis, providing multifaceted protective effects in FC rats with anxiety and depression. This study provides a new perspective on the development of protective measures and the prevention of constipation in patients with emotional disorders and diseases in daily life.