Irritable bowel syndrome (IBS) associated with early-life stress (ELS) commonly manifests as anxiety and visceral hypersensitivity. However, the pathogenic mechanisms underlying these effects are not Show more
Irritable bowel syndrome (IBS) associated with early-life stress (ELS) commonly manifests as anxiety and visceral hypersensitivity. However, the pathogenic mechanisms underlying these effects are not fully understood. This study aims to investigate the role of brain-derived neurotrophic factor (BDNF) as a key mediator of ELS-induced changes through the brain-gut axis. A Sprague-Dawley male maternal separation (MS) rat model was used to induce anxiety and visceral hypersensitivity associated with ELS. BDNF levels were measured in the limbic system (cingulate gyrus, amygdala, and hippocampus) and serum. The correlation between BDNF levels, anxiety, and visceral hypersensitivity was analyzed. Corticotropin-releasing factor (CRF) expression in the hippocampus and the extent of visceral hyper-sensitivity were assessed in control, MS, and MS+K252a (a BDNF receptor antagonist) groups. MS rats exhibited higher levels of anxiety and visceral hypersensitivity compared to controls. BDNF production in the hippocampus was elevated in MS rats and positively correlated with anxiety (r = -0.78, p < 0.05) and visceral hypersensitivity (r = 0.93, p < 0.01). CRF expression, a key mediator of stress and visceral hypersensitivity, was also increased in the hippocampus of MS rats. Inhibition of BDNF signaling using K252a reduced CRF expression and alleviated visceral hypersensitivity. This study demonstrates that BDNF may mediate ELS-induced anxiety and visceral hypersensitivity through hippocampal TrkB-CRF signaling, providing a mechanistic basis for targeting BDNF in stress-related IBS. Show less
Tianwang Buxin Dan (TWBXD) is a classical Chinese formula traditionally prescribed to "nourish Yin, calm the mind and relieve bowel stagnation" in disorders characterized by heart-kidney disharmony, i Show more
Tianwang Buxin Dan (TWBXD) is a classical Chinese formula traditionally prescribed to "nourish Yin, calm the mind and relieve bowel stagnation" in disorders characterized by heart-kidney disharmony, insomnia, anxiety, and constipation. However, the mechanistic basis associating its gut-regulating and emotion-modulating effects along the gut-brain axis remains unclear. To investigate whether TWBXD ameliorates functional constipation comorbid with emotional disturbances by modulating mitogen-activated protein kinase/Extracellular Signal-Regulated Kinase/c-Jun N-terminal Kinase (MAPK/ERK/JNK) signaling, hypothalamic-pituitary-adrenal (HPA)-axis activity, and autophagy-related mitochondrial integrity in the colon and hippocampus. A diphenoxylate-induced rat model of functional constipation with anxiety/depression-like behavior was treated with low, medium, or high doses of TWBXD. Intestinal transit, fecal parameters, and distal colonic transit were also assessed. Emotional behaviors were evaluated using open-field and elevated plus-maze tests. Colonic and hippocampal histopathology and ultrastructure were examined using hematoxylin and eosin staining, Nissl staining, and transmission electron microscopy. Serum corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH), and corticosterone (CORT) levels were measured using enzyme-linked immunosorbent assay. MAPK/ERK/JNK-related proteins and brain-derived neurotrophic factor (BDNF) were analyzed by Western blotting. The major chemical constituents of TWBXD were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry(UHPLC-MS/MS). TWBXD dose-dependently improved intestinal transit, fecal moisture, and body weight gain, and alleviated anxiety-/depression-like behaviors. TWBXD preserved colonic mucosal architecture and hippocampal neuronal integrity, mitigated mitochondrial swelling and excessive autophagic vacuole formation, downregulated colonic phosphorylated ERK (p-ERK), phosphorylated JNK, and phosphorylated p38, restored hippocampal BDNF expression while normalizing p-ERK levels, and reduced serum CRF, ACTH, and CORT levels. TWBXD exerts multi-target therapeutic effects on functional constipation with emotional disturbances by suppressing MAPK/ERK/JNK overactivation, normalizing HPA-axis hyperactivity, and protecting mitochondrial structure and autophagy along the gut-brain axis, providing mechanistic support for its traditional use in gut-brain-related disorders. Show less