Integrating gene expression, neurochemical signatures, and neurocognitive profiles to decode cortical reorganization in IBS-D

Irritable bowel syndrome with diarrhea (IBS-D) is characterized by persistent gastrointestinal symptoms and marked alterations in brain structure. This study aimed to explore the neurobiological mechanisms that may link these structural changes to the disorder. We investigated hierarchical cortical organization in 31 IBS-D patients and 35 healthy controls (HCs) using morphometric similarity (MS) gradients derived from structural MRI features. Imaging-correspondence analyses were used to decode IBS-D related MS gradient changes with gene expression, neurotransmitter systems, and cognitive functions. Compared to HCs, IBS-D patients exhibited reduced MS gradients in limbic and temporal regions (e.g., entorhinal cortex, superior temporal gyrus) and elevated gradients in fronto-parietal areas (e.g., precuneus, rostral middle frontal cortex). These gradient alterations were spatially correlated with genes enriched for immune response pathways and neurotransmitter systems, including dopamine D2, serotonin 5-HT1a/1b, and GABAa receptors (adjusted R² = 0.38, p_spin = 0.046). Furthermore, gradient shifts overlapped with brain activation patterns linked to emotional regulation (e.g., valence, arousal) and attentional processes (p_FDR < 0.05). Our findings reveal that cortico-limbic gradient reorganization in IBS-D reflects interactions among immune-related genetic pathways and neurotransmitter dysregulation, providing novel targets for interventions addressing brain-gut axis disruptions.