Phosphoproteomic profiling reveals post-translational dysregulation in Huntington's disease patient-derived neurons.

Depression is one of the most prevalent and disabling mental disorders worldwide and is a major contributor to global disease burden and mortality []. Recent estimates suggest that approximately 350 million people are affected globally, with prevalence continuing to rise across diverse populations []. Depression increases the risk of suicidal ideation, suicide attempts, and premature death, and remains a leading cause of disability worldwide []. In addition to its core psychiatric symptoms, depression markedly impairs quality of life (QOL), worsens physical comorbidities, and imposes a substantial socioeconomic burden on individuals and healthcare systems [–]. Despite extensive research, its etiology remains multifactorial and incompletely understood, highlighting the need to identify modifiable risk factors and comorbid conditions that may contribute to its onset and progression. Chronic constipation is among the most common functional gastrointestinal (GI) disorders and is typically characterized by infrequent bowel movements, difficult or painful defecation, and a sensation of incomplete evacuation [, ]. Its prevalence varies across populations but is generally high, particularly among adults and older individuals. Constipation not only causes persistent physical discomfort but also disrupts daily functioning, psychological well-being, and social participation, leading to increased healthcare utilization and reduced QOL [–]. Accumulating clinical evidence further suggests that constipation is frequently accompanied by psychological distress, raising the possibility of a clinically meaningful association with depression []. One biologically plausible framework linking constipation and depression is the gut–brain axis, a bidirectional communication network that integrates neural, immune, endocrine, and metabolic pathways between the GI tract and the central nervous system [–]. Disturbances in gut function and intestinal homeostasis may influence emotional regulation and cognitive processes, whereas psychological stress and mood disorders may in turn affect GI motility and secretion [–]. Consistent with this concept, dysregulation of the gut–brain axis has increasingly been implicated in both functional GI disorders and mood disorders, particularly depression [–]. Clinical observations also indicate that individuals with functional bowel disorders frequently exhibit comorbid depressive symptoms, supporting the presence of shared or interacting pathophysiological mechanisms [, –]. Importantly, however, the relationship between constipation and depression may be bidirectional: constipation-related disturbances in gut function may contribute to depressive symptoms, whereas depression itself may also promote constipation through behavioral changes, altered diet, reduced physical activity, autonomic dysregulation, and neuroendocrine pathways.