The Gut-Brain Axis in Comorbidity of Inflammatory Bowel Disease and Anxiety/Depression: Mechanisms, Controversies, and Future Directions

Inflammatory bowel disease (IBD), including Crohn’s disease (CD), ulcerative colitis (UC), and IBD unclassified (IBD-U), frequently cooccurs with anxiety and depression, a comorbid pattern that severely impairs patients’ quality of life and has thus attracted increasing attention in clinical practice. The gut-brain axis (GBA)—an intricate bidirectional communication network encompassing neural, immune, endocrine, and microbial pathways—serves as a key framework for unraveling the biological underpinnings of this comorbidity. This review systematically synthesizes existing literature to dissect the GBA mechanisms driving IBD-anxiety/depression comorbidity, focusing on four core inflammatory pathways: immune inflammation, gut microbiota-metabolite interactions, neural signaling, and the hypothalamic-pituitary-adrenal (HPA) axis. We also critically examine ongoing research controversies in inflammopharmacology and propose future breakthrough directions grounded in current evidence. Our synthesis reveals that these four pathways form a self-reinforcing inflammatory vicious cycle: intestinal inflammation may disrupt central nervous system (CNS) function through proinflammatory factors, microbiota-derived metabolites, and neural signals, thereby contributing to emotional disorders. Conversely, psychological stress and negative emotions may exacerbate intestinal inflammation via neural and endocrine pathways. Key controversies include unresolved causal relationships between IBD and emotional disorders, debates over dominant regulatory mechanisms, poor reproducibility of gut microbiota studies, and variable efficacy of single-target anti-inflammatory interventions. Moving forward, future research should leverage longitudinal cohort designs, advanced omics technologies, and artificial intelligence tools to deepen mechanistic insights. Developing multi-target anti-inflammatory interventions and robust biomarker systems will facilitate integrated gastroenterological and psychiatric care, enabling precise diagnosis and treatment to enhance patients’ physical and mental rehabilitation.