Beyond the gut: neuroinflammation as a driver of anxiety and depression in inflammatory bowel disease

Abstract

Anxiety and depression frequently co-occur with inflammatory bowel disease (IBD), with prevalence rates substantially higher than in the general population. Emerging evidence further indicates that active IBD is associated with more severe psychological symptoms, while anxiety and depression can worsen intestinal inflammation, highlighting a bidirectional relationship. Chronic intestinal inflammation is increasingly recognized as a driver of neuroinflammation, a key mechanism underlying mood disorders. In IBD, disruption of the intestinal epithelial barrier permits metabolites and enteric signaling molecules to enter the circulation, triggering systemic inflammation and crossing the more permeable blood–brain barrier (BBB) to promote neuroinflammation. Other relevant components of the gut–brain axis contributing to IBD-associated neuroinflammation include the enteric nervous system, vagus nerve (VN), hypothalamic–pituitary–adrenal (HPA) axis, and tryptophan-kynurenine metabolism. Within the brain, neuroinflammation characterized by glial activation, inflammatory mediator release, and oxidative stress disrupts neurogenesis and synaptic plasticity in regions such as the hippocampus and prefrontal cortex, contributing to anxiety and depression. Conversely, anxiety and depression can amplify systemic inflammation through dysregulation of the VN and HPA axis, thereby exacerbating IBD. This reciprocal interaction adversely affects disease severity, quality of life, and therapeutic outcomes, underscoring the need to better define its underlying mechanisms. The present review synthesizes current clinical, translational, and experimental evidence on the bidirectional crosstalk between IBD and mood disorders. We also highlight key knowledge gaps, future research directions to identify the cellular and molecular mediators of this interaction, and emerging therapeutic strategies for the integrated management of both conditions.