The Role of Astrocytes in Inflammatory Bowel Disease and Co-occurring Depression: Mechanisms and Perspectives

In patients with inflammatory bowel disease (IBD), a high prevalence of comorbid major depressive disorder (MDD) has been observed. The two conditions also appear to show bidirectional clinical exacerbation. The classical gut-brain axis framework has not yet identified the specific molecular or cellular mediator that links peripheral intestinal inflammation to central mood dysfunction. Emerging evidence suggests that astrocytes might bridge this gap. In IBD, gut dysbiosis and peripheral inflammation propagate signals to the brain via humoral, neural, and endocrine pathways. These signals may promote astrocytic reactivity, possibly shifting the cells toward a reactive state with A1-like features. Such reactive astrocytes exhibit impaired glutamate clearance, compromised blood-brain barrier (BBB) integrity, disrupted energy support, diminished neurotrophic factor secretion, and sustained neuroinflammation. These deficits may lead to excitotoxicity, synaptic dysfunction, and destabilization of mood-regulating circuits, contributing to depressive-like behaviors. Astrocytes may also influence intestinal processes through the release of extracellular vesicles and interactions with enteric glial cells. This bidirectional communication could contribute to a potential self-reinforcing gut-brain-gut cycle. This review synthesises current evidence on astrocyte-mediated mechanisms in IBD and MDD comorbidity and outlines a framework for this bidirectional relationship. In IBD, gut dysbiosis and peripheral inflammation can propagate signals to the brain via humoral, neural, and endocrine pathways. These signals may promote astrocytic reactivity with complement component 3 (C3)-associated A1-like features, affecting glutamate homeostasis and energy support. These changes may contribute to altered synaptic and neuronal function relevant to depressive pathology, while efferent autonomic and hypothalamic-pituitary-adrenal (HPA)-axis signaling may further influence intestinal inflammation.