Tiffany C Ho, Gabriel A Vignolle, Danny J J Wang, Arpana Church
Inflammation has emerged as a compelling causal contributor to depression, serving both as a biological pathway underlying specific depressive symptoms (notably anhedonia, fatigue, and cognitive difficulties) and as a defining feature in a subtype of this disorder characterized by elevated levels of circulating cytokines. Understanding when and how immune dysfunction results in depression within clinical trials is needed to advance biomarker-guided clinical research and to accelerate novels treatments for those suffering from depression. In this context, gut microbes and intestinal epithelial barrier (IEB) integrity directly influence systemic cytokine levels and peripheral immune activation-these immune signals, in turn, modulate neural circuits involved in mood, reward, and stress reactivity through several pathways. Many of these signals converge on the blood-brain barrier (BBB), the permeability of which regulates the entry of peripheral cytokines and immune cells into the central nervous system and consequently shapes neuroinflammatory responses that contribute to depressive symptoms. In this narrative review, we contend that immune-gut-brain system is critical for understanding mechanisms and potential treatments for inflammatory depression. We synthesize evidence linking inflammation to IEB and BBB permeability, summarize barrier biomarkers relevant for depression, and highlight future directions of research that focus on fortifying dual barrier dysfunction as a novel intervention target for inflammatory depression. By considering the inflammatory mechanisms that shape IEB and BBB integrity, the field will be positioned to identify upstream drivers of these sources of inflammation, refine mechanistic models of transdiagnostic symptoms relevant to inflammation (anhedonia, fatigue, executive dysfunction), and develop more targeted or personalized intervention strategies for those suffering from these conditions.