Neuroinflammation, HPA Axis Dysregulation, Cytokine Activity and Nutritional Modulation in Depression: A PRISMA-compliant Systematic Review.

BACKGROUND: Depression is increasingly recognized as a multisystem disorder involving interconnected neuroinflammatory, neuroendocrine, metabolic and gut-brain mechanisms rather than isolated neurotransmitter abnormalities. Emerging evidence suggests that dysregulation of cytokine activity, hypothalamic-pituitary-adrenal (HPA) axis function, oxidative stress, mitochondrial dysfunction and gut microbiota collectively contribute to depressive pathophysiology. This review aimed to synthesise current evidence on these biological interactions and evaluate the potential role of nutritional modulation in influencing these pathways. SUMMARY: A PRISMA-informed systematic review was conducted using PubMed, Scopus, Web of Science, Embase, PsycINFO and Google Scholar for studies published between 2010 and 2025. Thirty-five eligible studies were included. The evidence demonstrates a self-reinforcing biological network in which chronic stress activates the HPA axis, leading to glucocorticoid receptor resistance, increased pro-inflammatory cytokines, neuroinflammation, oxidative stress and gut microbiota dysbiosis. These interconnected mechanisms contribute to depressive symptoms and may perpetuate disease progression. Nutritional interventions, including Mediterranean dietary patterns, omega-3 fatty acids, dietary fibre, probiotics, polyphenols and selected micronutrients, consistently showed potential to reduce inflammation, regulate HPA axis activity, improve gut microbial balance and mitigate oxidative stress. KEY MESSAGE: Depression should be conceptualised as a complex multisystem disorder driven by dynamic interactions among immune, endocrine, metabolic and microbiota-related pathways. Nutritional modulation represents a promising adjunctive strategy capable of targeting these interconnected biological mechanisms. Future longitudinal and interventional studies integrating multi-omics approaches are needed to validate causal pathways and develop personalised nutrition-based interventions for depression.