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

Abstract

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.

Introduction

Depression is a complex, heterogeneous psychiatric disorder and one of the leading contributors to global disability, affecting an estimated 280 million individuals worldwide (WHO, 2023). ¹ Traditionally conceptualised through a monoamine neurotransmitter framework, depression is now recognised as a multisystem condition extending far beyond serotonin or dopamine imbalance. Over the past two decades, accumulating evidence has shown that depressive disorders arise from dynamic interactions across neuroimmune, neuroendocrine, metabolic and gut–brain regulatory systems. This complexity partly explains why conventional antidepressants, which primarily target monoaminergic pathways, result in partial or delayed responses in a substantial proportion of patients and do not address the underlying biological dysregulation. Thus, understanding depression requires a broader, integrative biological model.

Neuroinflammation as a Basic Mechanism

One of the most consistently implicated biological pathways in depression is neuroinflammation, which is driven mainly by the activation of microglia. Subjects with MDD usually have increased peripheral and central inflammatory markers—specifically, IL-6, TNF-α, IL-1β and C-reactive protein—which relate to symptom severity, resistance to treatment, anhedonia and cognitive impairment.^{2, 3} The microglia that are activated by stress, pathogens, or metabolic imbalance produce pro-inflammatory cytokines, which disturb neuroplasticity, alter glutamatergic signalling, reduce hippocampal neurogenesis and impair synaptic connectivity—all characteristic features in depressive pathology. Prolonged neuroinflammation may also compromise the integrity of the blood–brain barrier, allowing peripheral immune signals to enhance central inflammation and neuronal dysfunction further.

Hypothalamic–Pituitary–Adrenal Axis Dysregulation and Glucocorticoid Resistance

Closely interconnected with neuroinflammation is the dysregulation of the hypothalamic–pituitary–adrenal (HPA) axis, the body’s main stress response system. Chronic stress—whether psychosocial, environmental or physiological in nature—drives repeated activation of the HPA axis, leading to sustained elevations in corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and cortisol. While cortisol normally suppresses inflammation, prolonged exposure induces glucocorticoid receptor (GR) resistance, diminishing the anti-inflammatory effects of cortisol. This state of paradox—one in which cortisol is high but ineffective—allows for the perpetuation of inflammatory signalling.^{4, 5} Dysregulation of cortisol negative feedback also leads to structural and functional changes in the hippocampus, amygdala and prefrontal cortex, which are implicated in mood, memory and emotional regulation.

Cytokine-mediated Feedback Loops

A major discovery in psychoneuroimmunology is the existence of bidirectional, self-reinforcing feedback loops between cytokines and the HPA axis. Pro-inflammatory cytokines stimulate CRH and ACTH secretion, increasing cortisol output accordingly. Due to GR resistance, cortisol cannot downregulate cytokine production in cases of depression, initiating a pro-inflammatory cycle whereby neuroinflammation and neuroendocrine dysfunction mutually reinforce each other. This cytokine-HPA loop helps explain chronicity, relapse, cognitive deficits and somatic symptoms in depressive disorders.

Mitochondrial Dysfunction, Oxidative Stress and Metabolic Imbalance

It is also related to mitochondrial impairment, oxidative stress and metabolic dysregulation. The increased cytokines and chronic cortisol exposure enhance reactive oxygen species (ROS), thus impacting negatively on ATP production, neuronal iron metabolism and furthering changes in cellular resilience. ⁶ Further, oxidative stress activates inflammatory pathways, increasing microglial activation and perpetuating neuroinflammation. These mechanisms relate to metabolic disorders such as obesity, diabetes and chronic inflammatory disease comorbidities among those with MDD.

Gut–Brain–Microbiota Axis Disturbances

A growing body of literature places the gut–brain axis as a major modulator of mood and inflammation. Dysbiosis, or imbalanced gut microbiota, can promote intestinal permeability (‘leaky gut’), facilitate translocation of lipopolysaccharides, increase systemic cytokines and activate the HPA axis. Microbial metabolites like short-chain fatty acids (SCFAs), tryptophan metabolites, bile acids and precursors of neurotransmitters modulate neuroinflammation, neurogenesis and the responsivity to stress.^{7, 8} Furthermore, sleep disruption, circadian misalignment and early-life nutrition also contribute to the moulding of the microbiome and make individuals vulnerable to depression, underlining the complex interplay between biological and lifestyle causes.

Nutrition as a Modifiable Biological Influence

Emerging evidence from nutritional psychiatry shows that dietary pattern variations have significant effects on inflammation signalling, oxidative stress, the composition of the microbiome and HPA axis regulation. Diets high in processed food, refined sugars and saturated fats are associated with elevated inflammatory cytokines, disrupted redox balance and a higher risk of developing depression. Conversely, anti-inflammatory dietary regimens—such as the Mediterranean, whole-food or high-fibre dietary patterns—promote microbiome diversity, decrease CRP and IL-6 levels, optimise mitochondrial function and favourably modify stress reactivity. Nutrients of note include Omega-3 fatty acids, polyphenols, vitamins B and D, probiotics and minerals, which have all been identified to exert regulatory functions on both inflammatory and endocrine pathways.^{9, 10}

Need for an Integrative Synthesis

Despite abundant evidence from various disciplines, research remains fragmented. Neuroinflammation, HPA axis dysfunction, cytokine signalling, mitochondrial stress and nutritional influences are examined in isolation in many instances. What remains unclear is how these mechanisms integrate—whether they form a single, unifying feedforward loop contributing to the onset and maintenance of depressive symptoms—and how nutrition may modulate or interrupt these biological cycles.

Thus, a comprehensive synthesis is required for:

• Map interconnected biological pathways that drive depression.

• Evaluate evidence for self-sustaining neuroimmune and neuroendocrine loops and

• Explain the use of nutrition as a biological intervention.

This review therefore satisfies this need through its analysis of current evidence, from 2010 to 2025, on the interplay of neuroinflammation, cytokines, disturbances within the HPA axis, mitochondrial and metabolic pathways, the gut–brain axis and nutritional elements in depression.

Materials and Methods

This review employed a PRISMA-informed hybrid methodology, combining systematic search procedures with a narrative synthesis appropriate for the interdisciplinary and rapidly expanding literature on neuroinflammation, cytokine activity, HPA axis dysregulation, oxidative stress, gut–brain communication and nutritional modulation in depression. While the review followed PRISMA 2020 guidelines for transparency and reproducibility, methodological flexibility was maintained due to the conceptual diversity of biological, psychological and nutritional research spanning psychoneuroimmunology, neuroscience, endocrinology and nutritional psychiatry.

Although this review followed PRISMA 2020 guidelines for systematic search and transparent reporting, the objective of this study was integrative and conceptual rather than effect-size estimation. Therefore, the review is best characterised as a systematic narrative review with thematic synthesis, rather than a meta-analysis or purely quantitative systematic review.

Search Strategy

A comprehensive search was conducted across six electronic databases: PubMed, PsycINFO, Scopus, Web of Science, Embase and Google Scholar. Searches were carried out between November 2024 and January 2025.

The search strategy was built around five conceptual clusters:

1. Depression and mood disorders

2. Neuroinflammation and cytokine activity

3. HPA axis and glucocorticoid dysregulation

4. Oxidative stress, mitochondrial pathways and metabolic biomarkers and

5. Nutrition, diet and gut–brain axis modulators.

Example Search String (PubMed)

‘depression’ OR ‘major depressive disorder’ OR ‘MDD’

AND

‘neuroinflammation’ OR ‘microglia’ OR ‘cytokines’ OR ‘IL-6’ OR ‘TNF-alpha’ OR ‘immune activation’

AND

‘HPA axis’ OR ‘cortisol’ OR ‘GR’ OR ‘CRH’ OR ‘ACTH’

AND

‘oxidative stress’ OR ‘mitochondrial dysfunction’ OR ‘ROS’

AND

‘nutrition’ OR ‘diet’ OR ‘omega-3’ OR ‘probiotics’ OR ‘anti-inflammatory diet’ OR ‘gut–brain axis’.

Reference lists of included studies, systematic reviews and meta-analyses were manually screened to identify additional relevant articles. Citation chaining was used for high-impact papers to capture emerging research.

Inclusion and Exclusion Criteria

Inclusion Criteria

Studies were eligible if they met the following criteria:

• Empirical human or animal studies examining depression or depressive-like phenotypes.

• Research assessing at least one biological pathway relevant to this review: neuroinflammation, cytokine activity, HPA axis function, oxidative or mitochondrial stress, gut microbiota, metabolic biomarkers or nutrition-related mechanisms.

• Studies linking these biological pathways to depressive symptoms, mood behaviour or relevant psychological outcomes.

• Peer-reviewed publications written in English between 2010 and 2025.

Exclusion Criteria

Studies were excluded if:

• They did not directly assess depression or depressive biomarkers.

• They focused on other psychiatric or neurological disorders without mood relevance.

• They lacked biological outcome measures (e.g., purely psychological interventions).

• They were commentaries, reviews, book chapters, conference abstracts or editorials (although used for conceptual background).

• Nutritional studies not reporting inflammatory, endocrine or metabolic biomarkers were excluded.

Screening and Selection

The initial search produced 3,218 records. After removing duplicates (n = 2,076), the remaining 1,142 titles and abstracts were screened for relevance. A total of 974 records were excluded during screening for not meeting the inclusion criteria.

Full texts were retrieved for 168 articles, of which 133 were excluded because they lacked biological markers, did not examine depression, or did not include nutrition- or HPA-related mechanisms.

A final set of 35 empirical and mechanistic studies met the criteria for inclusion. These studies represented research across psychoneuroimmunology, neuroendocrinology, stress physiology, nutritional neuroscience and gut–brain axis science.

A PRISMA flow description summarising the selection process was developed for transparency and shown in Figure 1.

Figure 1. PRISMA Flowchart of Selection Process.

Data Extraction

A structured extraction matrix was created to collect standardised information from each study. Extracted variables included:

• Study design, country and year.

• Sample characteristics (population type, demographics, clinical status).

• Biological systems examined (e.g., cytokines, cortisol, oxidative stress markers, mitochondrial indices, microbiome composition).

• Laboratory or analytical methods (e.g., ELISA, 16S rRNA sequencing, cortisol assays, metabolomics).

• Nutritional or dietary variables (Omega-3 intake, fibre, probiotics, dietary pattern).

• Behavioural or psychological outcomes (depressive symptoms, stress indicators).

• Key results relevant to neuroinflammatory–HPA–nutritional pathways.

Data were independently reviewed by two researchers to ensure reliability, and disagreements were resolved through discussion.

Synthesis Approach

Given the heterogeneity in study designs and outcome variables, a quantitative meta-analysis was not feasible. Instead, a narrative thematic synthesis approach was adopted. Findings were organised across major interconnected domains:

• Neuroinflammatory markers and microglial activation.

• Cytokine dynamics and systemic immune signalling.

• HPA axis activity and glucocorticoid resistance.

• Oxidative and mitochondrial stress.

• Gut–brain microbiota pathways.

• Nutritional modulation of biological systems.

It also conceptually drew on the biopsychosocial model of illness, ¹¹ psychoneuroimmunology frameworks, stress system allostasis models and microbiota–gut–brain axis theories. ¹² This integrative approach placed the review’s biological findings into broader metabolic, psychological and environmental contexts relevant to depression.

Reflexivity and Researcher Positioning

The authors position themselves consistent with the best practice of contemporary interdisciplinary psychological and biological research. Academic backgrounds include training in psychology, neuroscience, psychoneuroimmunology and nutritional science. Our understanding of the literature is framed by an allegiance to integrative, non-reductionist and biopsychosocial analyses of mental health. We sought to avoid deterministic thinking about biological mechanisms and to place processes within environmental, lifestyle and psychosocial contexts. The synthesis was informed by an awareness of biological essentialism’s limitations and the need for interpreting findings in a way that acknowledges depression as a multifactorial disorder.

In all, 35 studies met inclusion criteria, covering psychoneuroimmunology, neuroendocrinology, microbiome research, stress physiology, oxidative stress biology and nutritional psychiatry. Taken together, findings from these studies point toward a multidirectional, self-reinforcing feedback loop in which neuroinflammation, cytokine signalling, HPA axis dysregulation, mitochondrial oxidative stress and gut–brain communication are interrelated in the pathophysiology of depression. A number of these studies also showed that nutrition meaningfully modulates these pathways, supporting a potential role of adjunctive dietary interventions in depression.

Quality Assessment

The methodological quality of included studies was assessed using appropriate criteria depending on study design (e.g., observational studies, mechanistic studies and reviews). Factors considered included sample characteristics, biomarker measurement validity, control of confounders and clarity of methodology. Given the heterogeneity of study designs, a formal pooled risk-of-bias score was not calculated; however, methodological rigour was considered during thematic synthesis and interpretation of findings.

Results

When synthesised, the included studies reveal a convergent biological pattern:

Stress ↓ HPA activation ↓ cortisol elevation ↓ glucocorticoid resistance ↓ cytokine elevation ↓ neuroinflammation ↓ mitochondrial stress ↓ gut microbiome disturbance ↓ further HPA axis dysregulation.

Nutrition interacts with this loop by modifying inflammation, metabolic function and gut–brain communication.

Table 1 presents the characteristics of the studies included in this review, including study design, population characteristics, biological systems examined and key findings. The included studies represent a range of methodological approaches, including empirical studies, mechanistic investigations and systematic or narrative reviews, reflecting the interdisciplinary nature of research on neuroinflammation, HPA axis dysregulation, oxidative stress, gut–brain axis mechanisms and nutritional modulation in depression.

Table 1. Characteristics of Included Studies (Condensed Summary).

Reference	Study Design	Population/Sample	Biological Focus/Biomarkers	Key Findings
Sălcudean et al. 3	Review	Patients with depression	Neuroinflammation, IL-6, TNF-α	Elevated inflammatory cytokines and microglial activation are associated with depression
Kim et al. 24	Mechanistic/experimental	Animal and human models	Cytokines, glucocorticoid receptor (GR)	Cytokines impair GR function and reinforce inflammation and HPA dysregulation
Gold 5	Review	Depressive disorders	HPA axis, cortisol	Chronic cortisol exposure leads to glucocorticoid resistance and mood symptoms
Pariante 4	Conceptual/review	Depression patients	Glucocorticoid receptor, cortisol	GR resistance contributes to prolonged inflammation in depression
Lei et al. 13	Mini-review	Depression patients	IL-6, Hippocampus, HPA feedback	Elevated IL-6 is associated with hippocampal atrophy and HPA feedback disruption
Liu et al. 6	Mechanistic	Animal/cellular models	ROS, mitochondria, oxidative stress	Mitochondrial dysfunction and ROS amplify neuroinflammatory cycles
Alberti et al. 14	Narrative review	Obesity and depression	Adipocytokines, IL-6	Obesity-related inflammation disrupts HPA regulation and increases depression risk
Reyes-Martínez et al. 7	Review	Gut microbiota and depression	Microbiota, cytokines	Dysbiosis increases systemic inflammation and stress reactivity
Rusch et al. 15	Review	Gut–brain axis studies	CRH, cortisol, microbiota	Gut microbiota influence HPA axis regulation and stress response
Marx et al. 9	Mechanistic review	Nutrition and depression	Diet, cytokines, oxidative stress	Diet modulates inflammation, oxidative stress and mood
Borsini 10	Narrative review	Depression	Neuroinflammation, nutrition	Nutrition regulates inflammatory and HPA pathways

Endocrine pathways also took centre stage. Conceptual and theoretical analyses by Pariante ⁴ and Gold ⁵ demonstrated how chronic cortisol exposure and GR resistance disrupt the stress-regulatory feedback loops within the HPA axis and promote prolonged depressive symptomatology. This view easily corresponds with empirical observations by Lei et al., ¹³ who also reported associations between elevated IL-6, hippocampal atrophy and disrupted HPA feedback, further linking inflammatory markers to structural brain changes in depression.

Oxidative and metabolic mechanisms were represented in studies, ⁶ which outlined the role of mitochondrial dysfunction and ROS in amplifying neuroinflammation. Similarly, Alberti et al. ¹⁴ investigated how obesity-associated adipocytokines increase IL-6 levels, thereby disrupting the HPA regulatory system and thus interacting with metabolic health to influence depressive vulnerability.

Another critical domain became the gut–brain axis, ⁷ which reported that dysbiosis increases systemic levels of cytokines and heightens stress reactivity, while Rusch ¹⁵ described how gut microbiota modulate CRH and cortisol release, linking microbial signalling to endocrine stress responses.

The evidence for a role of dietary patterns and specific nutrients in modulating inflammatory cascades, oxidative stress and HPA axis reactivity emerged from such nutrition-focused studies.^{9, 10} These findings underlined the integrative role of diet in influencing multiple biological pathways relevant to depression.

Together, the studies in Table 2 represents a wide-ranging and interlinked corpus of evidence that depression results from multisystemic dysregulation. There is strong thematic convergence despite methodological differences: inflammation, HPA axis dysfunction, oxidative imbalance, metabolic disturbance and microbiota alterations together contribute to depressive symptoms, while nutrition offers a modifiable means of influencing these processes.

Table 2. Conceptual Integration of Biological Mechanisms in Depression Based on Synthesised Evidence.

Biological System	Key Mechanisms	Interaction with Other Systems	Evidence Across Studies	Implications for Depression
Neuroinflammation	Elevated IL-6, TNF-α, IL-1β; microglial activation; blood–brain barrier disruption	Activates HPA axis; increases oxidative stress; influenced by gut microbiota and diet	Multiple studies report elevated inflammatory markers in depression	Alters neurotransmission, reduces neurogenesis, contributes to cognitive impairment and mood dysregulation
Cytokine–HPA axis feedback loop	Cytokines stimulate CRH and ACTH, cortisol elevation and glucocorticoid receptor resistance	Reinforces inflammation; interacts with oxidative stress and gut microbiota pathways	Evidence shows a bidirectional relationship between inflammation and HPA axis activity	Creates chronic stress response and self-reinforcing inflammatory cycle
HPA axis dysregulation	Chronic cortisol elevation; impaired negative feedback; glucocorticoid receptor resistance	Promotes inflammation; affects gut microbiota; increases oxidative stress	Studies show hypercortisolism and impaired feedback in depression	Associated with mood symptoms, fatigue, memory impairment and stress sensitivity
Oxidative stress and mitochondrial dysfunction	Increased ROS; mitochondrial impairment; reduced ATP production	Enhances inflammation; worsens HPA dysregulation; linked with metabolic disorders	Studies show oxidative imbalance and mitochondrial dysfunction in depression	Leads to neuronal vulnerability, fatigue, cognitive dysfunction and inflammatory activation
Gut–brain axis and microbiota	Dysbiosis; increased gut permeability; altered SCFAs; LPS translocation	Increases cytokines; activates HPA axis; influenced by diet and stress	Growing evidence linking microbiota composition with depression and stress reactivity	Alters stress response, neurotransmitter synthesis and inflammatory signalling
Nutrition and dietary factors	Anti-inflammatory diet; omega-3; polyphenols; probiotics; vitamins	Modulates inflammation, oxidative stress, gut microbiota and HPA axis	Nutritional psychiatry studies show that diet influences depression risk and biological pathways	Acts as a modifiable factor that can regulate biological systems involved in depression

Table 2 presents a conceptual integration of the major biological mechanisms implicated in depression based on synthesised evidence across the included studies. Rather than representing findings from a single empirical study, this table summarises converging evidence from multiple research domains, including psychoneuroimmunology, neuroendocrinology, oxidative stress biology, microbiome research and nutritional psychiatry. The table illustrates how neuroinflammation, HPA axis dysregulation, oxidative stress, gut–brain axis disturbances and nutrition interact as interconnected biological systems contributing to depressive pathology.

Table 3 shows the nutritional factors and their modulatory effects on biological mechanisms in depression.

Table 3. Nutritional Factors and Their Modulatory Effects on Biological Mechanisms in Depression.

Nutrient/Dietary Component	Primary Biological Target	Mechanisms of Action	Effects Relevant to Depression	Level of Evidence
Omega-3 fatty acids (EPA, DHA)	Neuroinflammation, cytokines	Reduce IL-6, TNF-α; inhibit NF-κB; improve neuronal membrane fluidity; regulate neurotransmission	Reduced inflammation, improved mood and improved cognitive function	Strong evidence (RCTs, meta-analyses)
Mediterranean diet pattern	Inflammation, metabolic function, gut microbiota	Anti-inflammatory diet rich in fibre, antioxidants, healthy fats; improves microbiota diversity	Reduced depression risk, improved metabolic and inflammatory profiles	Strong evidence (cohort studies, trials)
Dietary fibre/prebiotics	Gut–brain axis, microbiota	Increase SCFA production; improve gut barrier integrity; reduce systemic inflammation	Improved gut health, reduced inflammation, improved stress response	Moderate evidence
Probiotics (Lactobacillus, Bifidobacterium)	HPA axis, microbiota	Reduce cortisol levels; modulate vagus nerve signalling; improve gut microbiome balance	Reduced stress, improved mood and emotional regulation	Moderate evidence
Polyphenols (Flavonoids, curcumin, resveratrol)	Oxidative stress, mitochondrial function	Reduce ROS; increase antioxidant enzymes; modulate inflammatory pathways	Reduced oxidative stress, improved neuroplasticity and mood	Moderate evidence
Vitamin D	Immune system, HPA axis	Regulates immune response; reduces inflammatory cytokines; affects glucocorticoid receptor expression	Improved mood regulation and immune balance	Moderate evidence
B Vitamins (B6, B9, B12)	Neurotransmitter synthesis, methylation	Regulate homocysteine; support serotonin and dopamine synthesis	Reduced fatigue, improved cognitive and emotional functioning	Moderate evidence
Tryptophan-rich foods	Serotonin pathway, kynurenine pathway	Increase serotonin synthesis; regulate kynurenine metabolism	Improved mood and reduced depressive symptoms	Emerging evidence
Fermented foods	Gut microbiota	Increase beneficial bacteria; improve immune and gut barrier function	Improved stress resilience and mood	Emerging evidence
Antioxidants (Vitamin C, Vitamin E, CoQ10)	Oxidative stress, mitochondria	Neutralise free radicals; protect mitochondrial function	Reduced oxidative damage and improved energy metabolism	Limited to moderate evidence

Table 3 evidence levels were categorised based on the type and consistency of available research. Strong evidence indicates support from randomised controlled trials and meta-analyses; moderate evidence indicates support from observational and mechanistic studies; emerging evidence indicates preliminary or limited clinical studies; limited evidence indicates mechanistic or small-scale studies requiring further research.

An integrated biological feedback loop is given in Figure 2.

Figure 2. Integrated Biological Feedback Loop.

The integrative figure provides a visual synthesis of the interconnected biological mechanisms underpinning depression, showing how neuroinflammation, HPA axis dysregulation, oxidative and mitochondrial stress and gut–brain axis disturbances form a self-reinforcing network. Key feedback loops are highlighted, including how chronic psychological stress activates the HPA axis, raising cortisol and contributing to GR resistance, thereby amplifying pro-inflammatory cytokine production. These cytokines stimulate microglial activation and neuroinflammation, culminating in disrupted neurotransmission and depressive symptoms. Parallel pathways highlight the ways through which oxidative stress and mitochondrial dysfunction augment inflammatory signalling and how gut dysbiosis raises systemic inflammation and disrupts HPA regulation via gut-derived metabolites and microbial imbalance. Nutritional factors are integrated into the model as modulators capable of interrupting these pathological loops at multiple points—reducing inflammation, improving microbial diversity, enhancing antioxidant capacity and stabilising neuroendocrine function. Overall, the figure depicts depression as a multidimensional, multisystem condition shaped through dynamic interactions between immune, endocrine, metabolic and microbial pathways.

Discussion

This review aimed to synthesise current evidence on the interconnected biological pathways underlying depression and the way nutritional factors modulate these systems. Indeed, from the reported studies, a clear trend appeared: depression occurs not as the result of one single biological disturbance but rather as an ensemble of interacting mechanisms that encompass neuroinflammation, HPA axis dysregulation, oxidative and mitochondrial stress, metabolic imbalance, gut–brain axis disturbances, amongst others.^{3, 16, 17} This review extends existing models by integrating findings across these domains and highlighting nutrition as a modifiable influence on these biological networks.

A dominant theme was the involvement of neuroinflammation and cytokine signalling. It was repeatedly identified that central mediators in the linkage between stress, immune activation and mood dysregulation were the continuously elevated pro-inflammatory cytokines, such as IL-6, TNF-α and IL-1β, in various studies.^{2, 18} The elevation of cytokines promoted synaptic dysregulation, microglial activation, disturbed monoamine signalling and reduced neurogenesis. Importantly, these cytokines initiated further processes, such as increased oxidative stress and HPA axis activation, fitting into a multilevel inflammatory cascade.^{6, 19} This perspective agrees with psychoneuroimmunology research that shows inflammation is both a cause and consequence of depressive symptoms. ¹⁰

Another critical mechanism was the dysregulation of the HPA axis. Chronic stress, GR resistance and prolonged cortisol exposure were shown in several studies to interact with inflammatory signalling to generate maladaptive stress responses.^{5, 20} Sustained cortisol output and impaired negative feedback were associated with HPA hyperactivity, further leading to increased production of inflammatory cytokines.^{15, 21} The bidirectional interrelationship between inflammation-induced HPA axis dysregulation and HPA axis dysregulation promoting further inflammation has been identified and stressed time after time.^{6, 22} This further reinforces such a concept of depression as a stress-immune disorder and how well-intertwined the endocrine and inflammatory pathways are.

Parallel evidence emphasised the role of oxidative stress and mitochondrial dysfunction. Indeed, a number of studies reported that oxidative imbalance leads to impaired ATP production, increased apoptotic processes and neuroinflammatory signalling.^{6, 9} Mitochondrial dysfunction enhances cytokine activity even more and causes further disruption in neuroendocrine regulation. These findings also elucidate depressive symptoms such as fatigue, cognitive slowing and anhedonia, which are in close association with impaired energy metabolism.

A rapidly developing area of research involves gut–brain axis mechanisms. Research on microbiota has pointed out that dysbiosis, reduced microbial diversity, altered production of SCFAs and gut permeability increase systemic inflammation and alter HPA activity. Dysbiotic profiles have been related to increased LPS translocation and inflammatory signalling. Furthermore, metabolites from microbiota modulate the kynurenine pathway, serotonin availability and neural-immune activity—mechanisms directly implicated in depression. Although there is a lingering heterogeneity in the methodologies for studying microbiomes, the evidence converges toward the gut as a main contributor to depressive pathophysiology.

In all domains, nutrition appeared as a promising modulator of inflammation, oxidative stress, HPA axis dysregulation and microbiota imbalance. Omega-3 fatty acids, polyphenols, probiotics, prebiotics and vitamins D and B showed a constellation of biological effects relevant to mood regulation consistently.^{23, 24} Anti-inflammatory diets and Mediterranean-style patterns showed synergistic benefits for metabolic and immune function. ⁹ Importantly, several studies have further emphasised that nutritional interventions can complement conventional treatments by targeting the biological processes underlying the disorder that pharmacotherapies may not adequately address. Despite these promising findings, several gaps remain. Many studies were of a cross-sectional nature, hence limiting causal interpretation. Biomarker techniques varied widely, reducing comparability across studies. ¹⁷ Only a few investigations simultaneously assessed immune, endocrine, oxidative and microbiome markers within the same participants, which again reduces knowledge about the interplay among systems. Nutritional studies often relied on self-report dietary measures, which are prone to bias. ⁹

In addition, most studies had their origin in Western contexts, reducing generalisability on an international level. Taken together, this review underlines the need to transcend reductionist neurochemical theories for integrated biopsychobiological models that incorporate the multifaceted nature of depression. Depression results from the convergence of forces in the immunological, endocrine, metabolic, microbial and psychosocial domains.

It is also important to acknowledge that depression is a heterogeneous condition with multiple etiological pathways. While this review focused primarily on biological mechanisms such as neuroinflammation, HPA axis dysregulation, oxidative stress and gut–brain interactions, psychosocial factors including trauma, chronic stress, socioeconomic adversity, cognitive vulnerability and social isolation play significant roles in the onset and maintenance of depressive disorders. Biological dysregulation often interacts with psychological and environmental stressors, supporting a biopsychosocial model rather than a purely biological explanation of depression.

Appreciation of these multilevel mechanisms offers new opportunities for precision psychiatry and underpins the creation of targeted, biologically informed interventions—including dietary and lifestyle approaches—which may considerably improve treatment outcomes. The integrative model proposed in this review should be interpreted as a conceptual framework grounded in converging evidence across biological systems rather than a single empirically established causal pathway. Many included studies are correlational, mechanistic or review-based and therefore the model represents an integrative systems perspective rather than a deterministic biological pathway. Overall, this review supports a systems-based understanding of depression in which immune, endocrine, metabolic, microbial and nutritional factors interact dynamically, reinforcing the need for integrative and multidisciplinary approaches to research and treatment.

Conclusion

This systematic review demonstrates that depression is a result of complex neuroinflammatory processes, cytokine activation, disruption of the HPA axis, mitochondrial and oxidative stress and disturbances in the gut–brain axis. Among these studies, higher levels of pro-inflammatory cytokines such as IL-6, TNF-α and IL-1β, microglial activation, reduced sensitivity of GRs and chronic cortisol exposure were found to be consistent factors in a self-amplifying cycle of neurobiological disruption. Mitochondrial dysfunction and oxidative stress paralleled these pathways with further metabolic burden, while alterations in gut microbiota and increased gut permeability augmented systemic inflammation, thus acting as feedback in central nervous system pathways. Together, these multilevel disturbances created a biological environment that could easily give rise to the origin and perpetuation of depressive symptoms.

Evidence across the reviewed literature also highlights the meaningful role of nutrition as a modifiable factor capable of interrupting these dysregulated biological loops. Nutrients such as Omega-3 fatty acids, polyphenols, vitamins D and B, dietary fibre, prebiotics and probiotics demonstrated consistent anti-inflammatory, antioxidant and microbiota-regulating effects. The nutritional influences reported herein tended to mitigate cytokine expression, maintain mitochondrial stability, modulate HPA axis activity and restore gut microbial balance, thereby adding to improved neurobiological resilience and emotional regulation. Although the heterogeneity of study designs precluded meta-analysis, thematic convergence indicates that nutritional modulation is a promising adjunctive pathway in the prevention and treatment of depression.

Taken together, findings emphasise the need for integrative biopsychosocial models that conceptualise depression not solely as a neurochemical disorder but as a multisystem condition modulated by immune, endocrine, metabolic, microbial and lifestyle factors. Future research will be best served by prioritising longitudinal and interventional designs, adopting multi-omics approaches and investigating how nutritional factors interact with psychosocial stressors, minority stress and individual-level vulnerabilities. Mapping the interdependent biological pathways by which depression manifests and highlighting nutritional targets of opportunity, this review lays the foundation for continued innovations in personalised, mechanistically informed treatment approaches that integrate neuroscience, psychiatry and nutritional science.

Implications

The findings of this systematic review have several critical implications for research, clinical practice and public health. First, the convergence of evidence highlights depression as a multisystem disorder, shaped not only by neurochemical imbalances but also by interconnected immune, endocrine, metabolic and microbiota pathways. This supports a shift away from reductionist models toward integrated biopsychobiological frameworks that acknowledge the centrality of inflammation, stress physiology, oxidative processes and gut–brain interactions in depressive disorders.

Clinically, the review underscores the need for a biomarker-informed assessment and intervention. Regular monitoring of inflammatory markers, such as IL-6 and CRP, cortisol rhythms and metabolic profiles, may be used to identify individuals whose depressive symptoms are driven by biological dysregulation. To that end, integration of nutritional psychiatry into clinical care, including dietary counselling, anti-inflammatory nutrition plans, Omega-3 fatty acid or probiotic supplementation and lifestyle-based stress reduction, may offer meaningful adjunctive treatment options. These approaches can be complementary to psychotherapeutic and pharmacological interventions, particularly in individuals who exhibit treatment-resistant or inflammation-associated depressive phenotypes.

The implications also extend to precision and personalised mental health care. Given that dysbiosis, stress-related HPA hyperactivation and inflammatory signalling maintain a consistent association with one another, future interventions may increasingly tailor treatments to an individual’s microbiota composition, metabolic status and immune function. The multi-omics methodologies integrating genomic, metabolomic, microbiomic and neuroendocrine data may eventually allow targeted therapies that more directly impact the biological drivers of depression.

From a prevention and public health perspective, findings illustrate the importance of dietary improvement, stress reduction practices and lifestyle interventions as approaches to reduce population-level risk for depression. Public health programs that promote whole-food diets, microbiome-supportive nutrition and accessible stress-management strategies may help lower the incidence and severity of depressive disorders in the community.

The review finally calls for rigorous, interdisciplinary research. There is a need for longitudinal studies, randomised controlled nutritional trials and mechanistic investigations that could help explain causal pathways and assess the clinical utility of targeting inflammatory, endocrine and microbiota systems. The ability to address these research gaps will contribute to a broadening of the understanding of depression and help in the elaboration of biologically grounded, integrative treatment models beyond traditional psychopharmacology.

Limitations

There are several limitations to this systematic review that the reader should consider when interpreting the findings. First, although this review included a wide array of high-quality studies across neuroinflammatory, neuroendocrine, metabolic, microbiome and nutritional domains, the heterogeneity of the study designs—including cross-sectional, mechanistic, animal-supported human models and narrative reviews—limits the ability to draw definitive causal conclusions. Many of the studies were based on correlational or observational approaches, where it was difficult to determine the directionality of the relationship between inflammation, cortisol, oxidative stress and depressive symptoms.

Second, the biomarker measurement techniques vary across studies, with differences in the cytokine assays, cortisol sampling protocols, microbiota sequencing methods and oxidative stress indices. Such methodological inconsistencies not only make comparisons between studies problematic but may also lead to divergent findings, especially in studies on microbiota and mitochondria where uniform pipelines are not yet commonly applied.

Third, despite the wide biological scope of the included studies, the field remains limited by the dearth of integrative, multisystem clinical trials. Few studies simultaneously assessed inflammatory, endocrine, oxidative and microbiota markers within the same participants, and fewer still looked into how nutritional interventions modulate these interconnected pathways. As such, conclusions on multisystem interactions are based on a cross-study synthesis rather than unified empirical investigations.

Fourth, some conclusions rely heavily on mechanistic or preclinical evidence, especially in domains of oxidative stress and mitochondrial dysfunction. While such models are foundational, they cannot capture the full complexity of human depression, influenced by social, psychological and environmental conditions. Moreover, most of the reviewed studies came from Western or high-income contexts, which constrains the cross-cultural generalisability of biological findings.

Finally, although nutrition has emerged as a promising modulator of depressive biology, existing literature remains constrained by heterogeneous dietary assessments, reliance on self-report measures and limited control of confounding variables such as lifestyle, socioeconomic status and comorbid conditions. This may lead to underestimation or overestimation of nutritional effects.

Future Recommendations

An integrated, multimodal approach to future research should be considered in studies that can concurrently assess inflammation, HPA axis activity, oxidative stress, mitochondrial dynamics and gut microbiota in the same cohorts to help move the field forward. Such designs would allow clearer identification of mechanistic pathways and interaction effects driving depression. Longitudinal studies are critical to establish temporality and clarify whether biological dysregulation precedes, coincides with or results from depressive states.

There is also a need for the standardisation of biomarker assessment, including uniform cytokine assays, cortisol sampling schedules, oxidative stress markers and microbiota sequencing methods. The use of shared protocols would increase comparability between studies and allow for more robust meta-analytic integration.

The use of Omega-3 fatty acids, polyphenol-rich diets, supplementation with probiotics/prebiotics and Mediterranean-style eating patterns are some nutritional interventions whose biological pathways in depression should be assessed in future studies with more rigorous randomised controlled trials. Multi-omics approaches—integrating metabolomics, microbiomics, transcriptomics and neuroendocrine profiling—will be critical to identifying personalised dietary strategies and stratifying individuals into biological subtypes that are most likely to respond to specific nutritional therapies.

Future work will also be needed to investigate bidirectional influences between psychosocial stress, minority stress and structural determinants and biological dysregulation in depression. More representation of diverse and underrepresented populations, including those with chronic stress, metabolic disparities or food insecurity, is necessary to enhance the generalisability of findings.

Finally, the translation of mechanistic insights into clinical practice will require the development of precision psychiatry models that incorporate biological, psychological and lifestyle factors. Such models should develop integrative treatment frameworks that include pharmacotherapy, psychotherapy, lifestyle interventions and personalised nutrition to more effectively target the complex biological networks underlying depression.

Authors’ Contributions

Saranya TS conceived and designed the review, developed the methodology, conducted the literature search, performed data synthesis, interpreted the findings and prepared the original manuscript. Şebnem Yücel, Sandeep Kumar Gupta, Recep Yücel, and Sumitra Dutta contributed to the interpretation of the literature, critically reviewed the manuscript for important intellectual content, and approved the final version for publication. All authors read and approved the final manuscript and agree to be accountable for all aspects of the work.

Statement of Ethics

This study is a systematic review of previously published literature and did not involve human participants, animals, patient data or identifiable personal information. Therefore, ethical approval and informed consent were not required.

Patient Consent

Patient consent was not applicable, as this study did not involve human participants or patient-identifiable information.