The Neuro-Inflammation Link: Is Your Brain “On Fire”?

Author: Rohan Smith | Functional Medicine Practitioner | Adelaide, SA

Within the Adelaide functional medicine community, there is growing recognition that the traditional “chemical imbalance” model of depression is incomplete. A growing body of research suggests that, in a subset of individuals, depressive symptoms are associated with immune activation and chronic, low-grade inflammation. Neuroinflammation depression in Adelaide is linked to the kynurenine pathway, which plays a crucial role in mood regulation, inflammation, and mental health disorders like depression. At Elemental Health and Nutrition, mood concerns are explored through an inflammatory and metabolic lens, particularly when standard approaches have provided limited relief. This perspective aligns with broader work in neuro-inflammation and mood disorders.

Quick Answer: How Can Inflammation Influence Depression?

Inflammation may influence mood by activating the brain’s resident immune cells, known as microglia, and initiating a pattern known as “sickness behaviour” (2,4). Pro-inflammatory signalling can up-regulate the kynurenine pathway, diverting tryptophan away from serotonin synthesis and toward metabolites such as quinolinic acid (1,5). This biochemical shift has been associated with symptoms including low mood, fatigue, cognitive slowing, and reduced motivation (8,15,21).

The Science: The Kynurenine “Shunt”

When the body is exposed to ongoing physiological or psychological stress—such as infection, gut dysbiosis, or prolonged psychosocial stress—immune signalling may take precedence over neurotransmitter balance.

• IDO Enzyme Activation: Pro-inflammatory cytokines, including IL-6 and TNF-α, can activate the enzyme indoleamine 2,3-dioxygenase (IDO), increasing the conversion of tryptophan into kynurenine (1,5).
• Tryptophan Diversion: Under inflammatory conditions, supplemental tryptophan or 5-HTP may be preferentially metabolised along the kynurenine pathway rather than toward serotonin synthesis (12,17).
• Excitotoxic Stress: Elevated quinolinic acid is an NMDA-receptor agonist and has been linked to excitotoxic stress and structural vulnerability in mood-regulating brain regions such as the hippocampus (18,20).

Sickness Behaviour vs. Persistent Low Mood

“Sickness behaviour” is an adaptive, evolutionarily conserved response that promotes rest and energy conservation during acute illness (2,9). Difficulties arise when inflammatory signalling becomes chronic rather than time-limited.

• Anhedonia: Inflammatory mediators have been shown to interfere with dopaminergic reward pathways, contributing to reduced pleasure and motivation (16,19).
• Neuro-Fatigue: Inflammation can impair mitochondrial energy metabolism, which may contribute to cognitive fatigue and mental exhaustion. This pattern commonly overlaps with presentations seen in chronic fatigue and post-viral syndromes (15,22).

Advanced Inflammatory Mapping in Adelaide

In clinical practice, potential inflammatory contributors to mood symptoms are explored using objective biomarkers rather than symptoms alone:

• hs-CRP (High-Sensitivity C-Reactive Protein): A marker of systemic inflammation. Levels above approximately 1.0 mg/L have been associated with an increased risk of depressive symptoms in population studies (2,11).
• Homocysteine: Elevated levels may reflect impaired methylation capacity and have been linked to neuro-inflammatory processes (12,15).
• Organic Acids Testing (OAT): Measurement of kynurenic and quinolinic acid can help determine whether tryptophan metabolism is favouring the kynurenine pathway. This is commonly assessed using Organic Acids Testing (OAT) in functional medicine practice (1,21).

Botanical and Nutritional Anti-Inflammatory Support

When inflammation appears to be a contributing factor, evidence-informed nutritional and botanical strategies may be considered as part of a broader, individualised care plan:

• Curcumin (Phytosome formulations): Curcumin has demonstrated central nervous system activity and has been shown to influence inflammatory signalling pathways, including those involved in IDO activation (10,20).
• Omega-3 Fatty Acids (EPA/DHA): Higher EPA intake has been associated with reduced inflammatory signalling and modulation of microglial activity in both clinical and experimental research (13,19).
• Saffron (Crocus sativus): Clinical trials suggest saffron may improve symptoms in mild-to-moderate depression, with proposed mechanisms including antioxidant and anti-inflammatory effects (17,21).

Frequently Asked Questions

Can diet influence brain inflammation?
Yes. Diets high in ultra-processed foods and refined sugars are associated with increased gut permeability and endotoxin exposure, which may promote systemic and neuro-inflammatory responses (7,14,22).

Why don’t antidepressants work for everyone?
Elevated inflammatory markers, such as CRP above approximately 3.0 mg/L, have been associated with reduced response rates to SSRIs in some individuals. SSRIs primarily influence serotonin reuptake and do not directly address inflammatory diversion of tryptophan metabolism (2,6,18).

How long does it take to influence neuro-inflammation?
While dietary and lifestyle changes can affect inflammatory signalling relatively quickly, measurable changes in kynurenine metabolites and symptom patterns often occur over several weeks when interventions are maintained (10,20).

Key Insights

• Depressive symptoms are frequently associated with chronic, low-grade inflammation (2,4).
• The kynurenine pathway provides a biological framework linking inflammation and serotonin depletion (1,5).
• Neuro-inflammation has been linked to structural and functional changes in mood-regulating brain regions (18,20).
• Biomarkers such as hs-CRP and kynurenine metabolites can help clarify inflammatory contributions to mood symptoms (2,21).

Next Steps

If low mood persists despite conventional approaches, inflammatory or metabolic contributors may warrant further exploration. A structured assessment can help determine whether neuro-inflammatory pathways are relevant in an individual context.

References

1. Schwarcz R, et al. Kynurenines in the mammalian brain: When physiology meets pathology. Nat Rev Neurosci. 2012.
2. Miller AH, Raison CL. The role of inflammation in depression. Nat Rev Immunol. 2016.
3. Khandaker GM, et al. Association of serum IL-6 and CRP with depression. JAMA Psychiatry. 2014.
4. Setiawan E, et al. Role of neuroinflammation in major depressive disorder. JAMA Psychiatry. 2015.
5. Dantzer R, et al. From inflammation to sickness behavior. Nat Rev Neurosci. 2008.
6. Köhler O, et al. Anti-inflammatory treatment in depression. JAMA Psychiatry. 2014.
7. Felger JC, Lotrich FE. Inflammatory cytokines in depression. Neuroscience. 2013.
8. Slavich GM, Irwin MR. Stress, inflammation, and depression. Psychol Bull. 2014.
9. Kelley KW, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003.
10. Lopresti AL, et al. Curcumin for major depression. J Affect Disord. 2014.
11. Raison CL, et al. Infliximab for treatment-resistant depression. JAMA Psychiatry. 2013.
12. Myint AM, et al. Kynurenine pathway in major depression. J Affect Disord. 2007.
13. Kiecolt-Glaser JK, et al. Omega-3 supplementation and inflammation. Brain Behav Immun. 2011.
14. Dash S, et al. Gut microbiome and depression. Curr Opin Psychiatry. 2015.
15. Naviaux RK. Metabolic features of the cell danger response. Mitochondrion. 2014.
16. Capuron L, et al. Dopaminergic mechanisms of anhedonia. Mol Psychiatry. 2012.
17. Hausenblas HA, et al. Saffron and major depressive disorder. J Integr Med. 2013.
18. Haroon E, et al. Inflammation and behavior. Neuropsychopharmacology. 2012.
19. Pariante CM. Why are the inflamed depressed? Curr Top Behav Neurosci. 2017.
20. Ng QX, et al. Clinical use of curcumin in depression. JAMDA. 2017.
21. O’Mahony SM, et al. Tryptophan metabolism and the gut–brain axis. Behav Brain Res. 2015.
22. Lord RS, Bralley JA. Laboratory evaluations for integrative medicine. 2008.