Inflammation: Understanding the Fire that Fuels Mental Illness

Research over the last two decades has highlighted the central role of inflammation in shaping mental health—affecting neurotransmitter synthesis, release, and receptor sensitivity, as well as altering brain structure and function. Some researchers go so far as to say it’s the true “root cause.” Indeed, this may be the case for some. In most, it is a significant perpetuating factor intermixed and adversely co-mingling with other physiological processes, ultimately cascading into the experience of mood disturbances. Addressing inflammation is one of the most important steps one can take for their health and well-being.

What is Inflammation?

Simply put, it’s a normal and healthy response to injury or infection. It helps us heal and maintain homeostasis. It’s essential for survival and highly adaptive when acute and balanced. It’s an urban legend of sorts to strive for no inflammation. Similarly, stress is also healthy, essential, and adaptive…when acute and balanced. The stress response can initially decrease inflammation, bolster immunity, heighten focus, concentration, and energy. The problem is when it becomes chronic, as is so often the case in the modern era. With all things in nature, balance is key.

The Problem

When inflammation becomes chronic, it transforms from protective to destructive, affecting both body and mind. Chronic inflammation develops through multiple factors: infection, metabolic syndrome, smoking, alcohol, food sensitivities, processed foods, poor sleep, and adipose tissue accumulation (Hotamisligil, 2006; Calder et al., 2011).

Inflammation and Mood

Between 30 and 50% of people with depression show elevated inflammatory markers such as CRP, IL-6, and TNF-alpha (Raison et al., 2006; Miller & Raison, 2016). Elevated inflammatory cytokines correlate with treatment-resistant depression, cognitive impairment, and fatigue (Dowlati et al., 2010). Chronic low-grade inflammation is increasingly recognized as a mediator between stress, lifestyle factors, and mood symptoms.

How Inflammation Impacts the Brain

Monoamines and Neurotransmitter Dysfunction

Inflammation interferes with serotonin, dopamine, and norepinephrine pathways:

● Inflammation drives tryptophan down the kynurenine pathway, which results in less tryptophan being available in the CNS for serotonin synthesis.

● Shunting tryptophan down the kynurenine metabolic pathway results in the production of quinolinic acid, a neurotoxin (Schmidt et al., 2019).

● Reduced dopamine and norepinephrine release, receptor sensitivity, and reuptake contribute to anhedonia, low motivation, and fatigue.

Neuroplasticity and Structural Effects

In the face of inflammation, the brain’s natural growth factors are severely impacted. Pro-inflammatory cytokines impair neurogenesis and synaptic plasticity, particularly in the hippocampus, prefrontal cortex, and other limbic structures. Chronic inflammation can:

● Reduce BDNF (brain-derived neurotrophic factor), limiting neuronal growth and resilience.

● Promote glial activation and oxidative stress, further impairing connectivity.

● Increase apoptosis in CNS neurons, contributing to structural changes and volumetric reductions.

HPA Axis as a Mediator

The hypothalamic-pituitary-adrenal (HPA) axis links stress, inflammation, and mood. It’s the nexus bridging that fancy word with remarkable ramifications for mental health you may have heard before: neuroendocrinoimmunology. Chronic stress leads to:

● Elevated cortisol, which initially suppresses immune function but can become dysregulated over time.

● Glucocorticoid resistance in immune cells over time, paradoxically contributing to increased cytokine release, i.e., more inflammation.

Heightened inflammation in turn exacerbates depressive symptoms and cognitive deficits, creating a vicious, self-perpetuating cycle. As the brain is impacted with CNS apoptosis (cell death) and altered monoamine metabolism, key structures such as the hippocampus and prefrontal cortex—normally associated with memory, reasoning, planning, emotional regulation, and decision-making (i.e., stress response)—are no longer as vibrant and responsive, resulting in a diminished stress threshold. This promotes a greater inflammatory response, HPA axis activation, and more resultant CNS damage. A continuously diminished stress threshold ripples out, influencing the entire body, with mental health symptoms following suit.

● ↓ Neurotransmitter synthesis, release, and receptor sensitivity

● Altered amino acid metabolism: tryptophan → kynurenine → quinolinic acid (neurotoxin) + ↓ tryptophan availability in CNS for 5-HT

● ↓ Neurogenesis and neuroplasticity

● ↑ CNS apoptosis (hippocampus, prefrontal cortex) → ↓ memory, resilience, planning

● ↑ HPA Axis dysfunction (cortisol dysregulation) → ↑ stress

Stress → ↑ inflammation → ↑ CNS apoptosisHPT: Thyroid imbalances → ↓ metabolism, mood, energy; ↑ inflammationHPO/HPG Axis imbalances → ↓ estrogen, progesterone, testosterone

How Inflammation Manifests in Mental Health

Individuals experiencing inflammation-driven cognitive and mental symptoms may notice:

● Persistent low energy, fatigue, or brain fog

● Loss of motivation or interest in previously enjoyable activities

● Heightened irritability or emotional sensitivity

● Difficulty concentrating or decision-making

● Problems with memory

● Sleep disturbances, often early-morning awakening or unrefreshing sleep

Common Lifestyle and Physiological Contributors to Inflammation

● Chronic stress: Psychological stress elevates pro-inflammatory cytokines, disrupts circadian rhythms, and impairs neurotransmission.

● Diet: High intake of refined sugars, refined grains, processed foods, trans fats, and omega-6–heavy oils promotes systemic inflammation.

● Excess weight/adiposity: Adipose tissue is metabolically active, producing TNF-alpha and IL-6, contributing to persistent low-grade inflammation.

● Gut dysbiosis & permeability: Microbial imbalances, SIBO, or leaky gut allow LPS and other bacterial metabolites into circulation, activating systemic inflammation.

● Smoking & alcohol: Both increase oxidative stress, cytokine production, and HPA axis dysregulation.

● Sleep disruption: Poor sleep increases IL-6 and CRP, impairs neurotransmission, and reduces neuroplasticity.

● Environmental toxins: Heavy metals, BPA, and persistent organic pollutants contribute to immune activation.

Diet: The Largest Source of InflammationDietary Impact:

Up to 60% of systemic inflammation may be driven by dietary patterns (Raatz et al., 2020). Inflammation is linked with increased cytokine production and impacts mental health. It affects functional axes throughout the body → from bones and ligaments → autoimmune conditions. Inflammation becomes not only a chemical/biochemical stressor, but also a physical/structural and mental/emotional stressor due to its downstream effects. Therefore, a healthy diet is a form of stress reduction. Addressing inflammation is a form of self-care.

What You Can Do at Home Today

● Anti-inflammatory diet: Emphasize whole vegetables, fruits, fiber, healthy fats (omega-3s), adequate protein, and minimize processed/refined foods. Ex: Mediterranean-style diet is associated with less inflammation, CVD risk, and depression.

● Stress management: Meditation, breathwork, yoga, and movement lower systemic cytokines and improve HPA axis function.

● Sleep hygiene: Regular sleep schedule, limiting screen exposure, and supporting circadian rhythm.

● Weight optimization: Healthy body composition reduces adipose-driven inflammation.

● Gut support: Prebiotic foods, fermented foods, managing SIBO or dysbiosis, and avoiding unnecessary antibiotics.

● Avoid toxins: Minimize alcohol, smoking, and exposure to xenoestrogens and persistent pollutants.

● Exercise: Moderate activity reduces TNF-alpha, increases anti-inflammatory cytokines IL-1ra and IL-10, reduces oxidative stress while supporting neuroplasticity, IGF-1 in CNS as a growth factor in the hippocampus, increases insulin sensitivity in PNS (broad metabolic and mental health benefits), and disperses BDNF more broadly through other regions.

How We Can Help

At Seed to Fruit, we address the root causes of inflammation affecting mood and cognitive function. Using functional assessments and personalized protocols, we help you reduce systemic inflammation, restore neurotransmitter balance naturally, and support neuroplasticity. By targeting HPA axis function, gut health, and lifestyle contributors, we aim to improve resilience, motivation, and emotional stability.

Testing 

Functional testing can reveal inflammatory contributions to mood disturbances:

● hsCRP → systemic inflammation

● IL-6 → cytokine activity

● Histamine → immune activation and neurotransmitter effects

● GI → Dysbiosis, LPS, intestinal permeability drive inflammation

● Food sensitivities → immune-driven inflammatory triggers

Testing is critical because it helps pinpoint the sources—reducing guesswork, which results in an endless cycle of trial and error, years of lost vitality, thousands of dollars wasted, and, most importantly, unnecessary suffering. Personalized insights allow evidence-based lifestyle interventions to be implemented that truly target root causes rather than focusing on symptom suppression. Mental health and physical health are inseparable. By addressing inflammation as a foundational factor, we can help you reclaim clarity, energy, and emotional well-being.

References

● Raison, C. L., Capuron, L., & Miller, A. H. (2006). Cytokines sing the blues: Inflammation and the pathogenesis of depression. Trends in Immunology, 27(1), 24–31.

● Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nature Reviews Immunology, 16, 22–34.

● Dowlati, Y., et al. (2010). A meta-analysis of cytokines in major depression. Biological Psychiatry, 67(5), 446–457.

● Schmidt, F. M., et al. (2019). Inflammation and neurotransmitter metabolism in depression. Frontiers in Neuroscience, 13, 840.