Stress, the HPA-axis and neuroinflammation

ID:48848513The fight or flight reaction to acute stress results in a surge of hormones that includes both adrenaline and cortisol. Acute stressors occur rapidly and have an obvious onset and offset, are brief in ‘length’ and are generally considered as beneficial in terms of enhancing cognition, emotion and neurobiological systems such as the immune system. Chronic stress, in contrast to acute stress, is ongoing, often lacking a clear endpoint and is considered to be deleterious, contributing to immune and endocrine dysfunction, altered mood, and to several neurobiological and psychological diseases. The toxic burden of chronic stress was the topic of our recent webinar Stress, the HPA-axis and neuroinflammation, in which Dr Bailey discussed the benefits of nutritional intervention in reducing the impact of chronic stress on those pathways related to mood and cognitive function.

Elevated cortisol is neurotoxic

Cortisol levels fluctuate naturally throughout day the day, with levels highest in the morning (as part of the awakening response) and dropping off as the day progresses. The additional cortisol secreted by the adrenals influences and regulates many of the physiological changes that occur in response to stress. The abnormally high levels of cortisol that occur when the stress response is continuously activated exhibit neurotoxic activity on those hippocampal neurones that play a predominant role in regulating memory, learning and mood. Individuals with Cushing’s syndrome, for example, exhibit numerous mood and cognitive related symptoms, including depression, anxiety and cognitive dysfunction, symptoms that are alleviated following treatment for hypercortisolemia.[1]

Cortisol and the brain

The neurotoxic impact of cortisol on the hippocampus is determined in part by the maturation stage [hypothalamus], the level and sustainability of the cortisol released, and the severity and/or duration of the stressful event/s. Psychological stressors therefore fall into different categories depending on the individual’s age during stress exposure, the severity and chronicity of the stressor, and the level of the subjectively perceived threat. Stress experienced early in life is known to induce a vulnerability to stress later in life, increasing the risk for developing anxiety, depression and post traumatic stress disorder (PTSD). Women with a history of childhood abuse are, for example, more than twice as likely to develop depression as non-abused women. [2]

Psycho-emotional stress and 21st century living

Our exposure to psycho-emotional stress has increased generally, with many of us simply overwhelmed by the stresses of living in the hustle of the 21st century, an environment full of ‘insults’ which continuously activate the innate immune system and central stress axes. In addition, the underlying inflammation observed in both physical and mental illness is caused not only by excessive, inappropriate innate immune system activity and hyper stimulation of the central stress axes, but is also exacerbated by unhealthy pro-inflammatory ‘western’ diet patterns. [3]

Depression, HPA- axis and inflammation

There is now an extensive body of data showing that depression is associated with both a chronic low-grade inflammatory response and activation of cell-mediated immunity. The pro-inflammatory cytokine tumour necrosis factor alpha (TNF-α) induces an increase in cortisol that significantly correlates with depression and fatigue. Furthermore, results from a 2010 meta-analysis (18 studies) found significantly increased levels of interleukin (IL)-1β, IL-6, and TNF-α in post mortem brain samples of suicide victims compared with brain samples of healthy control individuals who did not die by suicide, implying a direct role of cytokines in mood disorders. [4, 5]

Cortisol and fatty acid metabolism

Studies have found a direct modulating effect of HPA-axis activity on long-chain fatty acid metabolism. Cortisol influences mobilisation, oxidation and synthesis of fatty acids and directly inhibits delta-5 and delta-6 desaturase-activity, enzymes responsible for unsaturation of fatty acid chains. High cortisol concentrations are therefore associated with a decrease in omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) concentrations. [6] As the downstream products of EPA and DHA have a direct pro-resolving role in terminating the inflammatory response, the impact of cortisol on omega-3 levels fuels the issue by further exacerbating the unregulated inflammatory response. High levels of proinflammatory products, low omega-3 levels (as the omega-3 index) and a high arachidonic acid (AA) to EPA ratio (as an inflammatory biomarker) are all associated with depression and the severity of depression. [7]

Serotonin production, recycling and degradation

A decrease in serotonin production and activity is a well-established feature of the pathophysiology of mood disorders. Cortisol and proinflammatory cytokines shift tryptophan away from serotonin production and increase serotonin transporter (SERT) activity, the latter resulting in the increased metabolism of serotonin to 5-hydroxyinodole acetic acid (5HIAA) that, again, is further exacerbated by low omega-3 status. [8, 9] Furthermore, proinflammatory cytokines are known to negatively influence levels of neurotrophins, molecules that promote neuronal survival and growth. [10]

Omega-3 intervention

Omega-3 deficiency (either dietary, or via metabolic abnormalities) is a known risk factor for the development of mood disorders and a known driver of the stress-related neuroinflammatory pathways linked to mood disorders and cognitive decline. The interest in omega-3 fatty acids for the management of mood disorders related to psychological stress (depression, anxiety, PTSD) has therefore grown considerably in the last decade, with several meta-analyses supporting the use of omega-3 fatty acids and highlighting the efficacy of EPA oils over EPA/DHA oils [11, 12], the most recent of which was published in 2015. [13] The ability of EPA to protect against IFN-α-induced depression (pre-treatment with EPA in hepatitis C patients) adds further support to its unique neuroactive actions. [14] The apparent exclusive nature of EPA in modulating mood disorders appears to centre on its ability to reduce inflammatory cytokine levels, reduce cortisol [15], partly initiated via a unique antagonist relationship with the pro-inflammatory omega-6 fatty acid arachidonic acid (AA) that is not shared with DHA. [16]


EPA supplements have been shown to be as effective as standard SSRIs in managing depression, [17] with efficacy most notable where there is predetermined omega-3 deficiency and pre-existing inflammation. [18] Therefore, as with any nutritional intervention using omega-3 fatty acids, ensuring that dosing strategies are determined according to each participant’s unique physiological need and establishing baseline levels of omega-3 appears crucial to establish risk and omega-3 suitability. Biomarkers offer a vital tool in determining the type and extent of intervention needed, with both the omega-3 index and the AA to EPA ratio being linked to increased risk for a number of health conditions, including mood disorders, cognitive decline and dementia. Their measurement makes it is possible to advise appropriately and personalise a treatment approach.


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2. Juruena MF, Werne Baes CV, Menezes IC, Graeff FG: Early life stress in depressive patients: role of glucocorticoid and mineralocorticoid receptors and of hypothalamic-pituitary-adrenal axis activity. Current pharmaceutical design 2015, 21:1369-1378.
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11. Martins JG: EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. Journal of the American College of Nutrition 2009, 28:525-542.
12. Sublette ME, Ellis SP, Geant AL, Mann JJ: Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. The Journal of clinical psychiatry 2011, 72:1577-1584.
13. Yang JR, Han D, Qiao ZX, Tian X, Qi D, Qiu XH: Combined application of eicosapentaenoic acid and docosahexaenoic acid on depression in women: a meta-analysis of double-blind randomized controlled trials. Neuropsychiatric disease and treatment 2015, 11:2055-2061.
14. Su KP, Lai HC, Yang HT, Su WP, Peng CY, Chang JP, Chang HC, Pariante CM: Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: results from a randomized, controlled trial. Biological psychiatry 2014, 76:559-566.
15. Jazayeri S, Keshavarz SA, Tehrani-Doost M, Djalali M, Hosseini M, Amini H, Chamari M, Djazayery A: Effects of eicosapentaenoic acid and fluoxetine on plasma cortisol, serum interleukin-1beta and interleukin-6 concentrations in patients with major depressive disorder. Psychiatry research 2010, 178:112-115.
16. Farooqui AA, Horrocks LA, Farooqui T: Modulation of inflammation in brain: a matter of fat. Journal of neurochemistry 2007, 101:577-599.
17. Jazayeri S, Tehrani-Doost M, Keshavarz SA, Hosseini M, Djazayery A, Amini H, Jalali M, Peet M: Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. The Australian and New Zealand journal of psychiatry 2008, 42:192-198.
18. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, Mischoulon D: Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Molecular psychiatry 2015.

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Dr Nina Bailey

About Dr Nina Bailey

Nina is a leading expert in marine fatty acids and their role in health and disease. Nina holds a master’s degree in Clinical Nutrition and received her doctorate from Cambridge University. Nina’s main area of interest is the role of essential fatty acids in inflammatory disorders. She is a published scientist and regularly features in national health publications and has featured as a nutrition expert on several leading and regional radio stations including SKY.FM, various BBC stations and London’s Biggest Conversation. Nina regularly holds training workshops and webinars both with the public and health practitioners.