By: Kim Ross, DCN, CNS, LDN, IFMCP

Positive mood and emotional well-being are essential to overall health, yet low mood affects a significant portion of the global population. According to the World Health Organization, 5% of adults (over 280 million people) worldwide experience some level of low mood or loss of pleasure and interest in activities. In comparison, it is estimated to affect about 10% of all adults in the United States.^1,2 Additionally, it is reported that low moods are 50% more common in women than men.²  

People struggling with low mood experience variable ranges of psychological and physical symptoms. These can include pervasive feelings of sadness or hopelessness, a lack of interest in activities, fatigue and difficulty concentrating. These symptoms are often accompanied by physical manifestations such as changes in appetite, sleep disturbances and decreased energy levels.2 Importantly, underlying immunological processes have been found to play a critical role in regulating mood states, opening avenues for innovative therapeutic approaches.¹

Immune System Activation and the Brain

An area of science called neuroimmunology has highlighted the deep, bidirectional connection and communication between the brain and immune system and its influence on mood regulation.^3–5 Immune cells, including microglia, astrocytes and cytokines, interact directly with neurons, contributing to the modulation of mood and cognitive function.^6,7

Studies suggest that systemic immune activation can affect the nervous system via production of cytokines, including  interleukin-1 beta (IL-1b), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α), which can cross the blood-brain barrier.¹ Alteration of the immune/brain interaction can affect neurotransmitter balance, affecting the production of serotonin, GABA, dopamine and norepinephrine, which are critical for mood stabilization.⁴

Cytokines and Neurotransmitter Balance

Cytokines can influence neurotransmitter balance by modulating key pathways responsible for serotonin, dopamine and glutamate/GABA synthesis and reuptake. For example, the cytokine interferon-gamma (IFN-g) can activate the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades tryptophan, a precursor to serotonin, into kynurenine. This shift reduces serotonin availability, affecting mood regulation.8 However, some kynurenine metabolites have neuroprotective properties, reinforcing the importance of having a healthy cytokine balance within the body.⁸

Similarly, some cytokines (IL-1b, IL-6, IFN-g, and TNF-α) have been shown to decrease the transport of tyrosine (a non-essential amino acid produced from phenylalanine), which is needed for the synthesis of dopamine and catecholamines.9  Cytokines have also been implicated in increasing glutamate activity through quinolinic acid production.¹⁰

Nutrition: Diet plays a critical role in immune and mood regulation. A nutrient and polyphenol-dense Mediterranean diet is rich in vegetables, fruits, omega-3 fatty acids and fiber. It has been shown to modulate cytokine levels and promote mental well-being.^11,12 

Exercise: Regular, moderate-intensity physical activity has been shown to promote cytokine balance. Exercise also helps to reduce stress and provides neuroprotection through the antioxidant system.¹³

Sleep: Poor sleep quality is associated with elevated levels of IL-6, TNF-α, nuclear factor-kB (NF-kB), and CRP (C-reactive protein), important markers of the immune system.¹⁴ Prioritizing sleep hygiene and achieving 7 to 9 hours of restorative sleep can help restore immune balance and positively influence mood.

Mind-Body Practices: Yoga, meditation and mindfulness practices can reduce stress, improve sleep and promote a balanced immune response, including the modulation of cytokines.¹⁵

Polyphenols, including flavonoids, curcumin, epigallocatechin gallate (EGCG) and oligomeric proanthocyanidins (OPCs), are found in a variety of plant-based foods, such as vegetables, berries, green tea and dark chocolate.¹⁶

Curcumin, the active compound in turmeric, exerts its mood benefits by regulating cytokine activity, mainly by reducing levels of TNF-α and IL-6. By maintaining a healthy cytokine response, curcumin supports neurotransmitter balance, especially the monoamines, serotonin, norepinephrine and dopamine.¹⁷ Further, preclinical data suggest that curcumin may bind to NMDA receptors to balance glutamate/GABA signaling.^18‡

Green tea extract contains a high concentration of EGCG, a compound known for its antioxidant and cytokine-modulating properties. The catechins in green tea also help boost dopamine levels, while theanine modulates glutamate, GABA, serotonin and dopamine levels, enhancing a sense of calm and providing cytokine balance.19,20 Green tea extract also supports neurogenesis and promotes the release of brain-derived neurotrophic factor (BDNF), which plays a critical role in mood regulation.^19‡

Pycnogenol, derived from the bark of the French maritime pine tree, is another potent immunomodulator that shows promising cognitive-enhancing effects by reducing oxidative stress and enhancing neurotransmitter activity.²¹ Over 450 articles have been published highlighting the plethora of benefits of this compound in multiple areas of health.^22‡

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The intricate relationship between the immune system and mood highlights the importance of cytokine modulation in mental health. By targeting key cytokines involved in mood regulation, it is possible to influence neurotransmitter pathways and foster positive emotional states.  Making lifestyle changes and using immune-modulating ingredients like pycnogenol and polyphenols offers a holistic approach to supporting mental well-being.

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1. Miller AH, Raison CL. Nat Rev Immunol. 2016;16(1). doi:10.1038/nri.2015.5
2. World Health Organization (WHO). Accessed June 29, 2024. https://www.who.int/news-room/fact-sheets/detail/depression
3. Zhou L, Foster JA. Neuropsychiatr Dis Treat. Published online 2015. doi:10.2147/NDT.S61997
4. Ross K. Explore. Published online 2023. doi:10.1016/j.explore.2023.02.007
5. Nutma E, Willison H, Martino G, Amor S. Clin Exp Immunol. 2019;197(3). doi:10.1111/cei.13279
6. Dantzer R.  Physiol Rev. 2018;98(1). doi:10.1152/physrev.00039.2016
7. Daëron M. Front Immunol. 2022;13. doi:10.3389/fimmu.2022.984678
8. Tsuji A, Ikeda Y, Yoshikawa S, et al.  Int J Mol Sci. 2023;24(6). doi:10.3390/ijms24065742
9. Mancini M, Natoli S, Gardoni F, Di Luca M, Pisani A.  Int J Mol Sci. 2023;24(6). doi:10.3390/ijms24065618
10. Ho TC, Teresi GI, Segarra JR, et al.  Front Psychiatry. 2021;12. doi:10.3389/fpsyt.2021.642976
11. Koelman L, Egea Rodrigues C, Aleksandrova K. Advances in Nutrition. 2022;13(1). doi:10.1093/advances/nmab086
12. Ventriglio A, Sancassiani F, Contu MP, et al. Clinical Practice & Epidemiology in Mental Health. Published online 2020. doi:10.2174/1745017902016010156
13. Docherty S, Harley R, McAuley JJ, et al. BMC Sports Sci Med Rehabil. 2022;14(1). doi:10.1186/s13102-022-00397-2
14. Irwin MR, Opp MR. Neuropsychopharmacology. 2017;42(1). doi:10.1038/npp.2016.148
15. Black DS, Slavich GM. Ann N Y Acad Sci. 2016;1373(1). doi:10.1111/nyas.12998
16. Winiarska-Mieczan A, Kwiecień M, Jachimowicz-Rogowska K, Donaldson J, Tomaszewska E, Baranowska-Wójcik E. Int J Mol Sci. 2023;24(3). doi:10.3390/ijms24032258
17. Peng Y, Ao M, Dong B, et al. Drug Des Devel Ther. 2021;15. doi:10.2147/DDDT.S327378
18. Ramaholimihaso T, Bouazzaoui F, Kaladjian A.  Front Psychiatry. 2020;11. doi:10.3389/fpsyt.2020.572533
19. Afzal O, Dalhat MH, Altamimi ASA, et al. Molecules. 2022;27(21). doi:10.3390/molecules27217604
20. Shamabadi A, Kafi F, Arab Bafrani M, Asadigandomani H, A. Basti F, Akhondzadeh S.  J Affect Disord. 2023;333. doi:10.1016/j.jad.2023.04.029
21. Simpson T, Kure C, Stough C. Front Pharmacol. 2019;10. doi:10.3389/fphar.2019.00694
22. Weichmann F, Rohdewald P.  Front Nutr. 2024;11. doi:10.3389/fnut.2024.1389374

The GI Immunology Roadmap: The Immune System as a Portal to Gut Health

Presented by: Samuel Yanuck, DC⁺

Join us for an enlightening session on the complex and fascinating relationship between the immune system and the gastrointestinal (GI) tract. This webinar is designed for healthcare professionals interested in understanding the intricate connections that shape our health and well-being.

Learning objectives:

• Review T helper cells and the STAT3-NFkB axis and their significance within the immune system


• Discover how immune responses local to the GI tract contribute to global immune regulation


• Recognize key clinical factors in leaky gut and strategies to turn your GI cases around

Common T Cell Patterns: Recognition & Intervention

Presented by: Samuel F. Yanuck, DC, FACFN, FIAMA⁺

T cells are a type of immune cell that play an important role in the adaptive immune response and have meaningful implications in a variety of health conditions. In this webinar, immunology thought-leader, Dr. Sam Yanuck, will demystify T cells, explain how they contribute to a wide array of symptoms, and reveal how to leverage these insights for more precise and personalized care plans.

Learn how to:

• Recognize immune-related clues in lab work


• Match immunologic patterns to appropriate interventions


• Identify these patterns in patients you’re already seeing

Self-Tissue Response: Key Insights for Clinical Success

Presented by: Samuel Yanuck, D.C., FACFN, FIAMA+ and Nathan Morris, M.D.⁺

Co-presented by Drs. Samuel Yanuck and Nathan Morris, this webinar will explore the underlying mechanisms of self-tissue response, describe key patterns to recognize and clinical strategies for supporting these patients, and offer new ways of personalizing your care using evidence-based genetic tools.

Learning Objectives:

• Recognize common patterns in your patients that drive self-tissue response


• Understand the underlying immunology driving these common patterns


• Address these patterns systematically by addressing their underlying immunological causes and by leveraging tools to help personalize your care

From Brain Fog to Mast Cell Activation: Unlocking the Underlying Connections

Presented by: Samuel F. Yanuck, D.C., F ACFN, FIAMA+

Thursday, May 13, 2021

Dr. Sam Yanuck⁺ explains why some of the most common patient challenges in your practice may be more connected than you think. In this webinar, learn how to identify and address the multiple connections between brain fog, mast cell activation, and other common complaints from patients in your practice.

Learning Objectives:

• Discover the interplay between brain fog and mast cell activation, and how to break the pattern


• Understand how brain fog and mast cell activation set the stage for the expression of other common patient patterns


• Learn how these other common patient patterns, such as gut microbial balance, also contribute to the bigger immunological picture in your patients