Kate Street

The immune system is increasingly recognised not only as a host defence mechanism, but also as a dynamic communication network that integrates signals across tissues, including the brain and gastrointestinal tract.1 This reflects a shift from viewing immunity as a discrete system to understanding it as part of a broader, interconnected physiological network.1Psychoneuroimmunology (PNI) is the field of research examining the bidirectional interactions between psychological processes, the nervous system, and immune function, and how these pathways collectively influence health outcomes.2 Within this framework, immune activity is shaped not only by pathogens or local tissue signals, but also by continuous input from neuroendocrine and metabolic systems.2Rather than operating independently, these systems form an integrated regulatory network that coordinates physiological responses to internal and external stressors.2<h3>Stress signalling, immune balance, and neuroimmune feedback</h3>One of the most well-characterised pathways in PNI is the relationship between psychological stress and immune regulation.2 When a stressor is perceived, the brain activates coordinated neuroendocrine responses involving the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system, resulting in the release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and ultimately cortisol.3The effects of stress on immune and neurobiological systems are not linear, rather they reflect a bidirectional network of feedback loops involving endocrine, immune, and neural pathways (see Figure 1).2While this acute response can temporarily enhance immunity and promote protection during infection, chronic or dysregulated stress signalling may inhibit immune function through its effects on inflammatory mediators, immune cell activation and proliferation, and the balance between pro- and anti-inflammatory responses.4 These mechanisms highlight how psychological and physiological stressors can shape immune resilience and inflammatory tone over time.
<img src="https://images.contentstack.io/v3/assets/blt948bd74310fc0ad0/bltd361a6d69b3f134a/6ab4a5752f8d8271b233a472/Screenshot_20260622_at_103614_am.png" alt="Screenshot_20260622_at_103614_am.png" class="embedded-asset" />Figure 1. The bidirectional interactions between stress physiology and the neuroimmune system.2<h3>When the immune system communicates with the brain</h3>Communication within PNI is bidirectional, with immune activity also influencing central nervous system function, contributing to changes in mood, cognition, and behaviour.5During immune activation, cytokines and other inflammatory mediators can send signals to the brain via neural, humoral, and cellular pathways.5 These signals interact with neural circuits and glial cells, including microglia (immune cells in the brain), which are increasingly recognised as key regulators of neuroimmune homeostasis.5This immune-to-brain communication provides a biological basis for the relationship between inflammatory states and experiences such as fatigue, reduced motivation, and altered cognitive function.5<h3>The gut as part of a wider neuroimmune network</h3>The gut plays an important role within the PNI network, integrating signals from the immune system, nervous system, and microbiome. It is a major site of immune activity and hosts a complex microbial ecosystem that continuously interacts with host physiology.6Communication between the gut, immune system, and brain occurs through multiple overlapping pathways, including:<ul><li>Neural signalling via the vagus nerve</li><li>Endocrine pathways involving the HPA axis</li><li>Immune mediators such as cytokines</li><li>Microbial-derived metabolites including short-chain fatty acids (SCFAs) and tryptophan metabolites.6</li></ul>Importantly, these interactions are also multidirectional.6 Stress-related neural and hormonal signalling can influence gastrointestinal physiology, including intestinal barrier function, motility, and microbial composition.6 In turn, microbial and immune signals can influence neuroendocrine and neural pathways.6Poor microbiome health is associated with various neurological and psychiatric disorders, including autism spectrum disorder, Alzheimer’s disease, Parkinson’s disease, depression, and anxiety.6Collectively, these pathways position the gut as a dynamic component of the broader neuroimmune network (see Figure 2).6

<img src="https://images.contentstack.io/v3/assets/blt948bd74310fc0ad0/blt57374852896e0432/6ab4a5762f8d8245b633a476/PNI_Figure_2.png" alt="PNI_Figure_2.png" class="embedded-asset" />
Figure 2. The bidirectional and tridirectional communication pathways linking the gut, immune system and brain.6<h3>Supporting immune resilience through an integrated approach</h3>Lifestyle factors such as sleep, physical activity, diet quality, and stress management can influence neuroendocrine activity, inflammatory signalling, and gut physiology, collectively contributing to immune balance.7Given the interconnected nature of these pathways, nutritional strategies that influence immune, gut, and neuroendocrine function are an emerging area of research. Probiotics have been investigated for their ability to interact with the intestinal environment and modulate immune signalling and barrier function, with effects appearing to be strain-specific.8<h3>Research spotlight: Wellmune®9</h3>Emerging evidence suggests that yeast-derived β-glucans, including Saccharomyces cerevisiae β-glucan (Wellmune®), may support aspects of innate immune function through interaction with pattern recognition receptors involved in immune surveillance and response.Preclinical and human data indicate these compounds may contribute to ‘trained immunity’, a process in which innate immune cells demonstrate an enhanced response to subsequent challenges following initial stimulation. This includes modulation of innate immune cell activity, such as macrophages and neutrophils, and downstream immune signalling pathways.While findings are generally supportive, variability in study populations, endpoints and formulations means the broader clinical relevance continues to be investigated.<h3>Conclusion</h3>PNI provides an evolving framework for understanding immune health as the product of continuous communication between the brain, gut, and immune system. Rather than being regulated in isolation, immune function is shaped by integrated neuroendocrine, inflammatory and microbial signals, offering a more holistic understanding of how psychological state, physiology, and environment collectively influence health outcomes.

<h3>References
</h3><ol><li>Poon MML, Farber DL. The Whole Body as the System in Systems Immunology. iScience. 2020;23(9):101509.</li><li>Bower JE, Kuhlman KR, Haydon MD, Boyle CC, Radin A. Cultivating a healthy neuro-immune network: A health psychology approach. Social and Personality Psychology Compass. 2019;13(9).</li><li>Mbiydzenyuy NE, Qulu LA. Stress, hypothalamic-pituitary-adrenal axis, hypothalamic-pituitary-gonadal axis, and aggression. Metabolic Brain Disease. 2024;39(8):1613–36.</li><li>Alotiby A. Immunology of Stress: A Review Article. Journal of Clinical Medicine. 2024;13(21):6394.</li><li>Bower JE, Kuhlman KR. Psychoneuroimmunology: an Introduction to Immune-to-Brain Communication and Its Implications for Clinical Psychology. Annual Review of Clinical Psychology. 2023;19(1):331–59.</li><li>Park JC, Chang L, Kwon HK, Im SH. Beyond the gut: decoding the gut–immune–brain axis in health and disease. Cellular and Molecular Immunology. 2025.</li><li>Chakif D, Furrer J. The impact of nutritional, environmental, and lifestyle factors on neurological disorders. Frontiers in Pharmacology. 2026;17.</li><li>Szota MP, Napiórkowska-Baran K, Wojtkiewicz A, et al. Current Understanding of Probiotic Strains and Immune Function: From Gut Microbiota to Systemic Immunity. International Journal of Molecular Sciences. 2026;27(10):4527.</li><li>De Marco Castro E, Calder PC, Roche HM. β‐1,3/1,6‐Glucans and Immunity: State of the Art and Future Directions. Molecular Nutrition &amp; Food Research. 2020;65(1):1901071.</li></ol>

<h3>Key highlights
</h3><ul><li>Psychoneuroimmunology (PNI) explores the bidirectional interactions between psychological processes, the nervous system, and immune function.</li><li>Stress signalling can influence immune balance through neuroendocrine pathways, including the HPA axis and sympathetic nervous system.</li><li>The gastrointestinal tract and gut microbiome are important contributors to neuroimmune communication, linking microbial, immune, and neural signalling pathways.</li><li>Emerging research is exploring how lifestyle factors and nutritional approaches may support immune resilience through these interconnected systems.</li></ul>

Key highlights

Recommended for you

Optimising exercise performance

Siberian ginseng for mental focus

Algae Oil | The original omega-3 source

Understanding the research