The anti-inflammatory function of the vagus nerve

Ross Hauser, MD

When we fight infections, when we try to heal from wound or injury, our natural reflexes set off an inflammatory response. The vagus nerve plays a major role in this neural (nerve) reflex mechanism. More specifically, the vagus nerve plays a role in the inflammatory reflex that controls the body’s immune responses and inflammation during pathogen invasion and tissue injury. 

Proinflammatory cytokines (messenger proteins that signal the need and growth of immune cells at the site of infection or wound), along with chemokines (messenger proteins that control where and when white blood cells show up at the site of infection of injury), reactive oxygen species (osteoarthritis increase productions of Reactive oxygen species (ROS) induced age-related changes in chondrocytes (cartilage cells). Simply Reactive oxygen species (ROS) is a chemical reaction that leads to oxidant damage and the breakdown of cells), nitrogen intermediates (such as nitric oxide – while anti-inflammatory in nature, over production of nitric oxide leads to chronic inflammation) and other inflammatory molecules are critically important in extracelluar pathogen clearance (the ability to get rid of dead, injured cells, and pathogen invaders), vasodilatation (reducing blood pressure), neutrophil (white blood cells that fight infection) recruitment, increased vascular permeability (the ability of blood to get immune cells to sites of injury and infection) and introduction of acute-phase proteins, such as C-reactive protein (when there is chronic inflammation CRP is elevated) and coagulation molecules. Inflammation is normally a local and temporary event. When the crisis ends, the immune system steps down. Unregulated, excessive or chronic inflammation is the cause of a range of disease syndromes including sepsis, rheumatoid arthritis, inflammatory bowel disease and other inflammatory and autoimmune disorders.  For more research on Ross Hauser, MD Reviews Cervical Spine Instability and Potential Effects on Brain Physiology.

The inflammation-sensing and inflammation-suppressing functions are the principal components of the inflammatory reflex. The appearance of pathogenic organisms (or antigens) activates the immune cells that release cytokines. These in turn activate sensory fibers that ascend in the vagus nerve to synapse or help trade messages among neurons. Another way in which the vagus nerve helps restore immune function is through the gut microbiota.  There is growing evidence that the gut microbiota communicate with the brain involves the vagus nerve.

In August 2023, university researchers in Leipzig, Germany (1) followed up on previously published research in suggesting that stimulating the vagus nerve could an answer to chronic inflammation. Here is what they wrote: “Modulation of the parasympathetic tone (the ability of your body to relax or slow down) leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. (In other words, if you are more relaxed you produce less inflammation). Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic (you are not able to regulate when you need to calm down) and increased sympathetic activities (your inability to regulate your inability to calm down has you in a state of constant stress). For more information please see my article: What does Sympathetic Dominance mean?

Moreover, it was demonstrated that a low parasympathetic (inability to calm down) and a high sympathetic activity (state of stress) in patients with rheumatoid arthritis predicts a poor therapeutic response to anti-tumor necrosis factor ((TNF (anti-inflammatory medication)) treatment compared to rheumatoid arthritis patients with a more balanced autonomic nervous system.

The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics (vagus nerve stimulation) might be a useful (treatment).”

Modulation of the parasympathetic tone (the ability of your body to relax or slow down) leads to extensive physiological reactions at several levels, including the decreased production of proinflammatory cytokines. (In other words, if you are more relaxed you produce less inflammation). Many studies have demonstrated that chronic inflammatory diseases are associated with reduced parasympathetic (you are not able to regulate when you need to calm down) and increased sympathetic activities (your inability to regulate your inability to calm down has you in a state of constant stress).

Moreover, it was demonstrated that a low parasympathetic (inability to calm down) and a high sympathetic activity (state of stress) in patients with rheumatoid arthritis predicts a poor therapeutic response to anti-tumor necrosis factor ((TNF (anti-inflammatory medication)) treatment compared to rheumatoid arthritis patients with a more balanced autonomic nervous system.

The autonomic equilibrium could be restored by electrical stimulation of the vagus nerve. Considering the patients who do not sufficiently respond to the available drugs, patients for whom the effectiveness of the drugs wanes over time, or have drug-related adverse events, a nonpharmacological approach such as bioelectronics (vagus nerve stimulation) might be a useful (treatment).

Inflammatory bowel diseases

A June 2021 study in the journal International immunology (2) writes: “The hallmark of inflammatory bowel diseases (IBD) is chronic intestinal inflammation with typical onset in adolescents and young adults.  . . There is an unmet need for new treatment options since modern medicines such as biological therapy with anti-cytokine antibodies still leave a substantial number of patients with persisting disease activity (Inflammation). The role of the central nervous system and its interaction with the gut in the pathophysiology of IBD have been brought to attention both in animal models and in humans after the discovery of the inflammatory reflex. The suggested control of gut immunity by the brain-gut axis represents a novel therapeutic target suitable for bioelectronic intervention.”

The Vagus nerve and Diabetes Type 2. A Matter of inflammation

A June 2023 paper published in the journal Cells (3) comes to us from Israeli researchers at Tel Aviv University and Haifa University, suggests connections between inflammation and Type 2 diabetes and the role of the vagus nerve. The researchers write: “At (the core of Type 2 diabetes) is insulin resistance, where chronic low-level inflammation is among its main causes.” As they write, “(as) it is crucial to modulate this inflammation,” the researchers  point to scientific neuroimmunological evidence on the protective roles of the vagal nerve in Type 2 diabetes and its clinical implications.

Here is a summary of the findings:

  • The vagus inhibits inflammation in a reflexive (automatic) manner via neuroendocrine and neuroimmunological routes (simply the immune response to various stressors and the inflammation created.) This (Inflammation) may also occur at the level of brain networks.
  • Second, studies have shown that vagal activity, as indexed by heart-rate variability (HRV), is inversely related to diabetes and that low HRV (the inability to recover from stress) is a predictor of Type 2 diabetes.
  • Ssome emerging evidence shows that vagal nerve activation may reduce biomarkers (glucose and hemoglobin A1c levels) and processes related to diabetes.

Inflammatory response can be stimulated by both Invasive stimulation and transcutaneous (skin level) vagus nerve stimulation

A May 2022 paper in the journal Neuroimmunomodulation (4) wrote that invasive stimulation (implantable device) of the vagus nerve produces anti-inflammatory effects; however, data on anti-inflammatory responses of transcutaneous (skin level) vagus nerve stimulation (tVNS) are rarely published. This study investigated changes in serum cytokine concentrations of interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor α (TNFα) following a short-term, non-invasive stimulation of the vagus nerve. The results show that active tVNS led to an immediate increase in the serum concentrations of certain pro-inflammatory cytokines such as IL-1β, IL-6, and/or IL-8 in two independent cohorts of healthy study participants.

1 Seifert O, Baerwald C. Stimulation of the vagus nerve as a therapeutic principle. German Version. Zeitschrift fur Rheumatologie. 2023 Jul 25. [Google Scholar]
2 Eberhardson M, Levine YA, Tarnawski L, Olofsson PS. The brain–gut axis, inflammatory bowel disease and bioelectronic medicine. International Immunology. 2021 Jun;33(6):349-56. [Google Scholar]
3 Sorski L, Gidron Y. The Vagal Nerve, Inflammation, and Diabetes—A Holy Triangle. Cells. 2023 Jun 15;12(12):1632.
4 Veiz E, Kieslich SK, Czesnik D, Herrmann-Lingen C, Meyer T, Staab J. Increased Concentrations of Circulating Interleukins following Non-Invasive Vagus Nerve Stimulation: Results from a Randomized, Sham-Controlled, Crossover Study in Healthy Subjects. Neuroimmunomodulation. 2022:1-0. [Google Scholar]


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