Vagus nerve regulates inflammation and metabolism

Vagus and inflammation, metabolismVagus nerve (cranial nerve X) function, a key regulator of inflammation and metabolism, is under assault in the modern environment. An excellent paper published in Nature Reviews Endocrinology presents a lucid review of the clinically important vagal inflammatory reflex, the role of impaired vagal function in type 2 diabetes and obesity, with therapeutic implications for reducing inflammation and regulating appetite. The authors state:

“The vagus nerve has an important role in regulation of metabolic homeostasis, and efferent vagus nerve-mediated cholinergic signalling controls immune function and proinflammatory responses via the inflammatory reflex. Dysregulation of metabolism and immune function in obesity are associated with chronic inflammation, a critical step in the pathogenesis of insulin resistance and type 2 diabetes mellitus.”

The vagus inflammatory reflex

Functional anatomy of the vagal inflammatory reflexThe vagal inflammatory reflex is a crucial factor in the brain’s regulation of inflammation…

Communication between the immune system and the brain is vital for controlling inflammation. The inflammatory reflex is a centrally integrated physiological mechanism in which afferent vagus nerve signaling, activated by cytokines or pathogen-derived products, is functionally associated with efferent vagus nerve-mediated output to regulate proinflammatory cytokine production and inflammation. The absence of this inflammatory reflex…results in excessive innate immune responses and cytokine toxicity.”

Vagal cholinergic control of inflammationWhen cytokines or pathogen-derived products activate the vagus nerve, it acts to regulate proinflammatory cytokine production and inflammation. When function of the inflammatory reflex is diminished there is excessive innate immune inflammatory activity. Disrupted immune regulation results in persistent pro-inflammatory cytokine activity and chronic inflammation.

“This state underlies the pathogenesis of a range of disease syndromes, including sepsis, rheumatoid arthritis, inflammatory bowel disease and other inflammatory and autoimmune disorders.”

Vagal output is a crucial mechanism for calming inflammation in the digestive tract and throughout the body.

Association with metabolism and obesity

Metabolic and immune dysregulation both contribute to chronic inflammation, and vagal stimulation can help remediate both.

“Chronic inflammation as a result of immune and metabolic dysregulation is a characteristic feature in patients with obesity and is causally linked with insulin resistance and other metabolic complications. Decreased vagus nerve activity in the context of obesity has been reported. Selective cholinergic activation within the efferent vagus nerve-mediated arm of the inflammatory reflex can suppress obesity-associated inflammation and reverse metabolic complications. These findings raise the intriguing possibility that dysregulation of vagus nerve-mediated signalling might contribute to the pathogenesis of obesity and its related comorbidities.

Importantly, the vagus nerve also acts to control appetite and feeding.

“Vagus nerve afferent and efferent signalling has an important role in the regulation of feeding behaviour and metabolic homeostasis. This finely tuned regulation is aimed at preserving energy balance and preventing fluctuations in body weight and metabolism that can be detrimental to the individual.”

It sends functional and metabolic information from the digestive and hepatic systems to the brain, and instructions from brain in return:

“Vagus nerve afferents innervating the gastrointestinal tract and liver are major constituents of a sensory system that detects changes in micronutrient and metabolic molecules. These nerve fibres transmit information detected by associated mechanoreceptors, chemoreceptors and specific metabolite receptors in the gut and hepatic portal system concerning levels of lipids, cholecystokinin, leptin, peptide YY, insulin and glucose to the brain…Vagus nerve efferents, on the other hand, provide brain-derived output to the gastrointestinal tract, liver and pancreas.”

Morever, vagal stimulation is necessary to maintain the gut barrier:

“…truncal vagotomy is associated with increased bacterial trans location across the intestinal mucosa, which suggests a tonic vagus nerve control of intestinal permeability and postprandial endotoxaemia.”

Vagal dysregulation in the inflammation of obesity

Inflammation is characteristic of obesity, associated with impaired vagal function…

“Disruption in metabolic and immune homeostasis in obesity is associated with hyperglycaemia, insulin resistance, dyslipidaemia and hypertension. This cluster of conditions characterizes the metabolic syndrome. Moreover, levels of proinflammatory cytokines and acute-phase proteins such as CRP are increased in individuals with obesity, indicating chronic inflammation. This inflammatory state is considered to be an essential pathophysiological constituent in obesity, underlying its adverse consequences and linking it to the other components of the metabolic syndrome. Several lines of evidence indicate that vagus nerve activity could be impaired in obesity, and enhancing cholinergic signaling within the inflammatory reflex can suppress obesity-associated inflammation and its adverse implications.”

There are numerous mechanisms by which obesity promotes systemic inflammation i association with disturbed vagal function.

Autonomic dysfunction and diminished vagus nerve activity occur frequently in individuals with obesity and type 2 diabetes mellitus. A 15-year follow-up study has revealed a strong relationship between autonomic dysfunction and insufficient vagus nerve activity (revealed by impaired heart rate recovery following exercise cessation), impaired glucose homeostasis and development of type 2 diabetes mellitus. Together, these preclinical and clinical findings support the hypothesis that diminished vagus nerve signaling in obesity could lead to enhanced inflammation and metabolic complications.”

Reducing obesity-associated inflammation with vagal support

Vagal cholinergic stimulation can alleviate the inflammation and metabolic complications of obesity:

“Targeting cholinergic mechanisms in the inflammatory reflex using α7nAChR agonists or a centrally-acting acetylcholinesterase inhibitor could alleviate inflammation and metabolic complications in obesity.”

Type 2 diabetes and cardiovascular risk can both be ameliorated by reducing inflammation through vagal support.

“The chronic inflammatory state associated with obesity is one such common step that could be targeted. Some anti-inflammatory approaches have already been explored in the treatment of obesity-linked disorders in preclinical and clinical scenarios. For example, patients with type 2 diabetes mellitus who were treated with a recombinant human IL-1 receptor antagonist (anakinra) experienced reductions in levels of IL-6 and CRP. Additionally, HbA1c levels in these patients were reduced and their pancreatic β-cell secretory function improved. Administration of salicylate—a known IKK inhibitor in rodents, which propagates proinflammatory signals—significantly improved glucose homeostasis, reduced free fatty acid levels and increased adiponectin levels in patients with type 2 diabetes mellitus.”

Therapeutic Considerations

In addition to stimulation of the vagus by devices and pharmacotherapy, there are numerous ‘hands-on’ therapies that stimulate the CNS from the periphery (chiropractic, cranial therapy, auriculotherapy, acupuncture, etc.) that, when properly rendered, increase parasympathetic (vagal) activity. The authors conclude:

“The inflammatory reflex mediated by the vagus nerve has been successfully exploited therapeutically in preclinical models of diseases with aetiologies characterized by excessive inflammatory responses. Insufficient efferent vagus nerve cholinergic output might have a causative role in the dysfunctional immune and metabolic regulation observed in obesity, as selective activation of the efferent cholinergic arm of the inflammatory reflex attenuates both inflammation and metabolic derangements. Although cholinergic suppression of inflammation can contribute specifically to alleviating metabolic complications, direct cholinergic effects on metabolic pathways could also have a role in alleviating symptoms associated with the metabolic syndrome and type 2 diabetes mellitus. These complex interactions and the contribution of central and peripheral mechanisms in this regulation are topics of ongoing study. Additionally, intracellular mechanisms by which cholinergic signals control obesity-associated inflammation and modulate insulin signaling are under investigation…The use of cholinergic modalities in combination with existing or new therapeutic approaches to target neural, endocrine and immune functions for therapeutic benefit in patients with obesity-related disorders should also be considered.”

They offer a summary by way of these key points:

  • The inflammatory reflex is a physiological mechanism through which the vagus nerve regulates immune function and inhibits excessive proinflammatory cytokine production
  • Vagus nerve signaling has an important role in the regulation of feeding behaviour and metabolic homeostasis
  • Disruption of metabolic and immune regulation in obesity results in inflammation, which mediates insulin resistance and the development of type 2 diabetes mellitus as well as other debilitating and life-threatening conditions
  • Activation of cholinergic signaling in the efferent arm of the inflammatory reflex alleviates obesity-associated inflammation and metabolic derangements
  • The inflammatory reflex can potentially be exploited for treatment of the metabolic syndrome, type 2 diabetes mellitus and other obesity-driven disorders

Readers may also be interested in how vagal activity regulates the brain-immune relationship.

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