Vagus Nerve Stimulation as a Treatment for Allergic Asthma

Around 262 million people worldwide grapple with asthma annually. A multi-institutional study led by Dr. Caroline Sévoz-Couche at Sorbonne University demonstrates the potential of vagus nerve stimulation (VNS) to treat allergic asthma, a subtype of asthma triggered by allergies.

Characterization of allergic asthma

Allergic asthma manifests as a collection of inflammatory conditions, including airway inflammation, excessive mucus secretion and increased airway responsiveness. Currently, the primary therapy for asthma is the use of bronchodilators, or beta agonists, which open up the airways and reduce mucus, as well as steroid and non-steroid anti-inflammatory medications. However, many patients with severe asthma who do not respond sufficiently well to conventional therapy require more serious interventions. Various receptors play important roles in regulating the inflammatory status of the airway. Muscarinic acetylcholine receptors (mAChRs) are involved in smooth muscle contraction within the airway, which can lead to airway hyperresponsiveness. On the other hand, nicotinic acetylcholine receptors (nAChRs) are involved in the anti-inflammatory response. Moreover, the cholinergic anti-inflammatory pathway (CAP) monitors inflammatory responses by inhibiting the synthesis of proinflammatory cytokines through α7naChR activation. Activation of the CAP can be achieved by pulsed electrical VNS and has been shown to be useful as a therapy in inflammatory disease models for conditions such as inflammatory bowel disease and rheumatoid arthritis. Thus, Sévoz-Couche’s team was interested in exploring this therapy for allergic asthma.

Using vagus nerve stimulation in house dust mite-induced asthma

Female mice, aged 6 to 8 weeks, were treated with house dust mite (HDM) extract to induce allergic airway inflammation. On day 14 post-treatment, the team stimulated the vagus nerve of the mice at 0.05, 0.1, 0.5 or 1 mA using electrodes around the midsection of each mouse, with 5 mice being used in each experimental group. On day 17, the mice were euthanized and samples from the bronchoalveolar lavage (BAL) fluid, blood and lung tissues were collected. Flow cytometry was used to analyze the BAL fluid and transmission electron microscopy the lung tissue to understand changes seen in the structure, cell infiltration and mucus production. Immunofluorescence staining was also used to detect proteins in the lung tissue, and airway responsiveness was measured by recording lung resistance and dynamic compliance in response to nebulized methacholine.

The key findings from this study were that:

• VNS at 0.1, 0.5 and 1 mA significantly reduced inflammatory cell infiltration in BAL fluid, specifically of eosinophils and macrophages, but pre-treatment with α-BGTX, an α7naChR-antagonist, reversed this effect.
• VNS at 0.1 mA significantly suppressed the production of type 2 cytokines in BAL fluid, specifically IL-4 and IL-5.
• VNS at 0.1 mA reduced bronchial epithelial hypertrophy and mucus hypersecretion induced by HDM.
• VNS at 0.1 mA blocked HDM-induced airway hyperresponsiveness, demonstrated by decreased lung resistance and increased dynamic compliance.

Vagus nerve stimulation as a treatment for allergic asthma shows promise in mice

Although VNS has shown positive results in treating other inflammatory diseases, the use of VNS in treating allergic asthma remains understudied, up until now. Dr. Sévoz-Couche and her team set out to address this gap and found promising results. VNS at 0.1 mA reduced HDM-induced inflammation, indicated by the reduced inflammatory cell infiltration, proinflammatory cytokine secretion, mucus hypersecretion and airway hyperresponsiveness. Furthermore, the effect of the α7naChR-antagonist in reversing this indicates that α7naChRs may play a role in the anti-inflammatory response.

For the millions of people who are suffering from allergic asthma every year, Sévoz-Couche et al’s results in mice are promising. If VNS could be used as a treatment for allergic asthma, it could provide relief to many patients who struggle to find treatment options that work for them. Furthermore, this study provides insight into the mechanisms that may be responsible for regulating inflammatory and anti-inflammatory responses in patients with asthma, which could be useful in the development of other treatments as well.

It is important to note, however, that the group sizes used for this study were relatively small, so it would be helpful to repeat this study with a larger sample size to confirm the results. Additionally, if this treatment were to be tested in clinical trials, there are several other factors that would be important to consider. For example, it would be important to know how long the treatment’s effect lasts as this impacts its viability as a treatment option and its application. Furthermore, it would be critical to know the most appropriate frequency of therapy usage in a patient, specifically if it would only be used in emergency settings or used as a recurring scheduled treatment in patients. While their study did explore the involvement of α7naChR in the anti-inflammatory response, it would be useful to explore other potential mechanisms or interactions that could have contributed to the observed results. Further testing is also required to see if these results would translate into humans and in patients with naturally occurring, as opposed to experimentally induced, asthma.

Long-term outcomes of the treatment

This study shows promise in the development of a non-drug treatment for allergic asthma, particularly important for individuals whose condition is resistant to conventional treatments. Beyond demonstrating the potential of VNS, their research delved into the interplay of native responses, shedding light on how they contribute towards the efficacy of VNS. It will be particularly important next to understand the long-term outcomes of this therapy and if and how it can be implemented in humans.

Reference

Sévoz-Couche C, Liao W, Foo HYC, et al. Direct vagus nerve stimulation: A new tool to control allergic airway inflammation through α7 nicotinic acetylcholine receptor. Br J Pharmacol. Published online March 2, 2024. doi:10.1111/bph.16334

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