This article is part of the IBD Index. Last updated on January 27, 2022.
Vagus nerve stimulation is an ongoing area of research and experimentation for me. If you want to follow along on my personal journey, follow me on Instagram! Eventually, I will update and expand this post as well.
Table of Contents
What is vagus nerve stimulation?
What is the vagus nerve?
What’s the science behind vagus nerve stimulation for IBD?
Activation of the HPA axis
Cholinergic anti-inflammatory pathway
Activation of sympathetic anti-inflammatory pathways
Is there clinical evidence for vagus nerve stimulation in IBD?
Are there any risks to vagus nerve stimulation?
How can I increase vagal tone at home?
Mind-body disciplines: yoga, tai chi, qigong, meditation
Other possible interventions
Review of the literature
Technical details of clinical vagus nerve stimulation
What is Vagus Nerve Stimulation?
In the clinical research setting, vagus nerve stimulation (VNS) refers to stimulation of the vagus nerve via electrical impulses. This can be done either invasively, via a surgical implant, or noninvasively, via electrodes stuck to the skin in the ear. (For technical details, check out this section at the bottom of this article.)
VNS has been approved by the FDA for the treatment of drug‐resistant epilepsy and depression, and interest is building for its application in the treatment of chronic inflammatory disorders such as rheumatoid arthritis (and of course, IBD). VNS is not yet available as a clinical treatment for IBD, but two small trials have been conducted in patients with Crohn’s Disease (CD), and two more trials are underway.
Outside of clinical research, talk of stimulating the vagus nerve typically refers to at-home practices that naturally stimulate the vagus nerve, including things like deep breathing and meditation. More on these techniques below!
What is the Vagus Nerve?
The vagus nerve is a lengthy cranial nerve that connects the brain with many of our internal organs, including the heart and the entire gastrointestinal tract. The nerve contains both afferent, or sensory, fibers (which carry information from the internal organs to the brain), and efferent, or motor, fibers (which carry “instructions” from the brain to the organs). VNS stimulates both the afferent and efferent fibers of the vagus nerve. (Source)
Some of the efferent effects of the vagus nerve include lowering heart rate and stimulating the production and secretion of digestive juices, as well as promoting intestinal motility. You might be familiar with these as the “rest and digest” functions of the parasympathetic nervous system (PNS); indeed, the efferent branch of the vagus nerve is the main component of the PNS.
But as you can see from the image below, the vast majority of the vagus nerve fibers are dedicated to information flow in the opposite direction – bringing sensory information from the organs to the brain. In addition to the gut and the heart, afferent vagal fibers innervate most every major organ system, including the lungs and liver. (Source)
What’s the Science Behind Vagus Nerve Stimulation for IBD?
Before getting into the mechanisms at play, I want to briefly mention some relevant epidemiological findings. Several studies have demonstrated a relationship between vagal tone and IBD, with both CD and UC associated with low vagal tone or disrupted sympathetic/parasympathetic balance compared to healthy controls. (Source 1, 2, 3) Additionally, among IBD patients, higher vagal/parasympathetic activity appears to be associated with lower inflammation and better disease outcomes.
Interestingly, another study found a small but significant positive association between vagotomy (removal or cutting part of the vagus nerve) and later development of IBD, particularly for CD. (Source)
VNS is posited to be beneficial for IBD (as well as other chronic inflammatory conditions) by reducing inflammation via several different pathways. These pathways involve complex mechanisms that are still debated in the literature (Source 1, 2, 3, 4), but the current majority consensus seems to be that the following three pathways contribute to the anti-inflammatory effects of VNS:
1. Activation of the HPA axis by vagal afferents
Afferent fibers of the vagus nerve in the gut sense inflammatory cytokines (such as IL-6, TNF-alpha, etc) released by local immune cells in response to a perceived threat. That signal travels to the brain, where it activates the HPA axis, ultimately resulting in cortisol release from the adrenal glands. Cortisol has systemic anti-inflammatory effects.
2. The cholinergic anti-inflammatory pathway
Efferent fibers of the vagus nerve synapse with nerves in the enteric nervous system, which then inhibit TNF-alpha production by immune cells nearby in the gut. It also appears that vagal efferents in this pathway have a similar inhibitory effect on immune cells in the spleen (which is the major source of inflammatory cytokines in systemic inflammation), although the exact interactions are debated.
(In case you were wondering about the name, “cholinergic” refers to the fact that acetylcholine is the neurotransmitter used by vagal efferent fibers.)
3. Activation of sympathetic anti-inflammatory pathways by vagal afferents
This pathway seems to be the least well-characterized, or at least the most debated, but it appears as though vagal afferent stimulation also activates sympathetic nerves that act both systemically and locally at the spleen to reduce TNF-alpha production by immune cells.
(For additional context, these sympathetic pathways are also the primary responders to systemic immune challenge that isn’t necessarily mediated by the vagus nerve [eg, in the case of an infection, where sensing of the immune threat happens somewhere in the body other than at the gut/vagus nerve interface]. That type of systemic inflammatory reaction would also typically lead to a fever.)
What I find fascinating about VNS as a possible IBD treatment is that it has the potential to act as an upstream holistic version of several interventions that we already know are somewhat effective.
What I mean is this: via the above-described pathways, VNS has the potential to increase cortisol secretion via the HPA axis, and decrease TNF-alpha production via the cholinergic anti-inflammatory pathway and the sympathetic/splanchnic anti-inflammatory pathway.
Glucocorticoids (like prednisone) are widely used and effective for reducing inflammation in IBD. TNF-alpha inhibitors are also widely used for IBD.
So it seems that VNS may provide a way to harness the anti-inflammatory effects of (somewhat) natural glucocorticoid release and TNF-alpha inhibition in a way that maintains the natural synergism of these systems, hopefully resulting in increased effectiveness with fewer side effects. (Of interest, there is indeed evidence that these systems work synergistically to reduce inflammation, and that this synergism may be disrupted in IBD.)
Weirdly, the one clinical trial that has been done (described below) did not report cortisol values, and the focus of VNS seems to be on triggering the cholinergic anti-inflammatory pathway, so maybe I’m off base with my musings above. We’ll see how things play out.
Is There Clinical Evidence for Vagus Nerve Stimulation in IBD?
Yes! We have a grand total of two clinical trials testing VNS in Crohn’s disease, one of which has published results. That trial tested VNS via a surgically-implanted device in 9 patients with CD, and reported a reduction of inflammatory markers and improvement in symptoms in 7 of them, with 6 in endoscopic remission and 5 in clinical remission. The other two were removed from the study because their disease worsened such that they needed to try other treatments, but they both elected to keep the VNS device as well.
The other trial has shared preliminary results in abstract form that indicate improvement in half of the included 16 patients. There are also two more trials are underway, one in adults with UC and one in children/adolescents with any type of IBD (ClinicalTrials.gov identifiers NCT03908073 and NCT03863704).
For a more detailed look at these trials, along with references for relevant review articles and animal/in vitro experimental data, you can check out the review of the literature section below.
Are There Any Risks to Vagus Nerve Stimulation?
The first published clinical trial mentioned above didn’t report any significant adverse events or tolerance issues. The full results from the second have not yet been published, and I don’t have a way to access them, but a review paper shared that 14 serious adverse events were reported in 9 out of 16 patients, with 3 early terminations. (Source)
However, it’s very possible that none of those events were related to the VNS treatment; in clinical trials, adverse events are reported even if they’re related to the patient’s disease, another medication, or something completely unrelated to the treatment or disease under study. Based on the overall safety profile of VNS gathered from VNS studies in conditions other than IBD (such as depression and epilepsy), I’ll be very surprised if significant safety issues are reported when the results are ultimately published.
How Can I Increase Vagal Tone at Home?
Since invasive VNS is not currently available to IBD patients outside of clinical trials, we must turn our attention to other methods of stimulating the vagus nerve for this article to have any practical value whatsoever.
I previously mentioned noninvasive VNS, which is done via electrodes on the surface of the skin of the ear (picture and description here). The technical details section at the bottom of this page includes a description of these devices, but it’s unclear whether these are available to the public. My guess is that they aren’t, and in any case, this would probably not be something I’d recommend to play around with on your own.
So what can you do to stimulate the vagus nerve and increase vagal tone?
Mind-Body Disciplines: Yoga, Tai Chi, Qigong, Meditation
The most reliably beneficial interventions are – you guessed it – mind-body disciplines such as yoga, tai chi, qigong, and meditation. These methods have all been shown clinically to improve vagal tone (along with a variety of other attendant health benefits). The mechanism at play is not very well characterized at this point, but it seems likely that breath control is a big factor, since slow, diaphragmatic breathing with long exhalations has also been shown to improve vagal tone. (Source 1, 2)
This paper describes the two ways that breathing can stimulate the vagus nerve:
“In our model there are two ways respiration can stimulate VN: directly and indirectly. In the direct route, slow breathing and extended exhalation are caused by vagal activity. This follows from the previously mentioned role of VN in respiratory affective and effective processing (slowing and exhalation). Controlled breathing in this form thus uses the vagal nerve as effector and increases its activity volitionally, if only momentarily.
“The indirect route involves stimulation through biofeedback and follows from physiological feedback theory: by adopting physiological body patterns associated with relaxation and low threat situations (i.e., slow breathing) vagal afferents project this state to the CNS, which interprets this as a reflection of the current contextual threat level, and proceeds by further adopting a rest-and-digest state top-down, again through VN. The indirect route is responsible for more long-term tonic changes of vagal tone. By either route, breathing styles with low respiration rate and low inhalation/exhalation ratio should show increases in vagal tone, though in slightly different timeframes.”
Still related to breathing is another intervention that has been clinically shown to improve vagal tone: left-nostril breathing.
This one was an unexpected find, and the simplicity of the technique belies its effectiveness. Based on the evidence thus far, it appears that breathing exclusively out of the left nostril for a period of time every day reliably increases vagal/parasympathetic tone over time.
The best study on this to date divided 85 volunteers into three groups: 30 each for right-nostril breathing (RNB) and left-nostril breathing (LNB), plus a control group of 25. After six weeks, HRV metrics indicated that the RNB group had significantly increased sympathetic activity, while the LNB had increased parasympathetic activity. (Source) The LNB group also experienced decreased resting heart rate, blood pressure, and mean arterial pressure, while the RNB group experienced increases in all those parameters.
How did they do it? Here’s the description of the practice from the paper: “For RNB and LNB groups, the subjects were allowed to be seated in a well-ventilated room of the Physiology department and were taught to practice right or left nostril breathing, for 1h every day between 5 and 6 PM for 6 weeks. For the purpose, they were asked to sit in an easy and steady posture with the head, neck, and trunk erect. They were instructed to bring the right hand up to the nose and close the left nostril (for RNB) or right nostril (for LNB) with the finger and then breathe through one nostril only. During this unilateral breathing the exhalation and inhalation were of equal duration and without any pause. Breathing was diaphragmatic and slow and controlled with no sense of exertion. For both inspiration and expiration, they were asked to count 1 to 5 in their mind (each count was roughly one second) for each phase, so that each respiratory cycle lasted for about 10 s.”
The control subjects apparently sat in the same room for the same amount of time without any specific breathing intervention. (It seems to me it would’ve been a better control if they’d been instructed to breathe counting to 5 in the same way as the experimental groups, so that the only variable was the use of the left, right, or both nostrils….but what do I know?)
Other Possible Interventions
One review article on cardio-vagal control also identifies a number of additional factors that appear to increase vagal tone (with the caveat that the evidence reviewed almost exclusively uses indirect measures such as heart rate variability that have been shown to be good proxies for vagus nerve activity, but do not directly measure vagal tone; that caveat also applies to the research mentioned above on mind-body exercises and left nostril breathing). These include:
- long-term caloric restriction
- consumption of fatty fish/omega-3 oils
- water immersion
- social contact/support, including physical touch
- contact with animals
- certain smells, like lavender and pine
- time in nature
- time at high altitudes
- physical activity
I’ve also seen widespread claims that gargling, humming, and singing stimulate the vagus nerve, and although this makes sense anatomically, I haven’t yet located the source/evidence for these claims. In any case, humming and singing are fun, joyful activities that we could probably all use more of regardless, so knock yourselves out.
Basically, if it feels like something is good for you but you aren’t sure how, a) it probably is good for you, so keep doing it, and b) don’t be surprised if the mechanism is the vagus nerve.
Finally, a couple reviews mentioned preliminary animal evidence that high-fat meals and fasting may stimulate the vagus nerve and induce the cholinergic anti-inflammatory pathway (described above), but I think the jury is still out on whether those things have any clinical relevance. (Source)
Review of the Literature
The two clinical trials conducted on VNS in IBD thus far are marked with an *asterisk. Two additional trials are underway. Two particularly good recent reviews on the topic are also summarized below. The remaining review articles specifically dealing with VNS in IBD are listed next, and additional references used in this article that don’t pertain directly to IBD are listed below that.
Bonaz et al. Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases. 2021. Front Neurosci.
- Thorough and recent review article on VNS for IBD, from who appears to be the leading researcher in the field. Gives good context/background, reviews mechanisms, and also summarizes relevant in vitro and animal research in addition to human research.
- Makes interesting comments at the end about the future of bioelectronic medicine, including suggestions for the miniaturization of the VNS device and a device able to trigger VNS automatically in response to low HRV. One system, AspireSRTM by Cyberonics Inc. (which is already approved in Europe) responds to seizures automatically based on sensing changes in heart rate, so that type of technology is already within our reach.
Cheng et al. Potential of Electrical Neuromodulation for Inflammatory Bowel Disease. 2020. Inflammatory Bowel Diseases.
- Another excellent review, including a helpful table summarizing the animal and clinical evidence for VNS, as well as sacral nerve stimulation, in IBD. Also includes a clear and succinct description of the various vagus-mediated anti-inflammatory pathways, and helpful diagrams/pictures depicting the methods of VNS (invasive and noninvasive).
- Discusses other methods of electrical neuromodulation that have potential relevance to IBD, including sacral nerve stimulation, tibial nerve stimulation, electroacupuncture, and spinal cord stimulation.
*Sinniger et al. A 12-month pilot study outcomes of vagus nerve stimulation in Crohn’s disease. 2020. Neurogastroenterol Motil.
- Uncontrolled pilot study in 9 patients with moderate active CD who were either treatment-naive or in failure of the immunosuppressant azathioprine.
- A Cyberonics electrode (the same one used for epilepsy; the same parameters were used as well) was surgically implanted and provided vagus nerve stimulation for 12 months.
- Two patients were removed from the study after 3 months due to worsening of their disease requiring other interventions, but both elected to keep the VNS as well.
- Of the remaining 7 patients, 5 were in clinical remission and 6 were in endoscopic remission with VNS as the only active therapy. C-reactive protein (CRP) and fecal calprotectin decreased in 6 and 5 patients, respectively, and all 7 restored their vagal tone and decreased their digestive pain score.
- The patients’ cytokinergic profile evolved toward a more “healthy profile”: Interleukins 6, 23, 12, tumor necrosis factor α, and transforming growth factorβ1 were the most impacted cytokines.
- Interestingly, VNS didn’t indiscriminately increase vagal tone; in patients who began the trial with abnormally high vagal tone, VNS brought it down.
- Comment in Bonaz et al 2021: “This regulation-modulation mechanism of VNS on the return to equilibrium of the ANS but also that of the cytokines is quite original and rare in therapy outside of the example of thymoregulatory drugs like lithium. This requires serious consideration of this fundamental question by continuing investigations in this field.”
- Associated citations:
- Clarençon et al. Long term effects of low frequency (10 hz) vagus nerve stimulation on EEG and heart rate variability in Crohn’s disease: a case report. 2014. Brain Stimul. (Case report of first patient treated in the trial)
- Kibleur et al. Electroencephalographic correlates of low-frequency vagus nerve stimulation therapy for Crohn’s disease. 2018. Clin Neurophysiol. (Summary of the EEG findings from the nine patients in the trial)
*D’Haens et al. The effects of vagus nerve stimulation in biologic-refractory Crohn’s disease: a prospective clinical trial. 2018. Gastroenterology.
- Not yet completed/published, but preliminary results showed clinical and endoscopic improvement for half of the 16 CD patients undergoing VNS (either alone or in combination with pharmaceutical therapies) after 16 weeks.
- The same VNS device was used, but with different parameters.
More review articles related to VNS and IBD:
- Bonaz et al. Is-there a place for vagus nerve stimulation in inflammatory bowel diseases?. 2018. Bioelectronic Med.
- Bonaz et al. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. 2017. J Intern Med.
Other references (not specific to IBD) used throughout article for descriptions of mechanisms:
- Populin et al. Neuronal regulation of the gut immune system and neuromodulation for treating inflammatory bowel disease. 2021. FASEB Bioadv.
- Breit et al. Vagus Nerve as Modulator of the Brain-Gut Axis in Psychiatric and Inflammatory Disorders. 2018. Front Psychiatry.
- Bonaz et al. Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation. 2016. J Physiol.
- Berthoud et al. Functional and chemical anatomy of the afferent vagal system. 2000. Autonomic Neuroscience.
Technical Details of Clinical Vagus Nerve Stimulation
The following snippets are from the 2021 Bonaz review article “Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases.” Probably most people won’t care about the technical specs of VNS, but I thought it was interesting, so wanted to share!
“The commonly used VNS parameters that activate vagal afferents in epilepsy and depression are: frequency, 20–30 Hz; intensity, 0.5–1.5 mA; pulse width, 500 μs; on‐time, 30 s; off‐time, 5 min. VNS parameters may easily be adjusted with a programming wand. The implantation of a VNS device is performed under general anaesthesia usually by a neurosurgeon familiar with this technique. Surgery lasts ∼1 h. An electrode (Model 302, Cyberonics) is wrapped around the left VN in the neck, near the carotid artery, tunnelled under the skin and connected to a bipolar pulse generator (Model 102) implanted subcutaneously in the left chest wall or in the axilla.”
“The effect of VNS in epilepsy and depression is mediated through the activation of vagal afferent fibres, performed at high frequency of stimulation (20–30 Hz), but the activation of the CAP is mediated through vagal efferent fibres and involves a low‐frequency (1–10 Hz) stimulation of the VN.” [Note: he explains later that experimental evidence has shown that even low frequency still stimulates afferent fibers as well as efferent.]
“The Cerbomed Nemos device (Erlangen, Germany) is an external device that provides tVNS by using a dedicated intra‐auricular electrode (like an earphone) which stimulates the auricular branch of the VN (Stefan et al. 2012). This device received the European clearance (CE mark) in 2010 for epilepsy and is currently available in Germany, Austria, Switzerland, and Italy. Likewise, the Electrocore LLC Gammacore device (Basking Ridge, NJ, USA) is a non‐invasive VN stimulator that uses proprietary electrical signals to treat primary headache. Such a device could be used, like the NEMOS, for inflammatory digestive disorders.”
“It is also possible to stimulate the VN at the left cervical level with the Gammacore device marketed by Electrocore LLC (Basking Ridge, NJ, United States) represented by two round stainless steel disks serving as a contact surface with the skin. This device, recommended in the treatment of headaches, epilepsy, and depression (Ben-Menachem et al., 2015), delivers a stimulation lasting 2 min with a frequency of 20 Hz. There is presently no clinical trial registered with this technique in Clinical.Trial.gov.”