The demonstration that the vagal system affects inflammation regulation has endorsed exploratory attempts at therapeutics. Neuromodulation suggests using devices to control the nervous system’s electrical activity in order to restore organ function and health, partially avoiding toxicity, collateral damage, and poor compliance [32]. Epileptic syndromes, depression, and chronic gastroenterological and rheumatological disorders were initially the main targeted fields. In the late 19th century, vagus nerve stimulation (VNS) was first employed to treat epilepsy. VNS is now authorized for the treatment of depression and refractory epilepsy. With rising efficacy of up to 10 years, VNS, used to treat drug-resistant epilepsy, drives a 50% reduction in seizure frequency and intensity in 40–60% of patients, demonstrating that this treatment is a slow-acting therapy [33].

In gastroenterology, clinicians have focused on inflammatory bowel disease (IBD). IBD is characterized by an imbalance of the autonomic nerve system, vagal dysfunction in UC [34], and sympathetic dysfunction in CD [35], which may contribute to its pathogenesis. High serum TNF-α levels and salivary cortisol levels were connected with low vagal tone in CD patients, supporting the idea that the HPA axis and the autonomic nervous system are out of balance [36].

Positive correlations between vagotomies and subsequent IBD have been found, and this is especially true for CD, which highlights the importance of VN integrity in the prevention of IBD [18]. Hence, it stands to reason that in those who are at risk, the degree of vagal tone is a good indicator of the emergence of an inflammatory illness. Vagal hypotonia, which, in turn, keeps this inflammatory state in place, can be caused by the systemic inflammation seen with IBD or other chronic inflammatory illnesses. Furthermore, due to its central effects, persistent inflammation can cause depression, which, in turn, might trigger an inflammatory flare-up of the illness [37,38].

In two early studies, Lindgren et al. measured the cardiac responses to tilt (acceleration and brake index) and deep breathing (E/I ratio) in 40 UC and 33 CD patients to assess autonomic nerve function. They discovered sympathetic dysfunction in CD and vagal dysfunction in UC [34,35]. An increasingly popular noninvasive test to evaluate autonomic function is heart rate variability (HRV). In 27 IBD patients who were in remission and 28 healthy controls, Mouzas et al. evaluated HRV. When compared to healthy controls, it was shown that UC and CD patients who were in remission appeared to have more vagal activity [39]. According to Ganguli et al. in 2007, patients with UC but not CD showed more sympathetic activity compared to controls [40]. In a recent study, CD patients in remission exhibited a considerably larger sympathetic–parasympathetic ratio, according to Zawadka-Kunikowska et al. [41].

Some vagal afferent fibers come into close touch with intestinal mucosal mast cells as they go to the tips of the jejunal villi. These findings offer the microanatomical foundation for mast cells in the gastrointestinal mucosa to communicate directly with the central nervous system [4]. It is interesting to note that the efferent VN interacts with enteric neurons instead of directly connecting to the gut’s resident macrophages. Therefore, enteric neurons rather than vagal efferent fibers directly mediate the vagal regulation of these intestinal macrophages [27,30]. Pro-inflammatory cytokines that stimulate vagal afferents cause the activation of vagal efferents, which prevents tissue macrophages from releasing these cytokines, including TNF and other pro-inflammatory cytokines such as IL-6 and IL-1β but not the anti-inflammatory cytokine IL-10 [42]. This is known as an inflammatory reflex.

The VNS maneuver requires the implantation of a device by a surgeon experienced in the specific field [43]. The maneuver takes about 1 h. An electrode is wrapped around the left VN neck area at the carotid artery, tunneled under the skin, and connected to a pulse generator implanted under the skin of the left chest. For the stimulation, the left VN is usually chosen because it is not involved in the regulation of heart rhythm [44]. The device is initially started at 0.25 mAmp, then progressively increased according to the patient’s need and tolerance. Stimulation is intended as continuous but is alternated with ON–OFF phases. Direct VNS delivered by an implanted pulse generator is typically secure and well tolerated. Hoarseness, increased coughing, changes in voice/speech, discomfort, throat or larynx spasms, headache, sleeplessness, indigestion, and other adverse effects are possible with VNS used to treat epilepsy [43]. The most frequent of them, typically transient, are hoarseness, coughing, throat tickling, and shortness of breath.

The effectiveness of various therapies is significantly influenced by the frequency of stimulation for VN activation [45]. The most prevalent applications of high frequency (20–30 Hz) are in the treatment of epilepsy and depression. High frequency is traditionally thought to trigger vagal afferents. Lower frequency (1–10 Hz), on the other hand, is thought to activate vagal efferents, which have anti-inflammatory characteristics. The end point of neurostimulation therapy in IBD coincides with the activation of the cholinergic system/CAIP activator (see above) through low-frequency stimulation (1–10 Hz) of the efferent fibers. VNS likely activates both its afferent (which activates the HPA) and efferent (which activates the CAIP) fibers to exert its anti-inflammatory effects in IBD.

An initial study of experimental 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis in rodents demonstrated that VNS was able to moderate inflammatory data and colic lesions [46].

A VNS study was recently performed in CD patients, for which the VNS was positioned in the therapeutic algorithm at the same level as an anti-TNF [47]. The majority of the patients (8/9) had active CD at the time of inclusion. Electrode Model 302 was implanted with bipolar pulse generator Model 102 (Cyberonics, Houston, TX, United States); 10 Hz, 500 s, 0.5 mA, 30 s ON, 5 min OFF, constantly were the stimulation parameters. Patients between the ages of 18 and 65 who had a Crohn’s disease activity index (CDAI) score between 220 and 450 (i.e., moderate or severe CD), with small bowel (ileum) and/or colonic CD, C-reactive protein (CRP) > 5 mg/L and/or fecal calprotectin >100 μg/g, as well as a Crohn’s disease endoscopic index of severity (CDEIS) score ≥ 7 (active) and had been diagnosed for more than 3 months, were treatment-naive, or had a stable treatment reference (two patients were failing azathioprine, while the remaining seven were treatment-naive) were included. At the time of inclusion, patients who were taking infliximab or another anti-TNF drug were ineligible. VNS was carried out constantly for a year. The first patient received an implant in April 2012 and the final one in March 2016. After three months of neurostimulation, due to a worsening of their condition, two individuals were taken out of the study, most likely as a result of the especially high inclusion scores for CDAI (>350), CDEIS (>14), and CRP (>88 mg/L), which implies that VNS is recommended for mild-to-moderate active CD due to its gradual effect, as seen for epilepsy [48]. The first patient got an ileo-cecal resection but decided to continue neurostimulation until the end of the research due to an initial positive result and drug treatment refusal; the second patient was excluded from the study after three months due to a deterioration of disease. Infliximab and azathioprine were used to treat the second patient, who likewise desired to continue using an active VNS. Five of the nine patients experienced a deep (clinical–biological–endoscopic) remission, with also restored vagal tone, after receiving VNS. Median CDAI passed from 264 to 88, median CRP from 7 to 3 mg/L, median calprotectin from 847 to 61 µg/g, and median CDEIS from 8 to 0. They noticed that the VNS effect did not occur right away but rather took at least three months to manifest: in patients with significant flares, VNS should not be utilized alone, at least in the first months. Three more paradigmatic pro-inflammatory cytokines in CD, IL6, IL12, and IL23 were likewise decreased following a 12-month VNS. It is interesting to note that VNS decreases the perception of abdominal pain. Except for one patient who had an excessively high vagal tone, the majority of the CD patients studied here had low vagal tones upon inclusion that were restored to normal in all patients after a 12-month VNS. Although VNS might have a placebo effect, clinical remission following maintenance treatment ranged from 12% to 20% under placebo at 12 months in clinical trials using anti-TNF medicines in CD [49]. With the typical slight side effect of hoarseness as its main manifestation, VNS was well tolerated. According to the authors, these data indicate that VNS is feasible in IBD, but the study needs to be expanded to allow for interpretation.

In a second pilot trial, D’Haens et al. examined the effects of VNS over a period of 16 weeks in 16 patients who had colonic or small intestinal CD with biologic resistant disease [50]. Patients had CDAI 220–450, calprotectin >200 µg/g, an endoscopic score of activity (SES-CD: Simple Endoscopic Scale for Crohn’s Disease) with a minimal ulcer score of 2 or 3 in at least one segment, a history of inadequate response and/or intolerance or adverse events to one or more TNF-α inhibitors (e.g., infliximab, adalimumab, or certolizumab pegol), and an 8-week washout of biologics (group 1) or concomitant biologic therapy (Group 2). One minute of daily stimulation was started two weeks after a VNS device was implanted; between weeks 4 and 6, this was extended to five minutes; in the event that CDAI remission was not reached by week 8, stimulation was increased to four times daily. CDAI decreased from 294 to 201, calprotectin 2974 to 590, and SED-CD from 22.3 to 17.5. Seven of the sixteen patients obtained a CDAI-70 response and four of the sixteen patients CDAI remission. In terms of side effects, one patient developed a postoperative infection due to the device.

In nine ileo-colonic CD patients, Kibleur et al. evaluated the effects of VNS on inflammation and brain activity. They found that 12 months of chronic VNS improved CDAI, fecal calprotectin, anxiety state, and vagal tone, which were associated with a decline in the electroencephalogram’s α frequency band [51].