Decade-long follow-up finds vagus nerve stimulation feasible and safe in Crohn’s disease

Patients with mild to moderate Crohn’s disease who received an implanted vagus nerve stimulator have now been followed for up to ten years, and the results of that long-term observation have been published in the journal Bioelectronic Medicine. The report, from a French team that first implanted the devices between 2012 and 2016, describes what happened to nine patients after their original one-year pilot study ended. Three patients remained in remission on vagus nerve stimulation alone for the full decade of follow-up, without any additional Crohn’s disease therapy, while several others controlled their disease with the implant alone for three to seven years before eventually needing biologics or surgery. The authors are careful to frame the work as a proof of concept rather than a demonstration of efficacy, since the study involved only nine people, had no control group, and no statistical analysis was possible.

Vagus nerve stimulation is not a new idea in medicine. The technique, which delivers intermittent electrical pulses to the vagus nerve through an electrode wrapped around the nerve in the neck, is already approved for drug-refractory epilepsy and has an established safety record in that field. What makes the nerve interesting for inflammatory disease is its biology. The vagus nerve is the main parasympathetic branch of the autonomic nervous system and innervates the entire digestive tract. It carries anti-inflammatory signaling both through its afferent fibers, which engage the hypothalamic-pituitary-adrenal axis, and through its efferent fibers, which drive the so-called cholinergic anti-inflammatory pathway. That pathway suppresses the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin-6 by peripheral immune cells, acting through alpha7 nicotinic acetylcholine receptors on macrophages. People with Crohn’s disease tend to have low vagal tone, a state associated with higher inflammation, which is the rationale for trying to boost vagal activity electrically.

The nine patients in the original pilot study ranged from 20 to 52 years old and had mild to moderate ileo-colonic Crohn’s disease, with activity scores between 220 and 450 on the Crohn’s disease activity index. After the one-year pilot ended, all nine chose to keep their stimulators active, including two patients who had been withdrawn early because their disease worsened in the first three months.

The decade of follow-up revealed strikingly individual courses. Three patients, numbered P1, P3 and P8 in the report, never needed any other treatment and were still in remission after ten years of active stimulation, with colonoscopies at four and ten years showing no inflammatory activity in one of them. Patient 7 achieved endoscopic remission after three years but asked to have the device switched off, though not removed, because she wanted to become pregnant; she was later lost to follow-up. Three other patients, P5, P6 and P9, did well on stimulation alone for four to seven years before relapsing, most of these relapses clustering during the Covid-19 period, and then required biologics alongside the implant. Patient 9, who refused steroids and biologics for years, managed repeated flares with antibiotics alone before finally accepting infliximab, after which colonoscopy showed complete remission.

The two patients implanted with the most severe disease fared worst. Patient 2 had severe endoscopic activity, a markedly elevated C-reactive protein level and a fecal calprotectin reading of 1577 micrograms per gram, along with an ileal fistula and abscess, and needed an ileocecal resection within three months of implantation. Patient 4 required infliximab just three months after surgery of the device. Both eventually reached stable remission, but only with combined therapy. The authors draw a practical lesson from this: implanting a stimulator in someone with very active, severe disease appears to be the wrong strategy, and the device should be considered for patients whose inflammation is low to moderate rather than blazing.

Beyond the clinical scores, the study tracked objective markers of vagal function. Individual trajectories varied widely, with some patients showing sustained increases and others fluctuating or declining, and several follow-up values were simply missing because recordings became voluntary after the rigorous first protocol year. Digestive pain, rated on a visual analog scale, fell from moderate to low within the first year and stayed low for six years, with one exception. Median anxiety and depression scores on the hospital scale dropped below the clinical threshold in the first year and remained there, a pattern the authors attribute partly to known central neuromodulatory effects of vagus nerve stimulation on mood and pain processing rather than to inflammation control directly.

Safety was a clear positive. No local infections occurred at the stimulation site, no neurostimulators or electrodes had to be removed, and no patient experienced severe side effects. The main complaint was discomfort from the electrical output, including the voice hoarseness classically seen in epilepsy patients, and this varied from pronounced in some patients to absent in others. All patients remained adherent to the therapy, and all but the one who switched off for pregnancy still had active devices at the end of follow-up. The authors note this contrasts favorably with biologic drugs, which carry risks of infections, skin reactions such as psoriasis, and loss of effect over time, and which roughly half of patients fail to respond to adequately in the first place.

The report is candid about its weaknesses. With nine patients, no sham control, no randomization, no blinding, and substantial missing data, particularly for fecal calprotectin because patients were reluctant to collect stool samples, the findings cannot establish efficacy or identify who will respond. The authors also acknowledge a fundamental interpretive problem: for patients who never relapsed under stimulation alone, there is no way to know whether they would have relapsed without the implant. What the study does establish is that long-term invasive cervical vagus nerve stimulation is feasible, safe and acceptable in this population, and that a subset of patients showed a durable therapeutic signal worth testing properly.

The wider field is moving quickly. An independent open-label study in seventeen biologic-refractory Crohn’s patients reported significant reductions in disease activity, fecal calprotectin and mucosal inflammation after four months of intermittent stimulation, and the United States Food and Drug Administration has recently approved an implanted vagus nerve system for rheumatoid arthritis based on a 242-patient trial showing sustained benefit through twelve months. Non-invasive approaches are also advancing: transcutaneous auricular stimulation, which tickles the ear’s vagal branch with electrodes rather than surgery, activates similar brain regions to cervical stimulation and showed safety and symptom improvement in a small trial of children and young adults with mild to moderate inflammatory bowel disease. Researchers are now exploring closed-loop systems that would read a patient’s autonomic state, perhaps through wearable sensors measuring nighttime heart rate variability, and adjust stimulation automatically. Whether vagus nerve stimulation earns a place in routine Crohn’s disease care will depend on the large, controlled trials the authors say are still needed.

Subject of Research: Long-term observational follow-up of implanted vagus nerve stimulation in patients with Crohn's disease

Article Title: Vagus nerve stimulation in Crohn’s disease: long-term outcomes, mechanistic insights, and the promise of non-invasive approaches

Article References: Sinniger, V., Pellissier, S., & Bonaz, B. (2026). Vagus nerve stimulation in Crohn’s disease: long-term outcomes, mechanistic insights, and the promise of non-invasive approaches. Bioelectronic Medicine, 12(1), Article 11. https://doi.org/10.1186/s42234-026-00205-z

Image Credits: AI Generated

DOI: 10.1186/s42234-026-00205-z

Keywords: vagus nerve stimulation, Crohn's disease, bioelectronic medicine, neuromodulation, inflammatory bowel disease, heart rate variability, cholinergic anti-inflammatory pathway, pilot study, non-invasive VNS, biologics, proof of concept, Vagus