Neuroimmune Modulation Through Vagus Nerve Stimulation Reduces Inflammatory Activity in Crohn's Disease Patients: A Prospective Open-label Study

Abstract

Background and aims: Crohn's disease [CD] is a debilitating, inflammatory condition affecting the gastrointestinal tract. There is no cure and sustained clinical and endoscopic remission is achieved by fewer than half of patients with current therapies. The immunoregulatory function of the vagus nerve, the 'inflammatory reflex', has been established in patients with rheumatoid arthritis and biologic-naive CD. The aim of this study was to explore the safety and efficacy of vagus nerve stimulation in patients with treatment-refractory CD, in a 16-week, open-label, multicentre, clinical trial.

Methods: A vagus nerve stimulator was implanted in 17 biologic drug-refractory patients with moderately to severely active CD. One patient exited the study pre-treatment, and 16 patients were treated with vagus nerve stimulation [4/16 receiving concomitant biologics] during 16 weeks of induction and 24 months of maintenance treatment. Endpoints included clinical improvement, patient-reported outcomes, objective measures of inflammation [endoscopic/molecular], and safety.

Results: There was a statistically significant and clinically meaningful decrease in CD Activity Index at Week 16 [mean ± SD: -86.2 ± 92.8, p = 0.003], a significant decrease in faecal calprotectin [-2923 ± 4104, p = 0.015], a decrease in mucosal inflammation in 11/15 patients with paired endoscopies [-2.1 ± 1.7, p = 0.23], and a decrease in serum tumour necrosis factor and interferon-γ [46-52%]. Two quality-of-life indices improved in 7/11 patients treated without biologics. There was one study-related severe adverse event: a postoperative infection requiring device explantation.

Conclusions: Neuroimmune modulation via vagus nerve stimulation was generally safe and well tolerated, with a clinically meaningful reduction in clinical disease activity associated with endoscopic improvement, reduced levels of faecal calprotectin and serum cytokines, and improved quality of life.

Keywords: Crohn’s disease; neuroimmune modulation; vagus nerve.

Graphical Abstract

Figure 1.

The inflammatory reflex. The vagus nerve functionally projects into the coeliac plexus which relays signals to the sympathetic splanchnic nerve. Activation promotes release of acetylcholine [ACh] from choline acetyltransferase [ChAT]-expressing T cells which inhibits the release of tumour necrosis factor [TNF] from splenic macrophages. Vagus nerve endings also project into the gut wall and interface with the enteric nervous system through the myenteric plexus, but the role of ChAT⁺ T cells in the gut has not yet been fully elucidated. NE, norepinephrine/noradrenaline. Reprinted from International Immunology 2021;33:349–56].

Figure 2.

Study device and design.

Figure 3.

Patient disposition.

Figure 4.

Clinical efficacy. [A] Change from baseline in CDAI [mean ± SEM] and [B] CDAI [mean ± SEM] over time in the All Patients Efficacy population [n = 16] and in the 12-patient Stimulation Monotherapy subpopulation. [C] Percent of All Patients or [D] Stimulation Monotherapy patients who achieved clinical remission [CDAI <150], CDAI-70 [CDAI decrease from baseline ≥70], and CDAI-100 [CDAI decrease from baseline ≥100]. CDAI and its change from baseline were analysed with a paired mixed-effects model [restricted maximum likeliness; REML] and adjusted with Bonferroni’s multiple comparisons test. **p <0.01, ***p <0.001. CDAI, Crohn’s Disease Activity Index; SEM, standard error of the mean.

Figure 5.

Bowel inflammation. [A] SES-CD for each patient at screening visit and Week 16/Early Termination visit. The hollow point denotes patient in SES-CD remission. [B] Histopathology subcomponent score in biopsies of the most affected region of the ileum [samples from six subjects; mean ± SEM]. Ileal histopathology change from baseline was analysed by restricted maximum likeliness [REML]. * p <0.01. SES-CD, Simple Endoscopic Score Crohn’s Disease; ET, early termination; SEM, standard error of the mean.

Figure 6.

Disease-related biomarkers. [A] Faecal calprotectin [mean ± SEM] and [B] serum hsCRP [mean ± SEM] over time in the All Patients Efficacy population and in the 12-patient Stimulation Monotherapy subpopulation. Change from baseline was analysed by paired restricted maximum likeliness [REML] and adjusted with Bonferroni’s multiple comparisons test. *p <0.05, **p <0.01. hsCRP, high-sensitivity C-reactive protein; SEM, standard error of the mean.

Figure 7.

Serum cytokines: TNF, IFN-γ, and IL-17 [mean ± SEM]. Change from baseline was analysed by paired Wilcoxon test. *p <0.05. SEM, standard error of the mean; TNF, tumour necrosis factor; IL, interleukin.