Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases

Abstract

The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn's disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.

Keywords: TNF; cholinergic anti-inflammatory pathway; heart rate variability; inflammatory bowel diseases; vagus nerve; vagus nerve stimulation.

FIGURE 1

Integrative pathways of the brain–gut axis. Vagal and splanchnic digestive afferents connect to the nucleus tractus solitarius, in close relationship with the dorsal motor nucleus of the vagus, from which vagal efferents originate, thus composing an autonomic loop of the brainstem, involved in the regulation of instinctual motility, acid secretion, food intake and satiety. This loop is modulated by the autonomic loop comprising the hypothalamus, the hippocampus, the amygdala, the anterior cingulate and the insular and prefrontal cortex. This last loop receives, coordinates and integrates visceral information enabling neuroendocrine, emotional, cognitive and behavioral responses. These two central loops explain how stress, sensations and thoughts can influence the functioning of the intestine and vice versa. Adapted from Bonaz et al. (2019). DMNV, dorsal motor nucleus of the vagus nerve; ILM, intermediolateralis nucleus; NTS, nucleus tractus solitarius; RVLM, rostral ventrolateral medulla.

FIGURE 2

Different pathways of the anti-inflammatory properties of the vagus nerve: (1) through activation of the HPA axis via vagal afferents and through vago-parasympathetic efferents (red), (2) through sympathetic efferents (blue) arising from thoraco-lumbar spinal preganglionic neurons through the vago-sympathetic pathway where vagal afferents activate central descending pathways (e.g., LC, A5, C1, PVH) targeting spinal pre-ganglionic neurons. Targeting the VN for its anti-inflammatory properties (pink) in chronic inflammatory diseases (orange) such as inflammatory bowel diseases appears as potentially effective therapeutics. Adapted from Bonaz et al. (2017a). A5, A5 noradrenergic group (in the brainstem); ACh, acetylcholine; C1, C1 adrenergic group (in the brainstem); CAN, central autonomic network; CCK, cholecystokinin; DMNV, dorsal motor nucleus of the vagus nerve; EPI, epinephrine; HPA, hypothalamic–pituitary–adrenal; IBD, inflammatory bowel diseases; LC, locus coeruleus; NE, norepinephrine; NTS, nucleus tractus solitarius; PVH, paraventricular nucleus of the hypothalamus; TNFα, tumor necrosis factor-alpha; α7nAChR, alpha7nicotinic acetylcholine receptor.

FIGURE 3

The microbiota–gut–brain axis. The microbiota exerts an effect on the gut-brain axis, impacting the biochemistry of the peripheral and central nervous system. Commensal and/or pathogenic bacteria and their metabolites are translocated across the intestinal barrier and act on both the digestive immune system and vagal afferents. Similarly, the brain acts on the various organs, including the digestive tract, and can thus regulate the survival and proliferation of the intestinal microbiota.

FIGURE 4

Specific inverse relationship between the resting parasympathetic vagal tone and TNF-alpha plasma level in Crohn’s disease (CD) patients. CD patients with high parasympathetic vagal tone exhibit a lower level of TNF-alpha than those with low parasympathetic vagal tone. Parasympathetic vagal tone was assessed by power spectral analysis of HRV and TNF-alpha level was assessed by ELISA-based technic. Data expressed as mean ± sem (adapted from Pellissier et al., 2014).

FIGURE 5

Pilot study of vagus nerve stimulation (VNS) in patients with moderate to severe Crohn’s Disease (CD). Twelve-month-VNS effect on cytokinergic profile. A plasma cytokinergic profile for controls (red), before (black), 6-month (gray) and 12-month (pink) VNS has been assessed using PCA analysis of plasma multicytokines assay for all CD patients [IL1b, IL2, IL6, IL10, IL12(p70), IL17A, IL21, IL23, MIP1α, IFNγ, GM-CSF, TNFα, TGFβ1 and MCP1]. The control values are well grouped, while profiles before VNS are very scattered, indicating that CD patients have their own cytokinergic profile. After 6 months, and even more after 12 months of VNS, the points are tightened, indicating that cytokine levels evolve through a more “common” profile. Ellipses are centered on the barycenter (big dots) of each group. Adapted from Sinniger et al. (2020).

FIGURE 6

Twelve-month-vagus nerve stimulation (VNS) effect on vagal tone. High frequencies are expressed in normal units (HFnu) and are extracted from heart rate variability analysis.