Vagal Nerve Stimulation Versus Sacral Nerve Stimulation for Control of Inflammation

Introduction

About 5%–7% of the general population in Western societies are affected by immune-mediated inflammatory diseases ( ) that include, but are not limited to, ankylosing spondylitis, psoriasis, psoriatic arthritis, rheumatoid arthritis, and inflammatory bowel disease (IBD). IBD includes Crohn’s disease (CD) and ulcerative colitis (UC). In the United States, there are more than 1 million people suffering from IBD ( ). The prevalence is increasing. Although a number of medications are available for the treatment of symptoms of IBD, they do not cure the diseases and about one-third of patients with IBD will have to undergo surgical resection ( ) Therefore, novel and effective therapies are needed for IBD.

A cholinergic antiinflammatory pathway (CAP) has been proposed ( ). When a peripheral organ is inflamed due to various reasons, a signal is sent to the central nervous system (CNS) via vagal afferent fibers. Once the CNS receives such an inflammation signal, it produces an enhanced vagal outflow that inhibits release of proinflammatory cytokines in the spleen via the celiac ganglion and the α7 subunit of the nicotinic receptor AChR (α7 nAChR) ( ). The inhibition of proinflammatory cytokines leads to reduced inflammation, a spontaneous healing process mediated by this CAP.

Based on the theory of the CAP, vagal nerve stimulation (VNS) has been introduced for the treatment of inflammation. In patients with epilepsy undergoing treatment with VNS, a significant inhibition in peripheral blood production of tumor necrosis factor (TNF), IL-1β and IL-6 has been reported; encouraged by the findings, VNS was performed in patients with rheumatoid arthritis (RA), and attenuated RA disease severity and TNF ( ). VNS has also been introduced for the treatment of inflammation in the gut in both animal models of IBD ( ) and patients with CD ( ).

While VNS has been widely explored for its therapeutic potentials for various kinds of inflammation due to its systemic inhibition of proinflammatory cytokines in the spleen, this chapter is focused on its potential application for inflammation in the gut. Two special issues will also be introduced and discussed: (1) systemic inhibition of proinflammatory cytokines via the spleen versus local inhibition of proinflammatory cytokines at the target organ; (2) VNS versus sacral nerve stimulation (SNS). Since the bowel is innervated by both the vagus nerve and sacral (pelvic) nerve, it is hypothesized that activation of the sacral-efferent nerve would exert similar antiinflammation effects on VNS, assuming the presence of local organ-based cholinergic antiinflammatory mechanisms.

Cholinergic Antiinflammatory Pathway

The concept of the CAP was initially proposed more than a decade ago. In an initial study with a drug (CNI-1493), it was found that vagotomy abolished the antiinflammatory action of the drug and most interestingly, electrical stimulation of the cervical vagal nerve produced a similar antiinflammatory effect of the drug ( ). Similar results were replicated in follow-up studies with inflammation, assessed by TNF-α and produced by a high dose of intravenous lipopolysaccharide (LPS) ( ).

As more information data has become available, the anatomical and functional model of the CAP has evolved. The current CAP model states that vagal efferent signals converge on the spleen, an organ that plays an important role in inflammation, where acetylcholine inhibits inflammation in a manner that requires the alpha-7 subunit of the nicotinic acetylcholine receptor ( ). In , Huston et al. demonstrated that the spleen was essential for the inhibition of systemic inflammation by vagal stimulation as neural denervation or removal of the spleen abolished the antiinflammatory effect of vagal stimulation ( ). The spleen does not receive cholinergic innervation, suggesting that efferent vagal fibers synapse onto the catecholaminergic splenic nerve, likely at the celiac ganglion ( ). Activation of the splenic nerve induces the release of norepinephrine, which acts on ACh-synthesizing T cells, called choline acetyltransferase T cells (ChAT) cells; these cells release ACh in the spleen, which causes macrophages to suppress release of major proinflammatory cytokines via the α7 nicotinic acetylcholine receptor ( ). Splenic macrophages express both nicotinic and beta adrenergic receptors, and both inhibit TNF-α production in vitro ( ). The action of the α7 nicotinic acetylcholine receptor was proposed to be in the splenic neuron ( ).

The CAP involved in the gut or intestinal CAP may be less complicated than CAP involving systemic inflammation. Based on available in-vivo preclinical findings, the intestinal CAP is proposed as follow ( ): in case of tissue injury in the gut, the sensory neuron in the gut mucosa sends a signal to the CNS via vagal afferents; the brain processes the signal and provides enhanced vagal efferent output; this vagal efferent output activates the cholinergic enteric nerve to release ACh that suppresses production of proinflammatory cytokines in the mucosal macrophages. An elegant study performed by the group of Boeckxstaens has shown that the antiinflammatory effect of VNS in a murine model of surgically induced inflammation is independent of the spleen or T cell ( ). In wild-type, splenic denervated, Rag-1, knockout mice and α7 nicotinic acetylcholine receptor (α7nAChR) knockout mice, VNS was found to attenuate surgery-induced intestinal inflammation and improve postoperative intestinal transit in wild-type, splenic denervated, and T-cell-deficient mice; however, VNS was found ineffective in α7nAChR knockout mice ( ). In the same study, anterograde labeling failed to detect vagal efferent contacting resident macrophages, but revealed close contacts between cholinergic myenteric neurons and resident macrophages, expressing α7nAChR. These findings were the bases of the proposed intestinal CAP. However, the mediating effect of the enteric nerve between vagal efferents and mucosal macrophages needs experimental evidence.

Vagal Nerve Stimulation for Intestinal Inflammation

Inspired by the proposed CAP, a number of studies have been performed to investigate the therapeutic potential of VNS for inflammation, including both systemic inflammation such as RA and peripheral inflammation, such as IBD. In this chapter, more discussion will be made on VNS for intestinal inflammation or IBD.

Patients with IBD suffer from chronic inflammation in the gut and include two subgroups of patients with CD and UC ( ). Inflammation in UC is mainly in the colon and superficial, whereas inflammation in CD is commonly transmural and throughout the gut. Although great progress has been made in the past decade for medical treatment of IBD, such as anti-TNF antibodies, there is still a high demand for effective therapies, as current medical therapies are limited due to their complications and side effects as well as the need for intestinal resection ( ). Therefore, the exploration of the potential of VNS for treating irritable bowel syndrome (IBS) is of great clinical significance. At present, however, most of research on VNS for IBD has been limited to laboratory animals and clinical data are very limited.