The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation

Abstract

Although the gastrointestinal (GI) tract contains intrinsic neural plexuses that allow a significant degree of independent control over GI functions, the central nervous system provides extrinsic neural inputs that modulate, regulate and integrate these functions. In particular, the vagus nerve (VN) provides the parasympathetic innervation to the GI tract, co-ordinates the complex interactions between central and peripheral neural control mechanisms. This review will discuss the physiological roles of the afferent (sensory) and motor (efferent) vagus in regulation of appetite, mood and the immune system, as well as the pathophysiological outcomes of VN dysfunction resulting in obesity, mood disorders and inflammation. The therapeutic potential of VN modulation to attenuate or reverse these pathophysiological outcomes and restore autonomic homeostasis will also be discussed.

Molecular and Functional Neuroscience in Immunity

“…Some of these fibers, innervating the lungs, airways, and other organs, express TRPV1, TRPA1, Na v 1.7, Na v 1.8, and Na v 1.9 and function as nociceptors (19, 51, 52). Vagal sensory neurons are activated during bacterial or viral infection, cellular damage, and airway allergenic responses (19, 44, 46, 53, 54). This activation is mediated by TNF, IL-1β, prostaglandins, serotonin, and other molecules released from immune cells, including neutrophils, macrophages, and eosinophils (19, 44).…”

“…This activation is mediated by TNF, IL-1β, prostaglandins, serotonin, and other molecules released from immune cells, including neutrophils, macrophages, and eosinophils (19, 44). These molecules increase neuronal sensitivity to noxious stimuli by lowering the threshold for evoking action potentials or directly activate sensory neurons (19, 53, 55) (Figure 2). Administration of lipopolysaccharide (LPS), cytokines (including IL-β and TNF), and pathogens such as Campylobacter jejuni to mice and rats stimulates vagus nerve afferent signaling, which can be traced to the NTS and then to other brainstem and forebrain regions (54, 56–59).…”

Mechanisms and Therapeutic Relevance of Neuro-immune Communication

“…The nodose ganglion and the jugular ganglion are anatomically distinct in rats and humans with much smaller representation of the jugular ganglion, while in mice the two ganglia are fused and are commonly designated as nodose ganglion (Mazzone and Undem, 2016). Vagal afferents are about 80% of the vagus nerve with central axon terminal releasing glutamate as a main neurotransmitter in the NTS, which is viscerotopically organized (Browning et al, 2017; Berthoud and Neuhuber, 2000). While nodose ganglia neurons provide abundant innervations to visceral organs, vagal afferents in the jugular ganglion preferentially innervate the airways and the esophagus (Mazzone and Undem, 2016; Kollarik et al, 2010).…”

“…Based on physiological responsiveness, vagal afferents can be grouped in mechanosensitive fibers represented by C-fibers and chemical-sensitive afferents activated by a variety of chemical stimuli, but less sensitive to mechanical stimuli (Mazzone and Undem, 2016). Vagal afferents are important mediators of satiety and respond to alterations in cholecystokinin, leptin, glucagon like peptide 1, peptide YY, and other nutrient and metabolic molecule levels (Browning et al, 2017; Pavlov and Tracey, 2012). Their activity is also modulated by gut motility and intestinal distention and the recent genetic molecular profiling of gastrointestinal vagal afferents has characterized subsets of neurons specifically associated with these functions (Williams et al, 2016).…”

“…The release of cytokines, such as IL-1β, and TNF, and other inflammatory mediators including prostaglandins, serotonin, and ATP from macrophages, neutrophils, mast cells and eosinophils has a major impact on vagal afferent terminals in the airways and lungs (Mazzone and Undem, 2016). These immune cell signaling molecules cause peripheral neuron sensitization, characterized by decreased threshold needed to evoke action potentials, or directly induce neuronal activation (Mazzone and Undem, 2016; Browning et al, 2017). Vagal afferent neurons within the subdiaphragmatic vagus nerve, innervating the gastrointestinal tract are in position to detect gastrointestinal pathogens, including Campylobacter jejuni and signal the brain (Lai et al, 2017; Goehler et al, 2005).…”