Altered Vagal Signaling and Its Pathophysiological Roles in Functional Dyspepsia

Abstract

The vagus nerve is crucial in the bidirectional communication between the gut and the brain. It is involved in the modulation of a variety of gut and brain functions. Human studies indicate that the descending vagal signaling from the brain is impaired in functional dyspepsia. Growing evidence indicate that the vagal signaling from gut to brain may also be altered, due to the alteration of a variety of gut signals identified in this disorder. The pathophysiological roles of vagal signaling in functional dyspepsia is still largely unknown, although some studies suggested it may contribute to reduced food intake and gastric motility, increased psychological disorders and pain sensation, nausea and vomiting. Understanding the alteration in vagal signaling and its pathophysiological roles in functional dyspepsia may provide information for new potential therapeutic treatments of this disorder. In this review, we summarize and speculate possible alterations in vagal gut-to-brain and brain-to-gut signaling and the potential pathophysiological roles in functional dyspepsia.

Keywords: functional dyspepsia; gut–brain axis; vagal afferent; vagal efferent; vagus nerve.

FIGURE 1

Altered vagal signaling in response to gastric distension and its associated pathophysiological changes in functional dyspepsia. Gastric distension and contraction activate mechanosensitive vagal afferents and send signals to the brain, leading to increased feeling of fullness, increased psychological behaviors and reduced pain sensation, and further via vagal efferents send signals to the gut, leading to increased gastric accommodation and emptying, and reduced duodenal motility. In functional dyspepsia, the sensitivity of vagal afferents to gastric distension is increased, accompanying increased feeling of fullness, psychological behaviors and pain, and impaired gastric accommodation and emptying, and duodenal motility. Blue arrows indicate an effect to increase or decrease nerve activity or physiological outcomes under normal physiological conditions. Orange arrows indicate an effect to increase or decrease nerve activity or physiological outcomes in functional dyspepsia and the size of the arrows indicate the levels of the effects.

FIGURE 2

Chemosensitive vagal afferent signaling in response to altered chemical stimuli observed in functional dyspepsia and the associated pathophysiological changes. Chemosensitive vagal afferents can sense chemical stimuli including nutrients, gut hormones, pH levels, and inflammation-associated factors. These signals are sent to the brain via vagal afferents where the information is processed leading to increased fullness, psychological behaviors, pain sensation, nausea, and vomiting, as well as reflex signals back to the gut, via vagal efferents, leading to increased gastric accommodation and reduced gastric emptying. Functional dyspepsia is associated with increased gastroduodenal permeability, infiltration of eosinophil and mast cells, altered microbiota profile and increased chemical stimuli, which may enhance vagal afferent signals to the brain contributing to the increased feelings of fullness, psychological behaviors, pain sensation, nausea and vomiting observed in functional dyspepsia. The chemical stimuli induced vagovagal reflex is impaired in functional dyspepsia (Feinle et al., 2001; Schwartz et al., 2001), which may lead to impaired gastric accommodation, and impaired inhibition on gastric emptying and gastroduodenal inflammation.

FIGURE 3

Therapeutic targets along vagal signaling pathways in functional dyspepsia. Restoring normal vagal signaling could be an important therapeutic target for functional dyspepsia, by normalizing any component in the vagal signaling loop, including normalizing gut signals, reversing vagal afferent hypersensitivity, normalizing brain stress related signals, and enhancing vagal efferent activity. Normalizing gut signals may target gastroduodenal permeability, mechanical stimuli, and chemical stimuli including nutrients, hormones, pH levels, and immune stimuli including microbiota.