Capsaicin-sensitive vagal afferent neurons contribute to the detection of pathogenic bacterial colonization in the gut

Abstract

Vagal activation can reduce inflammation and disease activity in various animal models of intestinal inflammation via the cholinergic anti-inflammatory pathway. In the current model of this pathway, activation of descending vagal efferents is dependent on a signal initiated by stimulation of vagal afferents. However, little is known about how vagal afferents are activated, especially in the context of subclinical or clinical pathogenic bacterial infection. To address this question, we first determined if selective lesions of capsaicin-sensitive vagal afferents altered c-Fos expression in the nucleus of the solitary tract (nTS) after mice were inoculated with either Campylobacter jejuni or Salmonella typhimurium. Our results demonstrate that the activation of nTS neurons by intraluminal pathogenic bacteria is dependent on intact, capsaicin sensitive vagal afferents. We next determined if inflammatory mediators could cause the observed increase in c-Fos expression in the nTS by a direct action on vagal afferents. This was tested by the use of single-cell calcium measurements in cultured vagal afferent neurons. We found that tumor necrosis factor alpha (TNFα) and lipopolysaccharide (LPS) directly activate cultured vagal afferent neurons and that almost all TNFα and LPS responsive neurons were sensitive to capsaicin. We conclude that activation of the afferent arm of the parasympathetic neuroimmune reflex by pathogenic bacteria in the gut is dependent on capsaicin sensitive vagal afferent neurons and that the release of inflammatory mediators into intestinal tissue can be directly sensed by these neurons.

Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System

“…Indeed, indole can modify epithelial cells and tight junction proteins (Bansal et al, 2010). Consistent with the importance of the vagus in informing the CNS about changes in the gut microbiome (Bercik et al, 2011;Bravo et al, 2011;Riley et al, 2013), electrophysiological studies demonstrated that application of indole to the mucosa, but not directly onto exposed intrinsic or extrinsic neurons, resulted in GLP-1R-dependent activation of vagal afferents. In terms of gut-brain axis wiring, most innervation of small intestinal epithelial cells is by submucosal neurons (Keast et al, 1984;Ekblad et al, 1987) and intrinsic primary afferent neurons may act as the starting point in gut-brain signaling (Perez-Burgos et al, 2014).…”

Visceral Inflammation and Immune Activation Stress the Brain

“…In addition, it has been shown that both vagal and spinal afferent neurons do not only respond to these microbial and immune messengers but can also, under their influence, undergo sensitization to other stimulants. For instance, both LPS and tumor necrosis factor-α (TNF- α) are capable of directly activating vagal afferent neurons in culture ( 71 ). In addition, LPS can stimulate sensory neurons via activation of the transient receptor potential ankyrin-1 (TRPA1) ion channel ( 72 ) and sensitize afferent fibers in mesenteric nerves to serotonin, bradykinin, and gut distension, an effect in which mast cells and cyclooxygenase-2 play a role ( 73 ).…”

Exercise and the microbiota

“…45 Evidence suggests that this parasympathetic neuroimmune reflex is dependent on vagal afferent neurons for the local release of intestinal inflammatory mediators in response to pathogenic gut bacteria. 46 Therefore, elevated vagal tone and parasympathetic influence, as seen in the resting state of athletes, may foster a preferential antiinflammatory milieu at the intestinalluminal interface, with an attendant conditioning influence on microbial composition.…”