Sensory neuron regulation of gastrointestinal inflammation and bacterial host defence

Abstract

Sensory neurons in the gastrointestinal tract have multifaceted roles in maintaining homeostasis, detecting danger and initiating protective responses. The gastrointestinal tract is innervated by three types of sensory neurons: dorsal root ganglia, nodose/jugular ganglia and intrinsic primary afferent neurons. Here, we examine how these distinct sensory neurons and their signal transducers participate in regulating gastrointestinal inflammation and host defence. Sensory neurons are equipped with molecular sensors that enable neuronal detection of diverse environmental signals including thermal and mechanical stimuli, inflammatory mediators and tissue damage. Emerging evidence shows that sensory neurons participate in host-microbe interactions. Sensory neurons are able to detect pathogenic and commensal bacteria through specific metabolites, cell-wall components, and toxins. Here, we review recent work on the mechanisms of bacterial detection by distinct subtypes of gut-innervating sensory neurons. Upon activation, sensory neurons communicate to the immune system to modulate tissue inflammation through antidromic signalling and efferent neural circuits. We discuss how this neuro-immune regulation is orchestrated through transient receptor potential ion channels and sensory neuropeptides including substance P, calcitonin gene-related peptide, vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide. Recent studies also highlight a role for sensory neurons in regulating host defence against enteric bacterial pathogens including Salmonella typhimurium, Citrobacter rodentium and enterotoxigenic Escherichia coli. Understanding how sensory neurons respond to gastrointestinal flora and communicate with immune cells to regulate host defence enhances our knowledge of host physiology and may form the basis for new approaches to treat gastrointestinal diseases.

Keywords: gastrointestinal inflammation; host defence; neuro-immunology; pain; sensory neuron; vagus nerve.

Fig. 1

Distinct types of sensory neurons innervate the gastrointestinal tract and mediate different functional outcomes. Three sensory neuron types innervate the gastrointestinal tract and are able to respond to various environmental and internal stimuli. The sensory neurons of the enteric nervous system, termed intrinsic primary afferent neurons (IPANs), have cell bodies in the myenteric and submucosal plexus layers of the gut. They form complete reflex circuits with enteric interneurons and motor neurons to regulate many aspects of digestive and gastrointestinal functions such as gut motility, blood flow, fluid transport, and secretion. The gut receives extrinsic innervation by sensory afferents from the dorsal root ganglia (DRGs) that mediate visceral pain, pressure, and neurogenic inflammation. The gut also receives extrinsic innervation by sensory afferents from the nodose/jugular ganglia, mediating satiety, nausea, gut homeostasis, and inflammatory reflex circuits. Therefore, sensory information from the gut is differentially processed by distinct neuronal types, resulting in different gastrointestinal sensations and functional outcomes. CNS, central nervous system.

Fig. 2

Sensory neuron detection of bacterial products. Sensory neurons of the dorsal root ganglion (A) and jugular/nodose ganglia (B) and intrinsic primary afferent neurons of the enteric nervous system (C) have been found to respond directly to pathogenic and commensal bacteria. Bacterial cell-wall components, metabolites, and toxins from different commensal and pathogenic bacteria interact with neuronal receptors or ion channels to induce changes in ion flux, signaling, and neuronal excitability. TLR4, Toll-like receptor 4; TRPA1, transient receptor potential ankryn-like 1; TLR5, Toll-like receptor 5; FPR, formyl peptide receptor; TRAAK, TWIK-related arachidonic acid-activated K+ channel; IPAN, intrinsic primary afferent neuron; PSA, polysaccharide A.