Neuroimmunophysiology of the gastrointestinal tract

Abstract

Gut physiology is the epicenter of a web of internal communication systems (i.e., neural, immune, hormonal) mediated by cell-cell contacts, soluble factors, and external influences, such as the microbiome, diet, and the physical environment. Together these provide the signals that shape enteric homeostasis and, when they go awry, lead to disease. Faced with the seemingly paradoxical tasks of nutrient uptake (digestion) and retarding pathogen invasion (host defense), the gut integrates interactions between a variety of cells and signaling molecules to keep the host nourished and protected from pathogens. When the system fails, the outcome can be acute or chronic disease, often labeled as "idiopathic" in nature (e.g., irritable bowel syndrome, inflammatory bowel disease). Here we underscore the importance of a holistic approach to gut physiology, placing an emphasis on intercellular connectedness, using enteric neuroimmunophysiology as the paradigm. The goal of this opinion piece is to acknowledge the pace of change brought to our field via single-cell and -omic methodologies and other techniques such as cell lineage tracing, transgenic animal models, methods for culturing patient tissue, and advanced imaging. We identify gaps in the field and hope to inspire and challenge colleagues to take up the mantle and advance awareness of the subtleties, intricacies, and nuances of intestinal physiology in health and disease by defining communication pathways between gut resident cells, those recruited from the circulation, and "external" influences such as the central nervous system and the gut microbiota.

Keywords: enteric nervous system; epithelium; neuroimmunology; visceral afferent.

Graphical abstract

Figure 1.

Enteric neuroimmune, epithelial, and enteroendocrine interactions in the gastrointestinal (GI) tract. Enteric nerves and enteric glia interact with immune, epithelial, and enteroendocrine cells to form complex circuits that promote digestion and simultaneously bolster host defense. See text for full details. ACh, acetylcholine; CCL2, chemokine (C-C motif) ligand 2; CGRP, calcitonin gene-related peptide; CSF, colony-stimulating factor; EMN, excitatory motor neuron; ICC, interstitial cells of Cajal; ILC, innate lymphoid cell; IMN, inhibitory motor neuron; IPAN, intrinsic primary afferent neuron; NO, nitric oxide; NMU, neuromedin U; SP, substance P; VIP, vasoactive intestinal peptide. Created with BioRender.com.

Figure 2.

Neuroimmune interactions in the gastrointestinal (GI) tract regulate visceral sensitivity. The activity in spinal primary afferent nerves is regulated by epithelial, enteroendocrine, immune, and enteric glial interactions. Spinal primary afferents are activated in conditions of inflammation or infection, and this can be sustained by sensitization and via alterations in the composition of the gut microbiota. See text for full details. CSF, colony-stimulating factor; DRG, dorsal root ganglia. Created with BioRender.com.