The intestinal neuro-immune axis: crosstalk between neurons, immune cells, and microbes

Abstract

The gastrointestinal tract is densely innervated by a complex network of neurons that coordinate critical physiological functions. Here, we summarize recent studies investigating the crosstalk between gut-innervating neurons, resident immune cells, and epithelial cells at homeostasis and during infection, food allergy, and inflammatory bowel disease. We introduce the neuroanatomy of the gastrointestinal tract, detailing gut-extrinsic neuron populations from the spinal cord and brain stem, and neurons of the intrinsic enteric nervous system. We highlight the roles these neurons play in regulating the functions of innate immune cells, adaptive immune cells, and intestinal epithelial cells. We discuss the consequences of such signaling for mucosal immunity. Finally, we discuss how the intestinal microbiota is integrated into the neuro-immune axis by tuning neuronal and immune interactions. Understanding the molecular events governing the intestinal neuro-immune signaling axes will enhance our knowledge of physiology and may provide novel therapeutic targets to treat inflammatory diseases.

Fig. 1. Neuroanatomy of the gastrointestinal tract.

Left panel: Neuroanatomy of extrinsic innervation of the gastrointestinal tract. Extrinsic parasympathetic, sympathetic and sensory neurons originate in the brainstem and spinal cord. Sympathetic innervation through the sympathetic chain of the spinal cord occurs through the extrinsic celiac, and superior and inferior mesenteric ganglia. The distal colon is innervated by the pelvic nerves. Innervation from specific DRG and the sympathetic chain represent individual examples of how the intestine is innervated from these sources. With respect to the intestine, thoracic DRGs are primarily proximal-innervating, while lumbar DRGs are primarily distal-innervating. Right panel: Neuroanatomy of the enteric nervous system. Intrinsic enteric neurons and glial cells reside in the myenteric and submucosal plexus layers of the intestine and innervate all intestinal layers. Extrinsic neurons innervate this network to integrate signals from the brainstem and spinal cord with the intestine.

Fig. 2. Neuronal crosstalk with intestinal macrophages and mast cells.

A Muscularis Macrophages (MMs) release bone morphogenic protein 2 on enteric neurons mediates intestinal motility; in turn, enteric neurons release CSF1 to promote MM survival. B During infection, extrinsic sympathetic neuron release of norepinephrine stimulates polyamine synthesis which prevents enteric neuron inflammasome-mediated cell death. C Neurons and mast cells communicate bidirectionally. Neurons produce neuropeptides and hormones that trigger mast cell activation and degranulation; in turn, mast cells can produce histamine, serotonin and tryptase that can regulate neuronal function. D In IBS, production of VIP triggers mast cell degranulation which is critical for disease progression.

Fig. 3. Neuronal crosstalk with intestinal innate and adaptive lymphocytes.

A Neuronal production of NMU promotes NMUR-dependent ILC2 production of IL-5 and IL-13, which mediate host defense against N. braliensis infection. B, C Neuronal norepinephrine and CGRP release limits IL-5 and IL-13 production by ILC2s, suppressing host defense against N. braliensis infection. D GDNF-family ligands (GFLs) released by enteric glial cells promote IL-22 production by RET-expressing ILC3s, promoting host defense against C. rodentium infection and host protection against DSS colitis-induced inflammation. E VIP production by VIP+ enteric neurons suppresses IL-22 production by ILC3s in a VIPR2-dependent manner, suppressing host defense against C. rodentium infection. F VIP production by VIP+ enteric neurons enhances IL-22 production by VIPR2-expressing ILC3s, mediating host protection during DSS colitis. G Cholinergic neuron production of acetylcholine mediates T cell production of IL-13 and IFNγ, which are crucial for host defense against intestinal Salmonella and N. braliensis infections. H Neurotransmitters and neuropeptides such as acetylcholine, VIP, substance P, and β2AR agonists regulate B cell differentiation into plasma cells and resulting production of immunoglobulins.

Fig. 4. Neuronal crosstalk with intestinal epithelial cells and tuning by the microbiota.

A Acetylcholine triggers luminal antigen sampling through goblet cell-associated antigen passages (GAPs), resulting in antigen presentation by tissue CD103 + DCs. B Neuronal IL-18 regulates goblet cell expression of antimicrobial peptides, which is critical for host protection against intestinal S. Typhimurium infection. C TRPV1 + Nav1.8+ DRG neuronal release of CGRP suppresses M cell development in the Peyer’s Patch, limiting invasion of S. Typhimurium. D The host intestinal microbiota tunes neuro-immune crosstalk by impacting neuronal, immune and epithelial function. A healthy microbiota facilitates proper neuro-immune signaling, whereas a dysbiotic microbiota inhibits this signaling.