Neonatal development of intestinal neuroimmune interactions

Abstract

Interactions between the enteric nervous system (ENS), immune system, and gut microbiota regulate intestinal homeostasis in adults, but their development and role(s) in early life are relatively underexplored. In early life, these interactions are dynamic, because the mucosal immune system, microbiota, and the ENS are developing and influencing each other. Moreover, disrupting gut microbiota and gut immune system development, and potentially ENS development, by early-life antibiotic exposure increases the risk of diseases affecting the gut. Here, we review the development of the ENS and immune/epithelial cells, and identify potential critical periods for their interactions and development. We also highlight knowledge gaps that, when addressed, may help promote intestinal homeostasis, including in the settings of early-life antibiotic exposure.

Keywords: early-life antibiotics; enteric nervous system; goblet cells; innate lymphoid cells; muscularis macrophages; neonatal microbiome.

Figure 1:. Basic Anatomy of the Enteric Nervous System.

The ENS is organized into two plexuses: the myenteric plexus (located between the circular and longitudinal muscle layers) and the submucosal plexus (located closer to the lumen, deep to the mucosa). Neurons are organized into ganglia. Myenteric motor neurons (green) project to the muscle layers to coordinate the contraction and relaxation required for peristalsis. Sensory neurons (pink) in both plexuses have projections to the luminal surface to detect intestinal contents. Submucosal secretomotor neurons (purple) project to the epithelial layer to coordinate secretion, absorption, and local blood flow. Additional neurons (blue) connect ganglia to each other within and between plexuses. Glia (yellow) are present throughout the bowel wall and are necessary for ENS function. Figure generated using BioRender.com.

Figure 2:. Enteric Neuron/Macrophage Crosstalk.

Enteric neuron and tissue resident macrophages have several mechanisms of communication to regulate intestinal homeostasis. One mechanism is symbiotic production of growth factors. Muscularis macrophages produce the enteric neuron growth factor BMP2 while enteric neurons and glia secrete CSF-1, an important growth factor for macrophages. In colons of antibiotic treated mice, there is a reduction in number of macrophages and subsequently in the level of BMP2, demonstrating that this relationship is microbiota dependent. This results in slower motility and abnormal smooth muscle contraction. Additionally, cholinergic enteric neurons signal to neuron associated macrophages in the lamina propria. Acetylcholine binds to the nAChR receptor on macrophages, inducing an anti-inflammatory phenotype and low levels of IL-23 production. Figure generated using BioRender.com.

Figure 3:. Enteric Neuron/ILC3 Crosstalk.

VIP-expressing enteric neurons are activated by feeding and other stimuli. VIP activates ILC3s via VIPR2 activation, inducing IL-22 expression and promoting host defense. This pathway is most effective in the presence of alarmins, i.e. in the setting of an enteric pathogen. Enteric glia activate RET expressing ILC3s by producing RET ligands in a microbiota-dependent manner. Glia and other cells in the intestine also express RET co-receptors to allow trans-activation of RET signaling ILC3s, which do not express the co-receptors autonomously. Figure generated using BioRender.com.

Figure 4:. Enteric Neuron/Goblet Cell Crosstalk.

Enteric neurons produce the cytokine IL-18 constitutively. This induces goblet cells to produce antimicrobial proteins under homeostatic conditions and promotes host defense in the context of Salmonella infection. Goblet cells can also form portals, known as goblet cell associated antigen passages (GAPs). GAPs facilitate physiologic and pathologic translocation of luminal bacteria and presentation to antigen presenting cells. Goblet cells are induced to form GAPs by acetylcholine activation of the mAChR4 receptor. Cholinergic enteric neurons have been hypothesized as an important source of acetylcholine for GAP activation. Figure generated using BioRender.com.