The Effect of Microbiota and the Immune System on the Development and Organization of the Enteric Nervous System

Abstract

The gastrointestinal (GI) tract is essential for the absorption of nutrients, induction of mucosal and systemic immune responses, and maintenance of a healthy gut microbiota. Key aspects of gastrointestinal physiology are controlled by the enteric nervous system (ENS), which is composed of neurons and glial cells. The ENS is exposed to and interacts with the outer (microbiota, metabolites, and nutrients) and inner (immune cells and stromal cells) microenvironment of the gut. Although the cellular blueprint of the ENS is mostly in place by birth, the functional maturation of intestinal neural networks is completed within the microenvironment of the postnatal gut, under the influence of gut microbiota and the mucosal immune system. Recent studies have shown the importance of molecular interactions among microbiota, enteric neurons, and immune cells for GI homeostasis. In addition to its role in GI physiology, the ENS has been associated with the pathogenesis of neurodegenerative disorders, such as Parkinson's disease, raising the possibility that microbiota-ENS interactions could offer a viable strategy for influencing the course of brain diseases. Here, we discuss recent advances on the role of microbiota and the immune system on the development and homeostasis of the ENS, a key relay station along the gut-brain axis.

Keywords: Enteric Nervous System (ENS); Microbiota; Microbiota–Gut–Brain Axis; Neuroimmune Interaction; Parkinson’s Disease.

Figure 1

Microbiota and diet control the activity of multiple cell types in the gut wall, including the ENS. For example, the bacterial metabolites SCFAs activate G-protein coupled receptors (eg, GPR41 and GPR43) on enteroendocrine cells of the intestinal epithelium resulting in enhanced production of GLP-1 and 5-HT and changes in gut motility. Gut microbiota also contribute to the conversion of primary bile acids into secondary bile acids, which activate TGR5 expressed by enteroendocrine cells and enteric neurons. TLR signalling (eg, TLR2 and TLR4) maintains subsets of enteric neurons and influences gut motility. In addition, microbiota is essential for the maintenance of mucosal glial cells, which express the neurotrophic factor GDNF and GFAP. 5-HT, Serotonin; α-MSH, α-melanocyte-stimulating hormone; GDNF, glial cell-derived neurotrophic factor; GFAP, glial fibrillary acidic protein; GLP-1, glucagon-like peptide-1; SERT, serotonin-selective reuptake transporter; Tph1, tryptophan hydroxylase 1.

Figure 2

BMP2 from muscularis macrophages (MMs) regulates the activity of enteric neurons (by activating BMPRII) while CSF1 from enteric neurons is essential for the development of MMs (which express CSF1R). Production of CSF1 and BMP2 is dependent on gut microbiota. Activation of MMs by norepinephrine (via β2 adrenergic receptors) contributes to their polarization into M2-type phenotype, which is associated with tissue homeostasis and wound healing. BMP2, bone morphogenetic protein 2; β2AR: β2 adrenergic receptors, CSF1, colony stimulating factor 1; NE, norepinephrine.