The enteric nervous system (ENS) is large, complex and uniquely able to orchestrate gastrointestinal behaviour independently of the central nervous system (CNS). An intact ENS is essential for life ...and ENS dysfunction is often linked to digestive disorders. The part the ENS plays in neurological disorders, as a portal or participant, has also become increasingly evident. ENS structure and neurochemistry resemble that of the CNS, therefore pathogenic mechanisms that give rise to CNS disorders might also lead to ENS dysfunction, and nerves that interconnect the ENS and CNS can be conduits for disease spread. We review evidence for ENS dysfunction in the aetiopathogenesis of autism spectrum disorder, amyotrophic lateral sclerosis, transmissible spongiform encephalopathies, Parkinson disease and Alzheimer disease. Animal models suggest that common pathophysiological mechanisms account for the frequency of gastrointestinal comorbidity in these conditions. Moreover, the neurotropic pathogen, varicella zoster virus (VZV), unexpectedly establishes latency in enteric and other autonomic neurons that do not innervate skin. VZV reactivation in these neurons produces no rash and is therefore a clandestine cause of gastrointestinal disease, meningitis and strokes. The gut-brain alliance has raised consciousness as a contributor to health, but a gut-brain axis that contributes to disease merits equal attention.
Modern research on gastrointestinal behavior has revealed it to be a highly complex bidirectional process in which the gut sends signals to the brain, via spinal and vagal visceral afferent pathways, ...and receives sympathetic and parasympathetic inputs. Concomitantly, the enteric nervous system within the bowel, which contains intrinsic primary afferent neurons, interneurons, and motor neurons, also senses the enteric environment and controls the detailed patterns of intestinal motility and secretion. The vast microbiome that is resident within the enteric lumen is yet another contributor, not only to gut behavior, but to the bidirectional signaling process, so that the existence of a microbiota-gut-brain "connectome" has become apparent. The interaction between the microbiota, the bowel, and the brain now appears to be neither a top-down nor a bottom-up process. Instead, it is an ongoing, tripartite conversation, the outline of which is beginning to emerge and is the subject of this Review. We emphasize aspects of the exponentially increasing knowledge of the microbiota-gut-brain "connectome" and focus attention on the roles that serotonin, Toll-like receptors, and macrophages play in signaling as exemplars of potentially generalizable mechanisms.
Although the gut contains most of the body's 5-hydroxytryptamine (5-HT), many of its most important functions have recently been discovered. This review summarizes and directs attention to this new ...burst of knowledge.
Enteroendocrine cells have classically been regarded as pressure sensors, which secrete 5-HT to initiate peristaltic reflexes; nevertheless, recent data obtained from studies of mice that selectively lack 5-HT either in enterochromaffin cells (deletion of tryptophan hydroxylase 1 knockout; TPH1KO) or neurons (TPH2KO) imply that neuronal 5-HT is more important for constitutive gastrointestinal transit than that of enteroendocrine cells. The enteric nervous system of TPH2KO mice, however, also lacks a full complement of neurons; therefore, it is not clear whether slow transit in TPH2KO animals is due to their neuronal deficiency or absence of serotonergic neurotransmission. Neuronal 5-HT promotes the growth/maintenance of the mucosa as well as neurogenesis. Enteroendocrine cell derived 5-HT is an essential component of the gastrointestinal inflammatory response; thus, deletion of the serotonin transporter increases, whereas TPH1KO decreases the severity of intestinal inflammation. Enteroendocrine cell derived 5-HT, moreover, is also a hormone, which inhibits osteoblast proliferation and promotes hepatic regeneration.
New studies show that enteric 5-HT is a polyfunctional signalling molecule, acting both in developing and mature animals as a neurotransmitter paracrine factor, endocrine hormone and growth factor.
The gastrointestinal tract contains its own set of intrinsic neuroglial circuits - the enteric nervous system (ENS) - which detects and responds to diverse signals from the environment. Here, we ...address recent advances in the understanding of ENS development, including how neural-crest-derived progenitors migrate into and colonize the bowel, the formation of ganglionated plexuses and the molecular mechanisms of enteric neuronal and glial diversification. Modern lineage tracing and transcription-profiling technologies have produced observations that simultaneously challenge and affirm long-held beliefs about ENS development. We review many genetic and environmental factors that can alter ENS development and exert long-lasting effects on gastrointestinal function, and discuss how developmental defects in the ENS might account for some of the large burden of digestive disease.
Serotonin is an important gastrointestinal signaling molecule. It is a paracrine messenger utilized by enterochromaffin (EC) cells, which function as sensory transducers. Serotonin activates ...intrinsic and extrinsic primary afferent neurons to, respectively, initiate peristaltic and secretory reflexes and to transmit information to the central nervous system. Serotonin is also a neurotransmitter utilized by a system of long descending myenteric interneurons. Serotonin is synthesized through the actions of 2 different tryptophan hydroxylases, TpH1 and TpH2, which are found, respectively, in EC cells and neurons. Serotonin is inactivated by the serotonin reuptake transporter (SERT)-mediated uptake into enterocytes or neurons. The presence of many serotonin receptor subtypes enables selective drugs to be designed to therapeutically modulate gastrointestinal motility, secretion, and sensation. Current examples include tegaserod, a 5-HT4 partial agonist, which has been approved for treatment of irritable bowel syndrome (IBS) with constipation in women and for chronic constipation in men and women. The 5-HT3 antagonists, granisetron and ondansetron, are useful in combating the nausea associated with cancer chemotherapy, and alosetron is employed in the treatment of IBS with diarrhea. Serotonergic signaling abnormalities have also been putatively implicated in the pathogenesis of functional bowel diseases. Other compounds, for which efficacy has not been rigorously established, but which may have value, include tricyclic antidepressants and serotonin selective reuptake inhibitors to combat IBS, and 5-HT1 agonists, which enhance gastric accommodation, to treat functional dyspepsia. The initial success encountered with serotonergic agents holds promise for newer and more potent insights and therapies of brain-gut disorders.
Enteric nervous system (ENS) development is relevant to Hirschsprung's disease (HSCR; congenital aganglionosis of the terminal bowel), which is still imperfectly treated. Mutations in genes encoding ...the RET receptor tyrosine kinase and endothelin receptor type B (EDNRB) are involved in HSCR pathogenesis; however, also important in ENS development are molecules that mediate events that are more restricted than those of RET and EDNRB , act later in development and which might not be HSCR-associated. Examples are molecules that function in the guidance of enteric neural crest-derived cells (ENCDCs) and vagal axons, and in regulating the terminal differentiation of enteric neurons from ENCDCs. It is probable that highly prevalent disorders of gastrointestinal sensation and motility result from subtle defects in ENS development.
The heterogeneity and multiple functions of enteric glia have recently been recognized. Guyer et al. have now confirmed the neurogenetic potential of enteric glial cells and have also found that some ...have an open chromatin configuration, suggesting that some glial cells are poised and ready to differentiate into neurons.
Varicella was troublesome when varicella vaccine (vOka) was licensed in the United States. Varicella's yearly death toll was ~100, indirect costs were massive, and varicella threatened ...immunocompromised children. Since licensure, varicella has almost disappeared; nevertheless, vOka attenuation has lacked a molecular explanation. Sadaoka et al. (T. Sadaoka, D. P. Depledge, L. Rajbhandari, J. Breuer, et al., mBio 13:e0186422, 2022, https://doi.org/10.1128/mbio.01864-22), however, have now identified 6 core single nucleotide polymorphisms (SNPs), which singly or in combination may contribute to VOka attenuation; moreover, they found a predominant variant allele of vOka encoding the viral glycoprotein gB that results in glutamine instead of arginine at amino acid 699. This change impairs fusion activity and the ability of varicella-zoster virus (VZV) to infect human neurons from axon terminals. Molecular virological studies of vOka are reassuring in suggesting that reversion to virulence is unlikely and should also help assuage current fears about VZV vaccination and alleviate unanticipated future problems. The impressive work of Sadaoka et al. thus represents an auspicious advance in knowledge.
Serotonin is a multifunctional signaling molecule. In this issue of Neuron, Zhu et al. (2022) demonstrate, surprisingly, that despite the diminutive size of the enteric serotonin neuronal pool, it is ...serotonin from these neurons that drives proliferation of colorectal cancer stem cells.
PDF
