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| Different types of intrinsic sensory neurons and extrinsic sensory nerve endings in the enteric nervous system. A range of intrinsic sensory neurons and extrinsic sensory nerve endings are known to exist in the enteric nervous system (ENS). (1) Dogiel type I neurons represents a class of myenteric interneuron in the colon that have been identified as being largely length sensitive and tension insensitive. (2) At least two classes of cholinergic and nitrergic myenteric neurons in the myenteric plexus have been demonstrated to be rapidly adapting myenteric excitatory neurons. (3) Extrinsic vagal afferent nerve endings innervate largely the upper gut and behave predominantly as slowly adapting tension receptors. (4) Spinal afferent nerve endings provide a very rich sensory innervation to the lower gut (distal colon) and are potently activated by stretch and increases in muscle tension. (5) Dogiel type II neurons in the myenteric plexus are both chemosensory and mechanosensitive and receive fast and slow synaptic inputs from other enteric neurons. (6) Intestinofugal neurons are usually thought of as secondorder neurons but have been shown to be directly mechanosensitive and respond to direct mechanical compression stimuli.
Source publication
The gastrointestinal tract is the only internal organ to have evolved with its own independent nervous system, known as the enteric nervous system (ENS). This Review provides an update on advances that have been made in our understanding of how neurons within the ENS coordinate sensory and motor functions. Understanding this function is critical fo...
Contexts in source publication
Context 1
... the gastro intestinal tract has been the focus of much attention. Since the gastrointestinal tract is the only internal organ that has evolved its own sensory neurons, there is intense interest in understanding how the mechanisms of activation of intrinsic sensory neurons differ from extrinsic sensory nerve endings in the gastrointestinal tract (Fig. 3). Additionally, understanding the relative contribution of intrinsic versus extrinsic sensory nerves to the generation of chemosensory and mechanosensory reflex responses is of supreme relevance to the development of future therapeutic interventions to modify gastrointestinal ...
Context 2
... understanding of the mechanisms underlying mechanotransduction of intestinofugal neurons in the ENS has progressed, although their precise functional role in the body remains somewhat mysterious. Intestinofugal neurons are neurons with cell bodies in the gut wall, typically in the myenteric plexus, that have axon projections out of the gut wall to sympathetic neurons in prevertebral ganglia 81,82 (Figs 2,3). When activated by mechanical stimulation of the gut, these neurons generate fast synaptic potentials 82-85 and sometimes slow 86 synaptic potentials in sympathetic neurons. ...
Context 3
... contrast to what is known about intrinsic sensory neurons in the ENS, which directly respond to chemical or mechanical stimuli without any synaptic transmission 28,70 , intestinofugal neurons in the distal colon [81][82][83]85 and proximal colon 84 are largely second-order neurons that are activated indirectly (Fig. 3) by fast synaptic inputs from other enteric neurons that do respond directly to sensory stimuli 81-85 . However, in both regions of the bowel, a population of intestinofugal neurons seem to be directly responsive to mechanical stimuli, since blockade of synaptic transmission in the colon does not prevent distension-activated firing of ...
Context 4
... that stretch-activated ion channels involve direct physical mechanotransduction. Whether members of the Piezo ion channel family are involved, as they are for direct mechanotransduction of somatic afferents in skin 96 , awaits further study. Intestinofugal neurons can also be directly mechanically sensitive and respond to Von Frey hair probing 97 (Fig. 3), confirming early suggestions that a population of these neurons can indeed be directly mechanosensitive 83,84 . The level to which these neurons participate in the dynamic control of gastrointestinal motility in vivo remains ...
Similar publications
Purpose
Hirschsprung disease (HSCR) is characterized by distal intestinal aganglionosis. While surgery is lifesaving, gastrointestinal (GI) motility disorders persist in many patients. Our objective was to determine whether enteric nervous system (ENS) abnormalities exist in the ganglionated portions of the GI tract far proximal to the aganglionic...
Citations
... We show that the device can record electrical signals-including the gastric slow wave, respiration signal and heart signalin a large animal model and can monitor slow wave activity in freely moving and feeding animals. The enteric nervous system (ENS) contains millions of neurons and associated electrically active cells that regulate motility and hormone secretion in the gastrointestinal (GI) tract 1,2 . Dysfunction in electrical signalling is associated with a wide range of debilitating GI disorders. ...
... These signals were also observed in separate experiments using the MiGUT system in different animals (n = 9, Supplementary Table 2 and Supplementary Fig. 6). Examination of a subset of channels in frequency range (1) shows similar waveforms with a propagation speed of ~3.3 cm s −1 , assuming linear electrode position, whereas no such propagation is observed in the contributions of frequency ranges (2) and (3) (Supplementary Fig. 7). Additionally, in a separate experiment, euthanization of the animal during MiGUT measurements, using a barbiturate cocktail, resulted in a cessation of all waveforms (Fig. 3d). ...
The ability to record high-quality electrophysiology data from the gastrointestinal tract and enteric nervous system is of use in understanding a variety of disorders and improving healthcare via early diagnosis. However, such measurements remain challenging because electrodes must be implanted surgically or worn on the skin, which results in a trade-off between signal quality and invasiveness. Here we report an ingestible device for gastric electrophysiology. The non-invasive system, which is termed multimodal electrophysiology via ingestible, gastric, untethered tracking (MiGUT), consists of encapsulated electronics and a sensing electrode ribbon that unrolls in the stomach following delivery to make contact with the mucosa. The device then records and wirelessly transmits biopotential signals to an external receiver. We show that the device can record electrical signals—including the gastric slow wave, respiration signal and heart signal—in a large animal model and can monitor slow wave activity in freely moving and feeding animals.
... 8,9 The inhibitory and excitatory components of the enteric nervous system (ENS), interstitial cells of Cajal (ICC), fibroblast-like cells, and gastric smooth muscle work in concert to coordinate the neuro-muscular activity necessary for normal stomach function. 10,11 Neurological illnesses that impact the digestive system typically present as anomalies in motor (rather than sensory or secretory) processes, gastric motility disorders can be considered as a major source of dyspeptic and gastroparesis symptoms. Through the ENS, the motor, secretory, sensory, storage, and excretory activities of the gastrointestinal tract are intricately controlled by the external and autonomic nervous systems. ...
Diabetic gastroparesis (DGP) is a common complication of diabetes mellitus, marked by gastrointestinal motility disorder, a delayed gastric emptying present in the absence of mechanical obstruction. Clinical manifestations include postprandial fullness and epigastric discomfort, bloating, nausea, and vomiting. DGP may significantly affect the quality of life and productivity of patients. Research on the relationship between gastrointestinal dynamics and DGP has received much attention because of the increasing prevalence of DGP. Gastrointestinal motility disorders are closely related to a variety of factors including the absence and destruction of interstitial cells of Cajal, abnormalities in the neuro-endocrine system and hormone levels. Therefore, this study will review recent literature on the mechanisms of DGP and gastrointestinal motility disorders as well as the development of prokinetic treatment of gastrointestinal motility disorders in order to give future research directions and identify treatment strategies for DGP.
... NPY family receptors expressed in the vagal afferent neurons 19 , part of the enteric nervous system (ENS) that surveys the gastrointestinal milieu and relays information to the brain 20 . In vitro studies using EEC cell lines have shown that CaSR, GPRC6A and LPR5 are all general protein sensors that induce the secretion of regulatory peptides 21 . ...
... While the mammalian ENS shows great complexity 144,145 , the gut innervations by neurons have recently been detailed in flies 63 . Enteric neurons regulate many aspects of physiology in flies and mammals 20,146 . Given their sensory capabilities, vagal afferents are best positioned to regulate food intake, either through gut hormones 147,148 or by distension of the GI tract 63,[149][150][151][152] . ...
Amino acid availability is monitored by animals to adapt to their nutritional environment. Beyond gustatory receptors and systemic amino acid sensors, enteroendocrine cells (EECs) are believed to directly percept dietary amino acids and secrete regulatory peptides. However, the cellular machinery underlying amino acid-sensing by EECs and how EEC-derived hormones modulate feeding behavior remain elusive. Here, by developing tools to specifically manipulate EECs, we find that Drosophila neuropeptide F (NPF) from mated female EECs inhibits feeding, similar to human PYY. Mechanistically, dietary L-Glutamate acts through the metabotropic glutamate receptor mGluR to decelerate calcium oscillations in EECs, thereby causing reduced NPF secretion via dense-core vesicles. Furthermore, two dopaminergic enteric neurons expressing NPFR perceive EEC-derived NPF and relay an anorexigenic signal to the brain. Thus, our findings provide mechanistic insights into how EECs assess food quality and identify a conserved mode of action that explains how gut NPF/PYY modulates food intake.
... Experimental studies have reported that VCR delays gastric emptying and inhibits gastrointestinal motility (Sninsky, 1987;Sharma, 1988;Peixoto Júnior et al., 2009;Lopez-Gomez et al., 2018), which may be related to the damage of the gastrointestinal wall and myenteric plexus by VCR ( (Sninsky, 1987;Lopez-Gomez et al., 2018;Smith, 1967)). The myenteric nerve plexus within the enteric nervous system (ENS) mainly controls gastrointestinal motility, and its injury usually leads to motility disorders (Spencer and Hu, 2020). Previous results from our lab have shown that VCR can damage myenteric neurons in mice (Gao et al., 2021). ...
... In the ENS, the myenteric nerve plexus is mainly responsible for the coordination of muscle movements that propel the content (Spencer and Hu, 2020). Therefore, the spatial organization and the number of enteric neurons in the myenteric nerve plexus were studied by immunofluorescence staining. ...
Aims: Vincristine (VCR), an antineoplastic drug, induces peripheral neuropathy characterized by nerve damage, limiting its use and reducing the quality of life of patients. VCR causes myenteric neuron damage, inhibits gastrointestinal motility, and results in constipation or paralytic ileus in patients. Oxytocin (OT) is an endogenous neuropeptide produced by the enteric nerve system, which regulates gastrointestinal motility and exerts neuroprotective effects. This study aimed to investigate whether OT can improve VCR-induced gastrointestinal dysmotility and evaluate the underlying mechanism.
Methods: Mice were injected either with saline or VCR (0.1 mg/kg/d, i. p.) for 14 days, and OT (0.1 mg/kg/d, i.p.) was applied 1 h before each VCR injection. Gastrointestinal transit and the contractile activity of the isolated colonic segments were assessed. The concentration of OT in plasma was measured using ELISA. Immunofluorescence staining was performed to analyze myenteric neurons and reactive oxygen species (ROS) levels. Furthermore, the indicators of oxidative stress were detected. The protein expressions of Nrf2, ERK1/2, P-ERK1/2, p38, and P-p38 in the colon were tested using Western blot.
Results: VCR reduced gastrointestinal transit and the responses of isolated colonic segments to electrical field stimulation and decreased the amount of neurons. Furthermore, VCR reduced neuronal nitric oxide synthase and choline acetyltransferase immunopositive neurons in the colonic myenteric nerve plexus. VCR increased the concentration of OT in plasma. Exogenous OT pretreatment ameliorated the inhibition of gastrointestinal motility and the injury of myenteric neurons caused by VCR. OT pretreatment also prevented the decrease of superoxide dismutase activity, glutathione content, total antioxidative capacity, and Nrf2 expression, the increase of ROS levels, and the phosphorylation of ERK1/2 and p38 MAPK following VCR treatment.
Conclusion: Our results suggest that OT pretreatment can protect enteric neurons from VCR-induced injury by inhibiting oxidative stress and MAPK pathways (ERK1/2, p38). This may be the underlying mechanism by which it alleviates gastrointestinal dysmotility.
... The brain and gut communicate directly through the vagus nerve and the autonomic nervous system in the spinal cord, as well as through the ENS, which establishes neural connections between the gut and the brain. 46,47 The autonomic nervous system consists of sympathetic and parasympathetic nerves, including the vagus nerve. Specific to TBI, disruption of the BGM axis can trigger subsequent complications. ...
Traumatic brain injury (TBI) is a common disease with a high rate of death and disability, which poses a serious threat to human health; thus, the effective treatment of TBI has been a high priority. The brain‐gut‐microbial (BGM) axis, as a bidirectional communication network for information exchange between the brain and gut, plays a crucial role in neurological diseases. This article comprehensively explores the interrelationship between the BGM axis and TBI, including its physiological effects, basic pathophysiology, and potential therapeutic strategies. It highlights how the bidirectional regulatory pathways of the BGM axis could provide new insights into clinical TBI treatment and underscores the necessity for advanced research and development of innovative clinical treatments for TBI.
... The ENS is composed of millions of neurons and a vast network of interconnected ganglia that play a crucial role in regulating processes, such as gut secretion, motility, and blood flow [12]. Sensory neurons in the ENS detect various stimuli and relay this information to the intrinsic neurons, which can then initiate appropriate responses [13]. These neurons are organized into two main plexuses. ...
The enteric nervous system (ENS), consisting of neurons and glial cells, is situated along the gastrointestinal (GI) tract’s wall and plays a crucial role in coordinating digestive processes. Recent research suggests that the optimal functioning of the GI system relies on intricate connections between the ENS, the intestinal epithelium, the immune system, the intestinal microbiome, and the central nervous system (CNS). Inflammatory bowel disease (IBD) encompasses a group of chronic inflammatory disorders, such as Crohn’s disease (CD) and ulcerative colitis (UC), characterized by recurring inflammation and damage to the GI tract. This review explores emerging research in the dynamic field of IBD and sheds light on the potential role of ENS alterations in both the etiology and management of IBD. Specifically, we delve into IBD-induced enteric glial cell (EGC) activation and its implications for persistent enteric gliosis, elucidating how this activation disrupts GI function through alterations in the gut–brain axis (GBA). Additionally, we examine IBD-associated ENS alterations, focusing on EGC senescence and the acquisition of the senescence-associated secretory phenotype (SASP). We highlight the pivotal role of these changes in persistent GI inflammation and the recurrence of IBD. Finally, we discuss potential therapeutic interventions involving senotherapeutic agents, providing insights into potential avenues for managing IBD by targeting ENS-related mechanisms. This approach might represent a potential alternative to managing IBD and advance treatment of this multifaceted disease.
... The motor function of the gastrointestinal tract (GIT) depends on a fine balance between excitatory and inhibitory neurotransmission in GIT smooth muscle. [1] Major excitatory and inhibitory agents are mediated through cholinergic and adrenergic mechanisms, respectively. [2] However, other mechanisms called 'non-adrenergic non-cholinergic (NANC) may also play a crucial role in regulating GIT motility' . ...
Objectives
Nitric oxide (NO) plays a key role in inhibiting the contractility of gut smooth muscles in various species, and NG-nitro-L-arginine methyl ester (L-NAME) is a critical NO synthase inhibitor. Previous research investigating the role of NO in regulating gut motility focused on adult animals. Therefore, more research is needed to determine their status in the gut of newborns. Our study intended to understand how NO impacts the large gut contractility, in vitro , in rats, both neonates and adults, to get a better insight into the physiological role of NO in regulating large gut motility, particularly in neonates.
Materials and Methods
In an organ bath preparation, the segments of a large gut (colon and rectum) were subjected to various concentrations of nitroglycerin (NG) (0.01–100 mM), a NO donor, cumulatively. In another group, pre-treatment with L-NAME (100 mM) was done to evaluate the blocking effect of NO on the contractile tension and frequency.
Results
NG induced relaxation in the colon and rectum of adult rats in a similar manner. NG caused significantly greater relaxation in neonates’ rectums than in their colons. In neonatal and adult rats, L-NAME pre-application inhibited NG-induced relaxation in contractile tension. Exposure to different concentrations of NG decreased contractile frequency in adult rats’ colons and rectum. However, L-NAME pre-treatment did not affect the decrease in contractile frequency caused by NG. In neonates, NG caused a concentration-dependent reduction in contractile frequency, and a decrease in contractile frequency in the rectum was more than that in the colon. However, L-NAME pre-treatment did not affect the reduction in contractile frequency caused by NG.
Conclusion
Nitrergic mechanisms have possibly been present since birth. The intensity of control by NO may be different in the colon and rectum. The differences in NO sensitivity in adults and neonates demonstrated the changes during development.
... It is well-known that the ENS influences this process, but it is still unclear how neurogenic peristalsis modulates all the complex motor patterns [23] together with other myogenic components [24]. Therefore, intrinsic and extrinsic innervations play a complementary role that is not clearly understood yet, even in healthy subjects, and should be deeply analyzed to find out their specific functionality using optogenetic techniques in the near future [25]. ...
... In this respect, the intrinsic neural circuits and the extrinsic neural pathways are exposed in detail in [25], but one could define the ENS as a complex neural network composed by intrinsic sensory neurons, interneurons for excitation and inhibition, motor neurons, and enteric ganglia [26]. Specifically, two plexuses located in the intramuscular (myenteric) and under the mucosal epithelium (submucosal) are mainly involved in colon movements and water/electrolyte secretion, respectively. ...
... Specifically, two plexuses located in the intramuscular (myenteric) and under the mucosal epithelium (submucosal) are mainly involved in colon movements and water/electrolyte secretion, respectively. Moreover, the two main types of enteric neurons in the myenteric plexus are synaptic (S-) and after-hyperpolarization (AH-) neurons that are currently under study to propose their possible mechanisms of activation [25]. ...
Chronic constipation affects around 20% of the population and there is no efficient solution. This perspective review explores the potential of colonic electric stimulation (CES) using neural implants and methods of bioelectronic medicine as a therapeutic way to treat chronic constipation. The review covers the neurophysiology of colonic peristaltic function, the pathophysiology of chronic constipation, the technical aspects of CES, including stimulation parameters, electrode placement, and neuromodulation target selection, as well as a comprehensive analysis of various animal models highlighting their advantages and limitations in elucidating the mechanistic insights and translational relevance for CES. Finally, the main challenges and trends in CES are discussed.
... The metabolites act as neurotransmitter precursors or neurotransmitters, and travel through the systemic circulation and modulate brain functions. These neuroactive biomolecules activate nerve ganglia located in the submucosal and the myenteric plexuses of the enteric nervous system (ENS) Utility of zebrafish-based models (Spencer and Hu, 2020;Sharkey and Mawe, 2023). Thus, they act as indispensable mediators in the boundary between the gut and the brain. ...
... The gut-brain axis is a dynamic, bidirectional communication pathway connecting the central nervous system (CNS), consisting of the brain and the spinal cord, with the enteric nervous system (ENS), a complex network of neurons, interconnected small ganglia, submucosal and myenteric neuronal plexuses [100]. Often referred to as the "second brain", the ENS can operate autonomously from the CNS to regulate gastrointestinal (GI) homeostasis [101]. ...
Autism spectrum disorder (ASD) is a neuropsychiatric condition characterized by impaired social interactions and repetitive stereotyped behaviors. Growing evidence highlights an important role of the gut–brain–microbiome axis in the pathogenesis of ASD. Research indicates an abnormal composition of the gut microbiome and the potential involvement of bacterial molecules in neuroinflammation and brain development disruptions. Concurrently, attention is directed towards the role of short-chain fatty acids (SCFAs) and impaired intestinal tightness. This comprehensive review emphasizes the potential impact of maternal gut microbiota changes on the development of autism in children, especially considering maternal immune activation (MIA). The following paper evaluates the impact of the birth route on the colonization of the child with bacteria in the first weeks of life. Furthermore, it explores the role of pro-inflammatory cytokines, such as IL-6 and IL-17a and mother’s obesity as potentially environmental factors of ASD. The purpose of this review is to advance our understanding of ASD pathogenesis, while also searching for the positive implications of the latest therapies, such as probiotics, prebiotics or fecal microbiota transplantation, targeting the gut microbiota and reducing inflammation. This review aims to provide valuable insights that could instruct future studies and treatments for individuals affected by ASD.
