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18 pages, 5401 KiB

Open AccessEditor’s ChoiceArticle

Oxaliplatin-Induced Damage to the Gastric Innervation: Role in Nausea and Vomiting

by Ahmed A. Rahman, Philenkosini Masango, Rhian Stavely, Paul Bertrand, Amanda Page and Kulmira Nurgali

Biomolecules 2023, 13(2), 276; https://doi.org/10.3390/biom13020276 - 01 Feb 2023

Cited by 2 | Viewed by 1617

Abstract

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of [...] Read more.

Nausea and vomiting are common gastrointestinal side effects of oxaliplatin chemotherapy used for the treatment of colorectal cancer. However, the mechanism underlying oxaliplatin-induced nausea and vomiting is unknown. The stomach is involved in the emetic reflex but no study investigated the effects of oxaliplatin treatment on the stomach. In this study, the in vivo effects of oxaliplatin treatment on eating behaviour, stomach content, intrinsic gastric neuronal population, extrinsic innervation to the stomach, levels of mucosal serotonin (5-hydroxytryptamine, 5-HT), and parasympathetic vagal efferent nerve activity were analysed. Chronic systemic oxaliplatin treatment in mice resulted in pica, indicated by increased kaolin consumption and a reduction in body weight. Oxaliplatin treatment significantly increased the stomach weight and content. The total number of myenteric and nitric oxide synthase-immunoreactive neurons as well as the density of sympathetic, parasympathetic, and sensory fibres in the stomach were decreased significantly with oxaliplatin treatment. Oxaliplatin treatment significantly increased the levels in mucosal 5-HT and the number of enterochromaffin-like cells. Chronic oxaliplatin treatment also caused a significant increase in the vagal efferent nerve activity. The findings of this study indicate that oxaliplatin exposure has adverse effects on multiple components of gastric innervation, which could be responsible for pica and gastric dysmotility. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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13 pages, 2502 KiB

Open AccessArticle

SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release

by Arun Balasubramaniam, Philip R. Tedbury, Simon M. Mwangi, Yunshan Liu, Ge Li, Didier Merlin, Adam D. Gracz, Peijian He, Stefan G. Sarafianos and Shanthi Srinivasan

Biomolecules 2023, 13(2), 207; https://doi.org/10.3390/biom13020207 - 20 Jan 2023

Cited by 2 | Viewed by 1983

Abstract

Background: Diarrhea is present in up to 30–50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte–enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage [...] Read more.

Background: Diarrhea is present in up to 30–50% of patients with COVID-19. The mechanism of SARS-CoV-2-induced diarrhea remains unclear. We hypothesized that enterocyte–enteric neuron interactions were important in SARS-CoV-2-induced diarrhea. SARS-CoV-2 induces endoplasmic reticulum (ER) stress in enterocytes causing the release of damage associated molecular patterns (DAMPs). The DAMPs then stimulate the release of enteric neurotransmitters that disrupt gut electrolyte homeostasis. Methods: Primary mouse enteric neurons (EN) were exposed to a conditioned medium from ACE2-expressing Caco-2 colonic epithelial cells infected with SARS-CoV-2 or treated with tunicamycin (ER stress inducer). Vasoactive intestinal peptides (VIP) expression and secretion by EN were assessed by RT-PCR and ELISA, respectively. Membrane expression of NHE3 was determined by surface biotinylation. Results: SARS-CoV-2 infection led to increased expression of BiP/GRP78, a marker and key regulator for ER stress in Caco-2 cells. Infected cells secreted the DAMP protein, heat shock protein 70 (HSP70), into the culture media, as revealed by proteomic and Western analyses. The expression of VIP mRNA in EN was up-regulated after treatment with a conditioned medium of SARS-CoV-2-infected Caco-2 cells. CD91, a receptor for HSP70, is abundantly expressed in the cultured mouse EN. Tunicamycin, an inducer of ER stress, also induced the release of HSP70 and Xbp1s, mimicking SARS-CoV-2 infection. Co-treatment of Caco-2 with tunicamycin (apical) and VIP (basolateral) induced a synergistic decrease in membrane expression of Na⁺/H⁺ exchanger (NHE3), an important transporter that mediates intestinal Na⁺/fluid absorption. Conclusions: Our findings demonstrate that SARS-CoV-2 enterocyte infection leads to ER stress and the release of DAMPs that up-regulates the expression and release of VIP by EN. VIP in turn inhibits fluid absorption through the downregulation of brush-border membrane expression of NHE3 in enterocytes. These data highlight the role of epithelial-enteric neuronal crosstalk in COVID-19-related diarrhea. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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18 pages, 5061 KiB

Open AccessArticle

Group I Metabotropic Glutamate Receptors Modulate Motility and Enteric Neural Activity in the Mouse Colon

by Anita J. L. Leembruggen, Yuqing Lu, Haozhe Wang, Volkan Uzungil, Thibault Renoir, Anthony J. Hannan, Lincon A. Stamp, Marlene M. Hao and Joel C. Bornstein

Biomolecules 2023, 13(1), 139; https://doi.org/10.3390/biom13010139 - 09 Jan 2023

Cited by 1 | Viewed by 1598

Abstract

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a [...] Read more.

Glutamate is the major excitatory neurotransmitter in the central nervous system, and there is evidence that Group-I metabotropic glutamate receptors (mGlu1 and mGlu5) have established roles in excitatory neurotransmission and synaptic plasticity. While glutamate is abundantly present in the gut, it plays a smaller role in neurotransmission in the enteric nervous system. In this study, we examined the roles of Group-I mGlu receptors in gastrointestinal function. We investigated the expression of Grm1 (mGlu1) and Grm5 (mGlu5) in the mouse myenteric plexus using RNAscope in situ hybridization. Live calcium imaging and motility analysis were performed on ex vivo preparations of the mouse colon. mGlu5 was found to play a role in excitatory enteric neurotransmission, as electrically-evoked calcium transients were sensitive to the mGlu5 antagonist MPEP. However, inhibition of mGlu5 activity did not affect colonic motor complexes (CMCs). Instead, inhibition of mGlu1 using BAY 36-7620 reduced CMC frequency but did not affect enteric neurotransmission. These data highlight complex roles for Group-I mGlu receptors in myenteric neuron activity and colonic function. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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22 pages, 8765 KiB

Open AccessEditor’s ChoiceArticle

Oxidative Stress-Induced HMGB1 Translocation in Myenteric Neurons Contributes to Neuropathy in Colitis

by Rhian Stavely, Lauren Sahakian, Rhiannon T. Filippone, Vanesa Stojanovska, Joel C. Bornstein, Samy Sakkal and Kulmira Nurgali

Biomolecules 2022, 12(12), 1831; https://doi.org/10.3390/biom12121831 - 07 Dec 2022

Cited by 5 | Viewed by 1935

Abstract

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released by dying cells to stimulate the immune response. During cell death, HMGB1 is translocated from the nucleus to the cytoplasm and passively released. High levels of secreted HMGB1 are observed in the [...] Read more.

High-mobility group box 1 (HMGB1) is a damage-associated molecular pattern released by dying cells to stimulate the immune response. During cell death, HMGB1 is translocated from the nucleus to the cytoplasm and passively released. High levels of secreted HMGB1 are observed in the faeces of inflammatory bowel disease (IBD) patients, indicating its role in IBD pathophysiology and potential as a non-invasive IBD biomarker. HMGB1 is important in regulating neuronal damage in the central nervous system; its pathological activity is intertwined with oxidative stress and inflammation. In this study, HMGB1 expression in the enteric nervous system and its relevance to intestinal neuroinflammation is explored in organotypic cultures of the myenteric plexus exposed to oxidative stimuli and in Winnie mice with spontaneous chronic colitis. Oxidative stimuli induced cytoplasmic translocation of HMGB1 in myenteric neurons in organotypic preparations. HMGB1 translocation correlated with enteric neuronal loss and oxidative stress in the myenteric ganglia of Winnie mice. Inhibition of HMGB1 by glycyrrhizic acid ameliorated HMGB1 translocation and myenteric neuronal loss in Winnie mice. These data highlight modulation of HMGB1 signalling as a therapeutic strategy to reduce the consequences of enteric neuroinflammation in colitis, warranting the exploration of therapeutics acting on the HMGB1 pathway as an adjunct treatment with current anti-inflammatory agents. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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18 pages, 4265 KiB

Open AccessArticle

Galanin Receptors (GALR1, GALR2, and GALR3) Immunoexpression in Enteric Plexuses of Colorectal Cancer Patients: Correlation with the Clinico-Pathological Parameters

by Jacek Kiezun, Marta Kiezun, Bartlomiej Emil Krazinski, Lukasz Paukszto, Anna Koprowicz-Wielguszewska, Zbigniew Kmiec and Janusz Godlewski

Biomolecules 2022, 12(12), 1769; https://doi.org/10.3390/biom12121769 - 27 Nov 2022

Cited by 4 | Viewed by 1761

Abstract

Galanin (GAL) is an important neurotransmitter released by the enteric nervous system (ENS) neurons located in the muscularis externa and submucosa enteric plexuses that acts by binding to GAL receptors 1, 2 and 3 (GALR1, 2 and 3). In our previous studies, the [...] Read more.

Galanin (GAL) is an important neurotransmitter released by the enteric nervous system (ENS) neurons located in the muscularis externa and submucosa enteric plexuses that acts by binding to GAL receptors 1, 2 and 3 (GALR1, 2 and 3). In our previous studies, the GAL immunoexpression was compared in colorectal cancer (CRC) tissue and the adjacent parts of the large intestine wall including myenteric and submucosal plexuses. Recently we have also found that expression levels of GALR1 and GALR3 proteins are elevated in CRC tissue as compared with their expression in epithelial cells of unchanged mucosa. Moreover, higher GALR3 immunoreactivity in CRC cells correlated with better prognosis of CRC patients. To understand the distribution of GALRs in enteric plexuses distal and close to CRC invasion, in the present study we decided to evaluate GALRs expression within the myenteric and submucosal plexuses located proximally and distally to the cancer invasion and correlated the GALRs expression levels with the clinico-pathological data of CRC patients. The immunohistochemical and immunofluorescent methods showed only slightly decreased immunoexpression of GALR1 and GALR3 in myenteric plexuses close to cancer but did not reveal any correlation in the immunoexpression of all three GAL receptors in myenteric plexuses and tumour progression. No significant changes were found between the expression levels of GALRs in submucosal plexuses distal and close to the tumour. However, elevated GALR1 expression in submucosal plexuses in vicinity of CRC correlated with poor prognosis, higher tumour grading and shorter overall survival. When myenteric plexuses undergo morphological and functional alterations characteristic for atrophy, GALRs maintain or only slightly decrease their expression status. In contrast, the correlation between high expression of GALR1 in the submucosal plexuses and overall survival of CRC patients suggest that GAL and GALRs can act as a components of local neuro-paracrine pro-proliferative pathways accelerating the invasion and metastasis of cancer cell. The obtained results suggest an important role of GALR1 in submucosal plexuses function during the progression of CRC and imply that GALR1 expression in submucosal plexuses of ENS could be an important predictive factor for CRC progression. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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15 pages, 3892 KiB

Open AccessArticle

A Novel Method for Identifying the Transition Zone in Long-Segment Hirschsprung Disease: Investigating the Muscle Unit to Ganglion Ratio

by Wendy Yang, Jenny Pham, Sebastian K. King, Donald F. Newgreen, Heather M. Young, Lincon A. Stamp and Marlene M. Hao

Biomolecules 2022, 12(8), 1101; https://doi.org/10.3390/biom12081101 - 10 Aug 2022

Cited by 2 | Viewed by 2109

Abstract

Hirschsprung disease (HSCR) is characterised by the absence of enteric ganglia along variable lengths of the distal bowel. Current gold standard treatment involves the surgical resection of the defective, aganglionic bowel. Clear and reliable distinction of the normoganglionated bowel from the transition zone [...] Read more.

Hirschsprung disease (HSCR) is characterised by the absence of enteric ganglia along variable lengths of the distal bowel. Current gold standard treatment involves the surgical resection of the defective, aganglionic bowel. Clear and reliable distinction of the normoganglionated bowel from the transition zone is key for successful resection of the entire defective bowel, and the avoidance of subsequent postoperative complications. However, the intraoperative nature of the tissue analysis and the variability of patient samples, sample preparation, and operator objectivity, make reproducible identification of the transition zone difficult. Here, we have described a novel method for using muscle units as a distinctive landmark for quantifying the density of enteric ganglia in resection specimens from HSCR patients. We show that the muscle unit to ganglion ratio is greater in the transition zone when compared with the proximal, normoganglionated region for long-segment HSCR patients. Patients with short-segment HSCR were also investigated, however, the muscle unit to ganglion ratio was not significantly different in these patients. Immunohistochemical examination of individual ganglia showed that there were no differences in the proportions of either enteric neurons or glial cells through the different regions of the resected colon. In addition, we identified that the size of enteric ganglia was smaller for patients that went on to develop HSCR associated enterocolitis; although the density of ganglia, as determined by the muscle unit to ganglia ratio, was not different when compared with patients that had no further complications. This suggests that subtle changes in the enteric nervous system, even in the “normoganglionated” colon, could be involved in changes in immune function and subsequent bacterial dysbiosis. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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Review

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16 pages, 996 KiB

Open AccessReview

The Potential Role of Microorganisms on Enteric Nervous System Development and Disease

by Atchariya Chanpong, Osvaldo Borrelli and Nikhil Thapar

Biomolecules 2023, 13(3), 447; https://doi.org/10.3390/biom13030447 - 27 Feb 2023

Cited by 1 | Viewed by 2050

Abstract

The enteric nervous system (ENS), the inherent nervous system of the gastrointestinal (GI) tract is a vast nervous system that controls key GI functions, including motility. It functions at a critical interface between the gut luminal contents, including the diverse population of microorganisms [...] Read more.

The enteric nervous system (ENS), the inherent nervous system of the gastrointestinal (GI) tract is a vast nervous system that controls key GI functions, including motility. It functions at a critical interface between the gut luminal contents, including the diverse population of microorganisms deemed the microbiota, as well as the autonomic and central nervous systems. Critical development of this axis of interaction, a key determinant of human health and disease, appears to occur most significantly during early life and childhood, from the pre-natal through to the post-natal period. These factors that enable the ENS to function as a master regulator also make it vulnerable to damage and, in turn, a number of GI motility disorders. Increasing attention is now being paid to the potential of disruption of the microbiota and pathogenic microorganisms in the potential aetiopathogeneis of GI motility disorders in children. This article explores the evidence regarding the relationship between the development and integrity of the ENS and the potential for such factors, notably dysbiosis and pathogenic bacteria, viruses and parasites, to impact upon them in early life. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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12 pages, 305 KiB

Open AccessEditor’s ChoiceReview

Enteric Neuromyopathies: Highlights on Genetic Mechanisms Underlying Chronic Intestinal Pseudo-Obstruction

by Francesca Bianco, Giulia Lattanzio, Luca Lorenzini, Maurizio Mazzoni, Paolo Clavenzani, Laura Calzà, Luciana Giardino, Catia Sternini, Anna Costanzini, Elena Bonora and Roberto De Giorgio

Biomolecules 2022, 12(12), 1849; https://doi.org/10.3390/biom12121849 - 10 Dec 2022

Cited by 9 | Viewed by 2084

Abstract

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is [...] Read more.

Severe gut motility disorders are characterized by the ineffective propulsion of intestinal contents. As a result, the patients develop disabling/distressful symptoms, such as nausea and vomiting along with altered bowel habits up to radiologically demonstrable intestinal sub-obstructive episodes. Chronic intestinal pseudo-obstruction (CIPO) is a typical clinical phenotype of severe gut dysmotility. This syndrome occurs due to changes altering the morpho-functional integrity of the intrinsic (enteric) innervation and extrinsic nerve supply (hence neuropathy), the interstitial cells of Cajal (ICC) (mesenchymopathy), and smooth muscle cells (myopathy). In the last years, several genes have been identified in different subsets of CIPO patients. The focus of this review is to cover the most recent update on enteric dysmotility related to CIPO, highlighting (a) forms with predominant underlying neuropathy, (b) forms with predominant myopathy, and (c) mitochondrial disorders with a clear gut dysfunction as part of their clinical phenotype. We will provide a thorough description of the genes that have been proven through recent evidence to cause neuro-(ICC)-myopathies leading to abnormal gut contractility patterns in CIPO. The discovery of susceptibility genes for this severe condition may pave the way for developing target therapies for enteric neuro-(ICC)-myopathies underlying CIPO and other forms of gut dysmotility. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

13 pages, 287 KiB

Open AccessEditor’s ChoiceReview

Applications of Single-Cell Sequencing Technology to the Enteric Nervous System

by Richard A. Guyer, Jessica L. Mueller and Allan M. Goldstein

Biomolecules 2022, 12(3), 452; https://doi.org/10.3390/biom12030452 - 15 Mar 2022

Cited by 3 | Viewed by 3245

Abstract

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, [...] Read more.

With recent technical advances and diminishing sequencing costs, single-cell sequencing modalities have become commonplace. These tools permit analysis of RNA expression, DNA sequence, chromatin structure, and cell surface antigens at single-cell resolution. Simultaneous measurement of numerous parameters can resolve populations including rare cells, thus revealing cellular diversity within organs and permitting lineage reconstruction in developing tissues. Application of these methods to the enteric nervous system has yielded a wealth of data and biological insights. We review recent papers applying single-cell sequencing tools to the nascent neural crest and to the developing and mature enteric nervous system. These studies have shown significant diversity of enteric neurons and glia, suggested paradigms for neuronal specification, and revealed signaling pathways active during development. As technology evolves and multiome techniques combining two or more of transcriptomic, genomic, epigenetic, and proteomic data become prominent, we anticipate these modalities will become commonplace in ENS research and may find a role in diagnostic testing and personalized therapeutics. Full article

(This article belongs to the Special Issue Enteric Nervous System: Normal Functions and Enteric Neuropathies)

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