261 results on '"enteric neurons"'
Search Results
2. Distribution and neurochemical characterisation of neurons containing neuregulin 1 in the enteric nervous system within the porcine small intestine
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Puchała Łukasz, Gonkowski Sławomir, Rytel Liliana, Wojtkiewicz Joanna, and Grzegorzewski Waldemar Jarosław
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neuregulin 1 ,enteric neurons ,domestic pig ,Veterinary medicine ,SF600-1100 - Abstract
The enteric nervous system (ENS) in the wall of the gastrointestinal tract is complex and comprises many neurons, which are differentiated in terms of structure, function and neurochemistry. Neuregulin 1 (NRG 1) is one of the neuronal factors synthesised in the ENS about the distribution and functions of which relatively little is known. The present study is the first description of the distribution of NRG 1 in the ENS in various segments of the porcine small intestine.
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- 2024
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3. Intestinal Region-Dependent Impact of NFκB-Nrf Crosstalk in Myenteric Neurons and Adjacent Muscle Cells in Type 1 Diabetic Rats.
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Barta, Bence Pál, Onhausz, Benita, Egyed-Kolumbán, Abigél, AL Doghmi, Afnan, Balázs, János, Szalai, Zita, Ferencz, Ágnes, Hermesz, Edit, Bagyánszki, Mária, and Bódi, Nikolett
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TYPE 1 diabetes ,SMALL intestine ,INSULIN therapy ,SMOOTH muscle ,MUSCLE cells ,SUBMUCOUS plexus - Abstract
Background/Objectives: Type 1 diabetes affects cytokines as potential inducers of NFκB signalling involved in inflammation and neuronal survival. Our goal was to assess the expression of NFκB p65 and its negative regulator, Nrf2, in myenteric neurons and adjacent smooth muscle of different gut segments after chronic hyperglycaemia and immediate insulin treatment. Methods: After ten weeks of hyperglycaemia, intestinal samples of control, streptozotocin-induced diabetic and insulin-treated diabetic rats were prepared for fluorescent immunohistochemistry, immunogold electron microscopy, ELISA and qPCR. Results: In the diabetic rats, the proportion of NFκB p65-immunoreactive myenteric neurons decreased significantly in the duodenum and increased in the ileum. The density of NFκB p65-labelling gold particles increased in the ileal but remained unchanged in the duodenal ganglia. Meanwhile, both total and nuclear Nrf2 density increased in the myenteric neurons of the diabetic duodenum. In smooth muscle, NFκB p65 and Nrf2 density increased in the small intestine of diabetic rats. While on the mRNA level, NFκB p65 and Nrf2 were induced, on the protein level, NFκB p65 increased and Nrf2 decreased in muscle/myenteric plexus homogenates. Insulin treatment had protective effects. Conclusions: Our findings reveal a segment-specific NFκB and Nrf expression in myenteric neurons and ganglionic muscular environments, which may contribute to regional neuronal survival and motility disturbances in diabetes. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Vitamin A deficiency triggers colonic methylation potentially impairing colonic neuron via downregulation SGK1/FOXO pathway
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Bei Tong, Junyan Yan, Zhujun Sun, Ruifang Luo, Fang Lin, Riqiang Hu, Ting Yang, Yuting Wang, and Jie Chen
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enteric neurons ,methylation ,SGK1/FOXO pathway ,vitamin A supplementation ,vitamin A deficiency ,Pediatrics ,RJ1-570 - Abstract
Abstract DNA methylation is widely involved in the modification of intestinal function, but the methylation mechanism in the enteric nervous system has not been studied in vitamin A deficiency (VAD). Herein, we firstly found that in the VAD group, gastrointestinal transit time was delayed compared with the vitamin A normal (VAN) group. RNA sequencing between VAD and VAN rats identified enriched pathways associated with enteric nerves and methylation transferase complexes. Then expression levels of DNA methyltransferases (DNMT1, DNMT3a and DNMT3b) were validated to significant increase in the VAD group. Representative reduced bisulfate sequencing showed that the VAD rats had high levels of DNA methylation in promoters and exons compared with the VAN rats. A combined methylomic and transcriptomic analysis identified that methylation levels of Sgk1, a key gene associated with enteric neural development, were elevated in the VAD group, and the activity of the SGK1/FOXO signaling axis was reduced. Furthermore, the colonic neuronal morphology and synaptic architecture were impaired in the VAD offspring. Interestingly, the above alterations in the VAD group were alleviated by vitamin A (VA) supplementation in the early postnatal period. These data suggest that VAD triggers colonic hypermethylation, which probably downregulates the SGK1/FOXO signaling pathway to cause colonic transfer dysfunction.
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- 2024
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5. Macrophage-induced enteric neurodegeneration leads to motility impairment during gut inflammation
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Breßer, Mona, Siemens, Kevin D, Schneider, Linda, Lunnebach, Jonah E, Leven, Patrick, Glowka, Tim R, Oberländer, Kristin, De Domenico, Elena, Schultze, Joachim L, Schmidt, Joachim, Kalff, Jörg C, Schneider, Anja, Wehner, Sven, and Schneider, Reiner
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- 2025
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6. Biopsy samples from patients with irritable bowel syndrome, but not from those with mastocytosis or unspecific gastrointestinal complaints reveal unique nerve activation in all gut regions independent of mast cell density, histamine content or specific gastrointestinal symptoms
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Vignali, Sheila, Buhner, Sabine, Greiter, Wolfgang, Daniel, Hannelore, Frieling, Thomas, Schemann, Michael, and Annahazi, Anita
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IRRITABLE colon ,MAST cell disease ,MAST cells ,HISTAMINE ,NERVES ,BIOPSY ,GUINEA pigs - Abstract
Introduction: We previously showed enteric nerve activation after application of colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS). The question remains whether this is a region-specific or a generalized sensitization. We tested the nerve-activating properties of supernatants from large and small intestinal regions of IBS patients with diarrhea (IBS-D) in comparison to those from mastocytosis patients with diarrhea (MC-D) or non-IBS/non-MC patients with GI-complaints. MC-D patients were included to test samples from patients with an established, severe mast cell disorder, because mast cells are suggested to play a role in IBS. Methods: Voltage-sensitive dye imaging was used to record the effects of mucosal biopsy supernatants from IBS-D, MC-D, and non-IBS/non-MC on guinea pig submucous neurons. Mast cell density and histamine concentrations were measured in all samples. Results: The median neuroindex (spike frequency × % responding neurons in Hz × %) was significantly (all p < 0.001) increased for IBS-D (duodenum and colon, proximal and distal each, 49.3; 50.5; 63.7; 71.9, respectively) compared to non-IBS/non-MC (duodenum and colon, proximal and distal each, 8.7; 4.9; 6.9; 5.4, respectively) or MC-D supernatants (duodenum and colon, proximal and distal each, 9.4; 11.9; 0.0; 7.9, respectively). Nerve activation by MC-D and non-IBS/non-MC supernatants was comparable (p>0.05). Mast cell density or histamine concentrations were not different between IBS-D, MC-D, and non-IBS/non-MC samples. Discussion: Nerve activation by biopsy supernatants is an IBS hallmark that occurs throughout the gut, unrelated to mast cell density or histamine concentration. At least as important is our finding that GI complaints per se were not associated with biopsy supernatant-induced nerve activation, which further stresses the relevance of altered nerve behavior in IBS. [ABSTRACT FROM AUTHOR]
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- 2024
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7. Phosphatase and Tensin Homolog Inhibition in Proteolipid Protein 1-Expressing Cells Stimulates Neurogenesis and Gliogenesis in the Postnatal Enteric Nervous System.
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Woods, Crystal, Flockton, Amanda R., and Belkind-Gerson, Jaime
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ENTERIC nervous system , *PTEN protein , *DEVELOPMENTAL neurobiology , *NEUROGENESIS , *SUBMUCOUS plexus , *CELL proliferation - Abstract
Phosphatase and tensin homolog (Pten) is a key regulator of cell proliferation and a potential target to stimulate postnatal enteric neuro- and/or gliogenesis. To investigate this, we generated two tamoxifen-inducible Cre recombinase murine models in which Pten was conditionally ablated, (1) in glia (Plp1-expressing cells) and (2) in neurons (Calb2-expressing cells). Tamoxifen-treated adult (7–12 weeks of age; n = 4–15) mice were given DSS to induce colitis, EdU to monitor cell proliferation, and were evaluated at two timepoints: (1) early (3–4 days post-DSS) and (2) late (3–4 weeks post-DSS). We investigated gut motility and evaluated the enteric nervous system. Pten inhibition in Plp1-expressing cells elicited gliogenesis at baseline and post-DSS (early and late) in the colon, and neurogenesis post-DSS late in the proximal colon. They also exhibited an increased frequency of colonic migrating motor complexes (CMMC) and slower whole gut transit times. Pten inhibition in Calb2-expressing cells did not induce enteric neuro- or gliogenesis, and no alterations were detected in CMMC or whole gut transit times when compared to the control at baseline or post-DSS (early and late). Our results merit further research into Pten modulation where increased glia and/or slower intestinal transit times are desired (e.g., short-bowel syndrome and rapid-transit disorders). [ABSTRACT FROM AUTHOR]
- Published
- 2024
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8. Biopsy samples from patients with irritable bowel syndrome, but not from those with mastocytosis or unspecific gastrointestinal complaints reveal unique nerve activation in all gut regions independent of mast cell density, histamine content or specific gastrointestinal symptoms
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Sheila Vignali, Sabine Buhner, Wolfgang Greiter, Hannelore Daniel, Thomas Frieling, Michael Schemann, and Anita Annahazi
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irritable bowel syndrome ,mastocytosis ,enteric neurons ,mast cells ,neuroimaging ,small bowel ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionWe previously showed enteric nerve activation after application of colonic mucosal biopsy supernatants from patients with irritable bowel syndrome (IBS). The question remains whether this is a region-specific or a generalized sensitization. We tested the nerve-activating properties of supernatants from large and small intestinal regions of IBS patients with diarrhea (IBS-D) in comparison to those from mastocytosis patients with diarrhea (MC-D) or non-IBS/non-MC patients with GI-complaints. MC-D patients were included to test samples from patients with an established, severe mast cell disorder, because mast cells are suggested to play a role in IBS.MethodsVoltage-sensitive dye imaging was used to record the effects of mucosal biopsy supernatants from IBS-D, MC-D, and non-IBS/non-MC on guinea pig submucous neurons. Mast cell density and histamine concentrations were measured in all samples.ResultsThe median neuroindex (spike frequency × % responding neurons in Hz × %) was significantly (all p < 0.001) increased for IBS-D (duodenum and colon, proximal and distal each, 49.3; 50.5; 63.7; 71.9, respectively) compared to non-IBS/non-MC (duodenum and colon, proximal and distal each, 8.7; 4.9; 6.9; 5.4, respectively) or MC-D supernatants (duodenum and colon, proximal and distal each, 9.4; 11.9; 0.0; 7.9, respectively). Nerve activation by MC-D and non-IBS/non-MC supernatants was comparable (p>0.05). Mast cell density or histamine concentrations were not different between IBS-D, MC-D, and non-IBS/non-MC samples.DiscussionNerve activation by biopsy supernatants is an IBS hallmark that occurs throughout the gut, unrelated to mast cell density or histamine concentration. At least as important is our finding that GI complaints per se were not associated with biopsy supernatant-induced nerve activation, which further stresses the relevance of altered nerve behavior in IBS.
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- 2024
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9. Intestinal Region-Dependent Impact of NFκB-Nrf Crosstalk in Myenteric Neurons and Adjacent Muscle Cells in Type 1 Diabetic Rats
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Bence Pál Barta, Benita Onhausz, Abigél Egyed-Kolumbán, Afnan AL Doghmi, János Balázs, Zita Szalai, Ágnes Ferencz, Edit Hermesz, Mária Bagyánszki, and Nikolett Bódi
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NFκB ,Nrf2 ,myenteric plexus ,enteric neurons ,intestinal smooth muscle ,hyperglycaemia ,Biology (General) ,QH301-705.5 - Abstract
Background/Objectives: Type 1 diabetes affects cytokines as potential inducers of NFκB signalling involved in inflammation and neuronal survival. Our goal was to assess the expression of NFκB p65 and its negative regulator, Nrf2, in myenteric neurons and adjacent smooth muscle of different gut segments after chronic hyperglycaemia and immediate insulin treatment. Methods: After ten weeks of hyperglycaemia, intestinal samples of control, streptozotocin-induced diabetic and insulin-treated diabetic rats were prepared for fluorescent immunohistochemistry, immunogold electron microscopy, ELISA and qPCR. Results: In the diabetic rats, the proportion of NFκB p65-immunoreactive myenteric neurons decreased significantly in the duodenum and increased in the ileum. The density of NFκB p65-labelling gold particles increased in the ileal but remained unchanged in the duodenal ganglia. Meanwhile, both total and nuclear Nrf2 density increased in the myenteric neurons of the diabetic duodenum. In smooth muscle, NFκB p65 and Nrf2 density increased in the small intestine of diabetic rats. While on the mRNA level, NFκB p65 and Nrf2 were induced, on the protein level, NFκB p65 increased and Nrf2 decreased in muscle/myenteric plexus homogenates. Insulin treatment had protective effects. Conclusions: Our findings reveal a segment-specific NFκB and Nrf expression in myenteric neurons and ganglionic muscular environments, which may contribute to regional neuronal survival and motility disturbances in diabetes.
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- 2024
- Full Text
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10. Ednrb −/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine
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Bhave, Sukhada, Guyer, Richard A, Picard, Nicole, Omer, Meredith, Hotta, Ryo, and Goldstein, Allan M
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Biomedical and Clinical Sciences ,Clinical Sciences ,Digestive Diseases ,Congenital Structural Anomalies ,Pediatric ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Oral and gastrointestinal ,endothelin receptor type B ,enteric nervous system ,enteric neurons ,hirschsprung disease ,single-cell RNA sequencing ,Biological sciences ,Biomedical and clinical sciences - Abstract
Hirschsprung disease is most often characterized by aganglionosis limited to the distal colon and rectum, and mice lacking the Endothelin receptor type B (Ednrb) faithfully recapitulate this phenotype. However, despite the presence of enteric ganglia in the small intestine, both human patients and Ednrb-/- mice suffer from dysmotility and altered gastrointestinal function, thus raising the possibility of enteric nervous system (ENS) abnormalities proximal to the aganglionic region. We undertook the present study to determine whether abnormalities with the ENS in ganglionated regions may account for abnormal gastrointestinal function. We performed single-cell RNA sequencing on ENS cells from the small intestine of Ednrb-/- mice and compared the results to a published single-cell dataset. Our results identified a missing population of neurons marked by the enzyme Gad2, which catalyzes the production of γ-Aminobutyric acid (GABA), in the small intestine of Ednrb-/- animals. This result was confirmed by immunostaining enteric ganglia from Ednrb-/- mice and their wild-type littermates. These data show for the first time that ganglionated regions of the Hirschsprung gut lack a neuronal subpopulation, which may explain the persistent gastrointestinal dysfunction after surgical correction of Hirschsprung disease.
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- 2022
11. Changes in the Phenotype of Intramural Inhibitory Neurons of the Porcine Descending Colon Resulting from Glyphosate Administration.
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Bulc, Michał, Całka, Jarosław, and Palus, Katarzyna
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SUBMUCOUS plexus , *GLYPHOSATE , *ENTERIC nervous system , *PHENOTYPIC plasticity , *VASOACTIVE intestinal peptide , *NEURONS - Abstract
Environmental contamination and the resulting food contamination represent a serious problem and pose a major threat to animal and human health. The gastrointestinal tract is directly exposed to a variety of substances. One is glyphosate, whose presence in the soil is commonly observed. This study demonstrates the effects of low and high glyphosate doses on the populations of intramural neurons of the porcine descending colon. An analysis was performed on neurons ex-pressing the vasoactive intestinal peptide, pituitary adenylate cyclase-activating peptide, a neuronal isoform of nitrogen oxide synthase, and galanin. Even a low dose of glyphosate increased the number of neurons immunoreactive against the studied substances. However, the changes depended on both the plexus analysed and the substance tested. Meanwhile, a high glyphosate dose resulted in quantitative changes (an increase in the number) within neurons immunoreactive against all the studied neuropeptides/enzymes in the myenteric plexus and both submucosal plexuses. The response of the enteric nervous system in the form of an increase in the number of neurons immunoreactive against neuroprotective substances may suggest that glyphosate has a toxic effect on enteric neurons which attempt to increase their survivability through the released neuroprotective substances. [ABSTRACT FROM AUTHOR]
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- 2023
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12. A Histomorphometric Analysis of Interganglionic Distance in the Myenteric Plexus of the Entire Large Intestine of Aborted Human Foetuses: A Cross-sectional Study
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Bhavani Prasad Goriparthi, Chandra Philip Xavier, Anita Ramdas, and Valsa Diana George
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aganglionosis ,enteric neurons ,ganglionated plexus ,nervous system ,Medical physics. Medical radiology. Nuclear medicine ,R895-920 ,Surgery ,RD1-811 - Abstract
Introduction: The Enteric Nervous System (ENS) contributes to the innervation of the gut and is considered the second brain in the gut. It is a part of the peripheral nervous system and the ganglionated plexus (GP) of enteric neurons, present in the layers of the digestive tract, is more complex than any other structure of the peripheral nervous system. The establishment of a valid standard method for quantitative analysis of the myenteric plexus has been a topic of debate among enteric neuropathologists and is essential for better characterisation of patients with gut dysmotility. Aim: To determine the histomorphometric analysis of the interganglion distance of the myenteric plexus in the entire large intestine of aborted human foetuses. Materials and Methods: A cross-sectional descriptive study was carried out in the Department of Anatomy at Pondicherry Institute of Medical Sciences, Pondicherry, India. The study duration was eight years and seven months, from October 2014 to May 2022. A total of 50 aborted human foetus samples were collected from Rajiv Gandhi Government Women and Children’s Hospital, Puducherry, India, from the Department of Obstetrics and Gynaecology. The age of the aborted human foetuses was determined based on Biparietal Diameter (BPD) and Crown Rump Length (CRL) and correlated with clinical history. The aborted human foetuses were assigned to two groups: group A (n=29), ≤20 Weeks of Gestation (WG), and group B (n=21), ≥20 WG. Nicotinamide Adenine Dinucleotide Phosphate (NADPH) diaphorase histochemistry, an enzyme histochemistry technique, was used to study the tissue preparations. Statistical significance was determined using Statistical Package for Social Sciences (SPSS) version 20.0, International Business Machines (IBM) corporation. The independent sample t-test was conducted for parametric analysis. Results: The interganglion distance was measured from the caecum (A1 segment) to the anal canal (A7 segment) in aborted foetuses of less than 20 WG. The mean values ranged from 78.86±38.09 μm to 126.94±23.87 µm in foetuses of less than 20 WG. The mean values ranged from 66.41±8.05 μm to 107.67±30.17 µm in aborted human foetuses of more than 20 WG. Conclusion: The anal canal showed a long interganglion distance. The average reference values were found to be helpful as a diagnostic tool for identifying disorders related to gut innervation and motility.
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- 2023
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13. Influence of bisphenol A and its analog bisphenol S on cocaine- and amphetamine-regulated transcript peptide-positive enteric neurons in the mouse gastrointestinal tract.
- Author
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Makowska, Krystyna, Fagundes, Kainã R. C., and Gonkowski, Sławomir
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GASTROINTESTINAL system ,BISPHENOL A ,ENTERIC nervous system ,SUBMUCOUS plexus ,NEURONS ,ALIMENTARY canal - Abstract
Introduction: Bisphenol A (BPA) is used in large quantities for the production of plastics and is present in various everyday objects. It penetrates living organisms and shows multidirectional adverse influence on many internal organs. For this reason, BPA is often replaced in plastic production by other substances. One of them is bisphenol S (BPS), whose effects on the enteric nervous system (ENS) have not been explained. Methods: Therefore, the present study compares the influence of BPA and BPS on the number of enteric neurons immunoreactive to cocaine-and amphetamine-regulated transcript (CART) peptide located in the ENS of the stomach, jejunum and colon with the use of double immunofluorescence method. Results: The obtained results have shown that both bisphenols studied induced an increase in the number of CART-positive enteric neurons, and the severity of changes depended on the type of enteric ganglion, the dose of bisphenols and the segment of the digestive tract. The most visible changes were noted in the myenteric ganglia in the colon. Moreover, in the colon, the changes submitted by BPS are more noticeable than those observed after BPA administration. In the stomach and jejunum, bisphenol-induced changes were less visible, and changes caused by BPS were similar or less pronounced than those noted under the impact of BPA, depending on the segment of the gastrointestinal tract and ganglion type studied. Discussion: The results show that BPS affects the enteric neurons containing CART in a similar way to BPA, and the BPS impact is even stronger in the colon. Therefore, BPS is not neutral for the gastrointestinal tract and ENS. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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14. Enteric Neuromics: How High-Throughput 'Omics' Deepens Our Understanding of Enteric Nervous System Genetic ArchitectureSummary
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Christine Dharshika and Brian D. Gulbransen
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Computational Biology ,Single Cell RNA-Sequencing ,Enteric Neurons ,Enteric Glia ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Recent accessibility to specialized high-throughput “omics” technologies including single cell RNA sequencing allows researchers to capture cell type- and subtype-specific expression signatures. These omics methods are used in the enteric nervous system (ENS) to identify potential subtypes of enteric neurons and glia. ENS omics data support the known gene and/or protein expression of functional neuronal and glial cell subtypes and suggest expression patterns of novel subtypes. Gene and protein expression patterns can be further used to infer cellular function and implications in human disease. In this review we discuss how high-throughput “omics” data add additional depth to the understanding of established functional subtypes of ENS cells and raise new questions by suggesting novel ENS cell subtypes with unique gene and protein expression patterns. Then we investigate the changes in these expression patterns during pathology observed by omics research. Although current ENS omics studies provide a plethora of novel data and therefore answers, they equally create new questions and routes for future study.
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- 2023
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15. Regulation of enteric nervous system via sacral nerve stimulation in opioid-induced constipated rats.
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Liyun Wang, Gharibani, Payam, Yi Yang, Yu Guo, and Jieyun Yin
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ENTERIC nervous system ,SACRAL nerves ,NEURAL stimulation ,NITRIC-oxide synthases ,ANIMAL droppings - Abstract
Objectives: Sacral nerve stimulation (SNS) has been employed for treating constipation. However, its mechanisms involving enteric nervous system (ENS) and motility are largely unknown. In this study, we investigated the possible ENS involvement of SNS in treating Loperamide-induced constipation in rats. Methods: Experiment-1 was designed to study the effects of acute SNS on whole colon transit time (CTT). In experiment-2, we induced constipation by Loperamide and then applied daily SNS or sham-SNS for 1 week. Choline acetyltransferase (ChAT), nitric oxide synthase (nNOS), and PGP9.5 in colon tissue were examined at the end of the study. Moreover, survival factors such as phosphorylated AKT (p-AKT) and Glial cell-derived neurotrophic factor (GDNF) were measures by immunohistochemistry (IHC) and western blot (WB). Key results: (1) SNS with one set of parameters shortened CTT starting at 90 min after phenol red administration (p < 0.05). (2) While Loperamide induced slow transit constipation with a significant reduction in fecal pellet number and feces wet weight, daily SNS for a week resolved constipation. (3) Moreover, SNS was able to shorten whole gut transit time comparing to sham-SNS (p = 0.01). (4) Loperamide reduced the number of PGP9.5 and ChAT positive cells, and downregulated ChAT protein expression and upregulated nNOS protein expression, whereas these detrimental effects were significantly reversed by SNS. (5) Furthermore, SNS increased expressions of both GDNF and p-AKT in colon tissue. (6) Vagal activity was reduced following Loperamide (p < 0.01); yet SNS normalized vagal activity. Conclusion: SNS with appropriate parameters improves opioid-induced constipation and reversed the detrimental effects of Loperamide on enteric neurons possibly via the GDNF-PI3K/Akt pathway. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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16. Influence of bisphenol A and its analog bisphenol S on cocaine- and amphetamine-regulated transcript peptide–positive enteric neurons in the mouse gastrointestinal tract
- Author
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Krystyna Makowska, Kainã R. C. Fagundes, and Sławomir Gonkowski
- Subjects
endocrine disruptors ,bisphenol A ,bisphenol S ,enteric neurons ,digestive tract ,mouse ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
IntroductionBisphenol A (BPA) is used in large quantities for the production of plastics and is present in various everyday objects. It penetrates living organisms and shows multidirectional adverse influence on many internal organs. For this reason, BPA is often replaced in plastic production by other substances. One of them is bisphenol S (BPS), whose effects on the enteric nervous system (ENS) have not been explained.MethodsTherefore, the present study compares the influence of BPA and BPS on the number of enteric neurons immunoreactive to cocaine-and amphetamine-regulated transcript (CART) peptide located in the ENS of the stomach, jejunum and colon with the use of double immunofluorescence method.ResultsThe obtained results have shown that both bisphenols studied induced an increase in the number of CART-positive enteric neurons, and the severity of changes depended on the type of enteric ganglion, the dose of bisphenols and the segment of the digestive tract. The most visible changes were noted in the myenteric ganglia in the colon. Moreover, in the colon, the changes submitted by BPS are more noticeable than those observed after BPA administration. In the stomach and jejunum, bisphenol-induced changes were less visible, and changes caused by BPS were similar or less pronounced than those noted under the impact of BPA, depending on the segment of the gastrointestinal tract and ganglion type studied.DiscussionThe results show that BPS affects the enteric neurons containing CART in a similar way to BPA, and the BPS impact is even stronger in the colon. Therefore, BPS is not neutral for the gastrointestinal tract and ENS.
- Published
- 2023
- Full Text
- View/download PDF
17. Development of the aganglionic colon following surgical rescue in a cell therapy model of Hirschsprung disease in rat
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John B. Furness, Enie Lei, Billie Hunne, Cameron D. Adams, Alan J. Burns, Jill Wykosky, Therese E. Fazio Coles, Linda J. Fothergill, Juan C. Molero, Ruslan V. Pustovit, and Lincon A. Stamp
- Subjects
hirschsprung disease ,stem cell therapy ,colon ,intestinal bypass ,enteric neurons ,enteric nervous system ,Medicine ,Pathology ,RB1-214 - Published
- 2023
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18. A combinatorial panel for flow cytometry‐based isolation of enteric nervous system cells from human intestine.
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Windster, Jonathan D, Sacchetti, Andrea, Schaaf, Gerben J, Bindels, Eric MJ, Hofstra, Robert MW, Wijnen, Rene MH, Sloots, Cornelius EJ, and Alves, Maria M
- Abstract
Efficient isolation of neurons and glia from the human enteric nervous system (ENS) is challenging because of their rare and fragile nature. Here, we describe a staining panel to enrich ENS cells from the human intestine by fluorescence‐activated cell sorting (FACS). We find that CD56/CD90/CD24 co‐expression labels ENS cells with higher specificity and resolution than previous methods. Surprisingly, neuronal (CD24, TUBB3) and glial (SOX10) selective markers appear co‐expressed by all ENS cells. We demonstrate that this contradictory staining pattern is mainly driven by neuronal fragments, either free or attached to glial cells, which are the most abundant cell types. Live neurons can be enriched by the highest CD24 and CD90 levels. By applying our protocol to isolate ENS cells for single‐cell RNA sequencing, we show that these cells can be obtained with high quality, enabling interrogation of the human ENS transcriptome. Taken together, we present a selective FACS protocol that allows enrichment and discrimination of human ENS cells, opening up new avenues to study this complex system in health and disease. Synopsis: This study describes flow‐cytometry based enrichment of human enteric neurons and glia using a combination of cell surface markers (CD56/CD90/CD24), which enables studies of the human ENS. Based on CD56/CD90/CD24 co‐expression, enteric nervous system cells can be enriched by flow cytometry with higher specificity and resolution than previous methods.Enteric neurons representing a minority of the ENS cluster can be resolved from enteric glial cells based on CD24 levels.CD56/CD90/CD24‐positive cells can be further processed for downstream analysis, such as scRNAseq, enabling interrogation of the human ENS transcriptome. [ABSTRACT FROM AUTHOR]
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- 2023
- Full Text
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19. Oxaliplatin-Induced Damage to the Gastric Innervation: Role in Nausea and Vomiting.
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Rahman, Ahmed A., Masango, Philenkosini, Stavely, Rhian, Bertrand, Paul, Page, Amanda, and Nurgali, Kulmira
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WEIGHT loss , *PARASYMPATHETIC nervous system , *GASTRIC mucosa , *INNERVATION , *NAUSEA , *FOOD habits , *OXALIPLATIN - 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 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. [ABSTRACT FROM AUTHOR]
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- 2023
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20. SARS-CoV-2 Induces Epithelial-Enteric Neuronal Crosstalk Stimulating VIP Release.
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Balasubramaniam, Arun, Tedbury, Philip R., Mwangi, Simon M., Liu, Yunshan, Li, Ge, Merlin, Didier, Gracz, Adam D., He, Peijian, Sarafianos, Stefan G., and Srinivasan, Shanthi
- Subjects
- *
COVID-19 , *SARS-CoV-2 , *VASOACTIVE intestinal peptide , *HEAT shock proteins , *GENE expression , *SUBMUCOUS plexus - 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 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. [ABSTRACT FROM AUTHOR]
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- 2023
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21. Advanced Glycation End-Products and Their Effects on Gut Health.
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Phuong-Nguyen, Kate, McNeill, Bryony A., Aston-Mourney, Kathryn, and Rivera, Leni R.
- Abstract
Dietary advanced glycation end-products (AGEs) are a heterogeneous group of compounds formed when reducing sugars are heated with proteins, amino acids, or lipids at high temperatures for a prolonged period. The presence and accumulation of AGEs in numerous cell types and tissues are known to be prevalent in the pathology of many diseases. Modern diets, which contain a high proportion of processed foods and therefore a high level of AGE, cause deleterious effects leading to a multitude of unregulated intracellular and extracellular signalling and inflammatory pathways. Currently, many studies focus on investigating the chemical and structural aspects of AGEs and how they affect the metabolism and the cardiovascular and renal systems. Studies have also shown that AGEs affect the digestive system. However, there is no complete picture of the implication of AGEs in this area. The gastrointestinal tract is not only the first and principal site for the digestion and absorption of dietary AGEs but also one of the most susceptible organs to AGEs, which may exert many local and systemic effects. In this review, we summarise the current evidence of the association between a high-AGE diet and poor health outcomes, with a special focus on the relationship between dietary AGEs and alterations in the gastrointestinal structure, modifications in enteric neurons, and microbiota reshaping. [ABSTRACT FROM AUTHOR]
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- 2023
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22. Oxidative Stress-Induced HMGB1 Translocation in Myenteric Neurons Contributes to Neuropathy in Colitis.
- Author
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Stavely, Rhian, Sahakian, Lauren, Filippone, Rhiannon T., Stojanovska, Vanesa, Bornstein, Joel C., Sakkal, Samy, and Nurgali, Kulmira
- Subjects
- *
INFLAMMATORY bowel diseases , *ENTERIC nervous system , *COLITIS , *CENTRAL nervous system , *NEURONS , *SUBMUCOUS plexus - 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 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. [ABSTRACT FROM AUTHOR]
- Published
- 2022
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23. Role of Macrophages and Mast Cells as Key Players in the Maintenance of Gastrointestinal Smooth Muscle Homeostasis and DiseaseSummary
- Author
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Magdalini Mischopoulou, Mario D’Ambrosio, Elisabetta Bigagli, Cristina Luceri, Gianrico Farrugia, and Gianluca Cipriani
- Subjects
muscularis macrophages ,enteric neurons ,cell to cell communication ,gastrointestinal functional disorders ,mast cells ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
The gut contains the largest macrophage pool in the body, with populations of macrophages residing in the mucosa and muscularis propria of the gastrointestinal (GI) tract. Muscularis macrophages (MMs), which are located within the muscularis propria, interact with cells essential for GI function, such as interstitial cells of Cajal, enteric neurons, smooth muscle cells, enteric glia, and fibroblast-like cells, suggesting that these immune cells contribute to several aspects of GI function. This review focuses on the latest insights on the factors contributing to MM heterogeneity and the functional interaction of MMs with other cell types essential for GI function. This review integrates the latest findings on macrophages in other organs with increasing knowledge of MMs to better understand their role in a healthy and diseased gut. We describe the factors that contribute to (muscularis macrophage) MM heterogeneity, and the nature of MM interactions with cells regulating GI function. Finally, we also describe the increasing evidence suggesting a critical role of another immune cell type, the mast cell, in normal and diseased GI physiology.
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- 2022
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24. Adult enteric nervous system in health is maintained by a dynamic balance between neuronal apoptosis and neurogenesis
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Kulkarni, Subhash, Micci, Maria-Adelaide, Leser, Jenna, Shin, Changsik, Tang, Shiue-Cheng, Fu, Ya-Yuan, Liu, Liansheng, Li, Qian, Saha, Monalee, Li, Cuiping, Enikolopov, Grigori, Becker, Laren, Rakhilin, Nikolai, Anderson, Michael, Shen, Xiling, Dong, Xinzhong, Butte, Manish J, Song, Hongjun, Southard-Smith, E Michelle, Kapur, Raj P, Bogunovic, Milena, and Pasricha, Pankaj J
- Subjects
Digestive Diseases ,Neurosciences ,Stem Cell Research - Nonembryonic - Non-Human ,Stem Cell Research ,Underpinning research ,1.1 Normal biological development and functioning ,Neurological ,Animals ,Apoptosis ,Enteric Nervous System ,Humans ,Mice ,Mice ,Transgenic ,Nestin ,Neurogenesis ,Receptors ,Nerve Growth Factor ,SOXE Transcription Factors ,enteric neurons ,adult neurogenesis ,enteric neural precursor cells ,neuronal apoptosis - Abstract
According to current dogma, there is little or no ongoing neurogenesis in the fully developed adult enteric nervous system. This lack of neurogenesis leaves unanswered the question of how enteric neuronal populations are maintained in adult guts, given previous reports of ongoing neuronal death. Here, we confirm that despite ongoing neuronal cell loss because of apoptosis in the myenteric ganglia of the adult small intestine, total myenteric neuronal numbers remain constant. This observed neuronal homeostasis is maintained by new neurons formed in vivo from dividing precursor cells that are located within myenteric ganglia and express both Nestin and p75NTR, but not the pan-glial marker Sox10. Mutation of the phosphatase and tensin homolog gene in this pool of adult precursors leads to an increase in enteric neuronal number, resulting in ganglioneuromatosis, modeling the corresponding disorder in humans. Taken together, our results show significant turnover and neurogenesis of adult enteric neurons and provide a paradigm for understanding the enteric nervous system in health and disease.
- Published
- 2017
25. Ednrb−/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine
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Sukhada Bhave, Richard A. Guyer, Nicole Picard, Meredith Omer, Ryo Hotta, and Allan M. Goldstein
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hirschsprung disease ,enteric nervous system ,enteric neurons ,endothelin receptor type B ,single-cell RNA sequencing ,Biology (General) ,QH301-705.5 - Abstract
Hirschsprung disease is most often characterized by aganglionosis limited to the distal colon and rectum, and mice lacking the Endothelin receptor type B (Ednrb) faithfully recapitulate this phenotype. However, despite the presence of enteric ganglia in the small intestine, both human patients and Ednrb−/− mice suffer from dysmotility and altered gastrointestinal function, thus raising the possibility of enteric nervous system (ENS) abnormalities proximal to the aganglionic region. We undertook the present study to determine whether abnormalities with the ENS in ganglionated regions may account for abnormal gastrointestinal function. We performed single-cell RNA sequencing on ENS cells from the small intestine of Ednrb−/− mice and compared the results to a published single-cell dataset. Our results identified a missing population of neurons marked by the enzyme Gad2, which catalyzes the production of γ-Aminobutyric acid (GABA), in the small intestine of Ednrb−/− animals. This result was confirmed by immunostaining enteric ganglia from Ednrb−/− mice and their wild-type littermates. These data show for the first time that ganglionated regions of the Hirschsprung gut lack a neuronal subpopulation, which may explain the persistent gastrointestinal dysfunction after surgical correction of Hirschsprung disease.
- Published
- 2022
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26. Impact of Dietary Fiber on West Nile Virus Infection.
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Ni, Duan, Tan, Jian, Niewold, Paula, Spiteri, Alanna Gabrielle, Pinget, Gabriela Veronica, Stanley, Dragana, King, Nicholas Jonathan Cole, and Macia, Laurence
- Subjects
WEST Nile fever ,DIETARY fiber ,SHORT bowel syndrome ,REGULATORY T cells ,WEST Nile virus ,SHORT-chain fatty acids ,DIVERTICULOSIS - Abstract
Dietary fiber supports healthy gut bacteria and their production of short-chain fatty acids (SCFA), which promote anti-inflammatory cell development, in particular, regulatory T cells. It is thus beneficial in many diseases, including influenza infection. While disruption of the gut microbiota by antibiotic treatment aggravates West Nile Virus (WNV) disease, whether dietary fiber is beneficial is unknown. WNV is a widely-distributed neurotropic flavivirus that recruits inflammatory monocytes into the brain, causing life-threatening encephalitis. To investigate the impact of dietary fiber on WNV encephalitis, mice were fed on diets deficient or enriched with dietary fiber for two weeks prior to inoculation with WNV. To induce encephalitis, mice were inoculated intranasally with WNV and maintained on these diets. Despite increased fecal SCFA acetate and changes in gut microbiota composition, dietary fiber did not affect clinical scores, leukocyte infiltration into the brain, or survival. After the brain, highest virus loads were measured in the colon in neurons of the submucosal and myenteric plexuses. Associated with this, there was disrupted gut homeostasis, with shorter colon length and higher local inflammatory cytokine levels, which were not affected by dietary fiber. Thus, fiber supplementation is not effective in WNV encephalitis. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
27. Enteric Nervous System Remodeling in a Rat Model of Spinal Cord Injury: A Pilot Study
- Author
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Chlo? Lef?vre, Anne Bessard, Philippe Aubert, Charles Joussain, Fran?ois Giuliano, Delphine Behr-Roussel, Marie-Aim?e Perrouin-Verbe, Brigitte Perrouin-Verbe, Charl?ne Brochard, and Michel Neunlist
- Subjects
digestive disorders ,enteric neurons ,neuromuscular response ,spinal cord injury ,Medical emergencies. Critical care. Intensive care. First aid ,RC86-88.9 - Abstract
The physiopathology of digestive disorders in patients with spinal cord injury (SCI) remains largely unknown, particularly the involvement of the enteric nervous system (ENS). We aimed in a rat model of chronic thoracic SCI to characterize (1) changes in the neurochemical coding of enteric neurons and their putative consequences upon neuromuscular response, and (2) the inflammatory response of the colon. Ex vivo motility of proximal and distal colon segments of SCI and control (CT) rats were studied in an organ chamber in response to electrical field stimulation (EFS) and bethanechol. Immunohistochemical analysis of proximal and distal segments was performed using antibodies again Hu, neuronal nitric oxide synthase, (nNOS), and choline acetyltransferase. Colonic content of acetylcholine and acetylcholinesterase was measured; messenger RNA (mRNA) expression of inflammatory cytokines was measured using reverse transcription quantitative polymerase chain reaction (RT-qPCR) approaches. Compared with the CT rats, the contractile response to bethanechol was significantly decreased in the proximal colon of SCI rats but not in the distal colon. The proportion of nNOS immunoreactive (IR) neurons was significantly reduced in the proximal but not distal colon of SCI rats. No change in proportion of choline acetyltransferase (ChAT)-IR was reported; the tissue concentration of acetylcholine was significantly decreased in the proximal colon of SCI rats. The expression of tumor necrosis factor alpha (TNF-?) and intercellular adhesion molecule-1 (ICAM-1) was significantly reduced in the proximal and distal colon of SCI rats. This study demonstrates that functional motor and enteric neuroplastic changes affect preferentially the proximal colon compared with the distal colon. The underlying mechanisms and factors responsible for these changes remain to be discovered.
- Published
- 2020
- Full Text
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28. Impact of Dietary Fiber on West Nile Virus Infection
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Duan Ni, Jian Tan, Paula Niewold, Alanna Gabrielle Spiteri, Gabriela Veronica Pinget, Dragana Stanley, Nicholas Jonathan Cole King, and Laurence Macia
- Subjects
dietary fiber ,gut microbiota ,West Nile Virus (WNV) ,infection ,immune response ,enteric neurons ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Dietary fiber supports healthy gut bacteria and their production of short-chain fatty acids (SCFA), which promote anti-inflammatory cell development, in particular, regulatory T cells. It is thus beneficial in many diseases, including influenza infection. While disruption of the gut microbiota by antibiotic treatment aggravates West Nile Virus (WNV) disease, whether dietary fiber is beneficial is unknown. WNV is a widely-distributed neurotropic flavivirus that recruits inflammatory monocytes into the brain, causing life-threatening encephalitis. To investigate the impact of dietary fiber on WNV encephalitis, mice were fed on diets deficient or enriched with dietary fiber for two weeks prior to inoculation with WNV. To induce encephalitis, mice were inoculated intranasally with WNV and maintained on these diets. Despite increased fecal SCFA acetate and changes in gut microbiota composition, dietary fiber did not affect clinical scores, leukocyte infiltration into the brain, or survival. After the brain, highest virus loads were measured in the colon in neurons of the submucosal and myenteric plexuses. Associated with this, there was disrupted gut homeostasis, with shorter colon length and higher local inflammatory cytokine levels, which were not affected by dietary fiber. Thus, fiber supplementation is not effective in WNV encephalitis.
- Published
- 2022
- Full Text
- View/download PDF
29. The Guts of the Opioid Crisis.
- Author
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Muchhala, Karan H., Jacob, Joanna C., Kang, Minho, Dewey, William L., and Akbarali, Hamid I.
- Subjects
- *
OPIOID epidemic , *PAIN management , *HOMEOSTASIS , *CHRONIC pain , *OPIOIDS - Abstract
Bidirectional interactions of the gut epithelium with commensal bacteria are critical for maintaining homeostasis within the gut. Chronic opioid exposure perturbs gut homeostasis through a multitude of neuro-immune-epithelial mechanisms, resulting in the development of analgesic tolerance, a major underpinning of the current opioid crisis. Differences in molecular mechanisms of opioid tolerance between the enteric and central pain pathways pose a significant challenge for managing chronic pain without untoward gastrointestinal effects. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
30. Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats
- Author
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Xue Jin, Payam Gharibani, Jieyun Yin, and Jiande D. Z. Chen
- Subjects
sacral nerve stimulation ,visceral hypersensitivity ,enteric neurons ,mast cells ,autonomic functions ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Background: Visceral hypersensitivity (VH) is one of the underlying pathophysiologies of irritable bowel syndrome. Mast cell overactivation has been found to be one of the main causes of VH. We investigated the effects and mechanisms of actions of sacral nerve stimulation (SNS) on visceral pain in a rodent model of VH.Methods: The VH was established by an intrarectal infusion of AA in 10-day-old pups. Rats were chronically implanted with electrodes for SNS and recording electromyogram (EMG) and electrocardiogram. The acute study was performed in 2-randomized sessions with SNS (14 Hz, 330 μs, 40% motor threshold or MT, 30 min) or sham-SNS. Later on, rats were randomized into SNS/sham-SNS groups and a chronic study was performed with 2 h-daily SNS or sham-SNS for 21 days. Visceromotor reflexes were assessed by abdominal EMG and withdrawal reflex (AWR). Colon tissues were collected to study colonic acetylcholine (ACh), the enteric neurons (ChAT, nNOS, and PGP9.5), mast cells activity [Tryptase, prostaglandins E2 (PGE2), and cyclooxygenases-2 (COX2)] and pain markers [nerve growth factor (NGF) and Sub-P].Key Results: Sacral nerve stimulation significantly improved visceromotor reflexes assessed by the EMG and AWR, compared with sham-SNS. SNS normalized the protein expressions of ChAT and nNOS and regulated mast cells activity by downregulating Tryptase, COX2, and PGE2. Neonatal AA administration upregulated NGF and Sub-P; chronic SNS significantly decreased these pain biomarkers. Concurrently, chronic SNS increased ACh in colon tissues and vagal efferent activity.Conclusions: Sacral nerve stimulation reduces VH in rats and this ameliorating effect might be attributed to the suppression of mast cell overactivation in the colon tissue via the modulation of autonomic nervous system functions.
- Published
- 2021
- Full Text
- View/download PDF
31. Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats.
- Author
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Jin, Xue, Gharibani, Payam, Yin, Jieyun, and Chen, Jiande D. Z.
- Subjects
SACRAL nerves ,NEURAL stimulation ,AUTONOMIC nervous system ,NERVE growth factor ,MAST cells - Abstract
Background: Visceral hypersensitivity (VH) is one of the underlying pathophysiologies of irritable bowel syndrome. Mast cell overactivation has been found to be one of the main causes of VH. We investigated the effects and mechanisms of actions of sacral nerve stimulation (SNS) on visceral pain in a rodent model of VH. Methods: The VH was established by an intrarectal infusion of AA in 10-day-old pups. Rats were chronically implanted with electrodes for SNS and recording electromyogram (EMG) and electrocardiogram. The acute study was performed in 2-randomized sessions with SNS (14 Hz, 330 μs, 40% motor threshold or MT, 30 min) or sham-SNS. Later on, rats were randomized into SNS/sham-SNS groups and a chronic study was performed with 2 h-daily SNS or sham-SNS for 21 days. Visceromotor reflexes were assessed by abdominal EMG and withdrawal reflex (AWR). Colon tissues were collected to study colonic acetylcholine (ACh), the enteric neurons (ChAT, nNOS, and PGP9.5), mast cells activity [Tryptase, prostaglandins E2 (PGE2), and cyclooxygenases-2 (COX2)] and pain markers [nerve growth factor (NGF) and Sub-P]. Key Results: Sacral nerve stimulation significantly improved visceromotor reflexes assessed by the EMG and AWR, compared with sham-SNS. SNS normalized the protein expressions of ChAT and nNOS and regulated mast cells activity by downregulating Tryptase, COX2, and PGE2. Neonatal AA administration upregulated NGF and Sub-P; chronic SNS significantly decreased these pain biomarkers. Concurrently, chronic SNS increased ACh in colon tissues and vagal efferent activity. Conclusions: Sacral nerve stimulation reduces VH in rats and this ameliorating effect might be attributed to the suppression of mast cell overactivation in the colon tissue via the modulation of autonomic nervous system functions. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
32. Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System
- Author
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Maria M. Buckley, Rebecca O’Brien, Eilish Brosnan, R. Paul Ross, Catherine Stanton, Julliette M. Buckley, and Dervla O’Malley
- Subjects
enteric neurons ,indole ,GLP-1 ,microbiota ,vagus nerve ,tryptophan ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
An intact gut epithelium preserves the immunological exclusion of “non-self” entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague–Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system.
- Published
- 2020
- Full Text
- View/download PDF
33. Glucagon-Like Peptide-1 Secreting L-Cells Coupled to Sensory Nerves Translate Microbial Signals to the Host Rat Nervous System.
- Author
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Buckley, Maria M., O'Brien, Rebecca, Brosnan, Eilish, Ross, R. Paul, Stanton, Catherine, Buckley, Julliette M., and O'Malley, Dervla
- Subjects
NERVOUS system ,PERIPHERAL nervous system ,SUBMUCOUS plexus ,NERVES ,VAGUS nerve ,MICROBIAL products - Abstract
An intact gut epithelium preserves the immunological exclusion of "non-self" entities in the external environment of the gut lumen. Nonetheless, information flows continuously across this interface, with the host immune, endocrine, and neural systems all involved in monitoring the luminal environment of the gut. Both pathogenic and commensal gastrointestinal (GI) bacteria can modulate centrally-regulated behaviors and brain neurochemistry and, although the vagus nerve has been implicated in the microbiota-gut-brain signaling axis, the cellular and molecular machinery that facilitates this communication is unclear. Studies were carried out in healthy Sprague–Dawley rats to understand cross-barrier communication in the absence of disease. A novel colonic-nerve electrophysiological technique was used to examine gut-to-brain vagal signaling by bacterial products. Calcium imaging and immunofluorescent labeling were used to explore the activation of colonic submucosal neurons by bacterial products. The findings demonstrate that the neuromodulatory molecule, glucagon-like peptide-1 (GLP-1), secreted by colonic enteroendocrine L-cells in response to the bacterial metabolite, indole, stimulated colonic vagal afferent activity. At a local level indole modified the sensitivity of submucosal neurons to GLP-1. These findings elucidate a cellular mechanism by which sensory L-cells act as cross-barrier signal transducers between microbial products in the gut lumen and the host peripheral nervous system. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
34. Minireview: Peripheral Nesfatin-1 in Regulation of the Gut Activity—15 Years since the Discovery
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Katarzyna Kras, Siemowit Muszyński, Ewa Tomaszewska, and Marcin B. Arciszewski
- Subjects
nesfatin-1 ,gut ,gastrointestinal disorders ,enteric neurons ,gut microbiota ,gut peptides ,Veterinary medicine ,SF600-1100 ,Zoology ,QL1-991 - Abstract
Nesfatin-1, discovered in 2006, is an anorexigenic molecule derived from the precursor protein NEFA/nucleobindin2. It is generally postulated that this molecule acts through a specific G protein-coupled receptor, as yet unidentified. Research conducted over the last 15 years has revealed both central and peripheral actions of nesfatin-1. Given its major central role, studies determining its inhibitory effect on food intake seem to be of major scientific interest. However, in recent years a number of experiments have found that peripheral organs, including those of the gastrointestinal tract (GIT), may also be a source (possibly even the predominant source) of nesfatin-1. This mini-review aimed to summarize the current state of knowledge regarding the expression and immunoreactivity of nesfatin-1 and its possible involvement (both physiological and pathological) in the mammalian GIT. Research thus far has shown very promising abilities of nesfatin-1 to restore the balance between pro-oxidants and antioxidants, to interplay with the gut microbiota, and to alter the structure of the intestinal barrier. This necessitates more extensive research on the peripheral actions of this molecule. More in-depth knowledge of such mechanisms (especially those leading to anti-inflammatory and anti-apoptotic effects) is important for a better understanding of the involvement of nefatin-1 in GIT pathophysiological conditions and/or for future therapeutic approaches.
- Published
- 2022
- Full Text
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35. Colorectal Cancer Cells Adhere to and Migrate Along the Neurons of the Enteric Nervous System
- Author
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Emilie Duchalais, Christophe Guilluy, Steven Nedellec, Melissa Touvron, Anne Bessard, Yann Touchefeu, Céline Bossard, Hélène Boudin, Guy Louarn, Michel Neunlist, and Laurianne Van Landeghem
- Subjects
Colorectal Cancer ,Enteric Neurons ,Adhesion ,Migration ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
In several types of cancers, tumor cells invade adjacent tissues by migrating along the resident nerves of the tumor microenvironment. This process, called perineural invasion, typically occurs along extrinsic nerves, with Schwann cells providing physical guidance for the tumor cells. However, in the colorectal cancer microenvironment, the most abundant nervous structures belong to the nonmyelinated intrinsic enteric nervous system (ENS). In this study, we investigated whether colon cancer cells interact with the ENS. Methods: Tumor epithelial cells (TECs) from human primary colon adenocarcinomas and cell lines were cocultured with primary cultures of ENS and cultures of human ENS plexus explants. By combining confocal and atomic force microscopy, as well as video microscopy, we assessed tumor cell adhesion and migration on the ENS. We identified the adhesion proteins involved using a proteomics approach based on biotin/streptavidin interaction, and their implication was confirmed further using selective blocking antibodies. Results: TEC adhered preferentially and with stronger adhesion forces to enteric nervous structures than to mesenchymal cells. TEC adhesion to ENS involved direct interactions with enteric neurons. Enteric neuron removal from ENS cultures led to a significant decrease in tumor cell adhesion. TECs migrated significantly longer and further when adherent on ENS compared with on mesenchymal cells, and their trajectory faithfully followed ENS structures. Blocking N-cadherin and L1CAM decreased TEC migration along ENS structures. Conclusions: Our data show that the enteric neuronal network guides tumor cell migration, partly via L1CAM and N-cadherin. These results open a new avenue of research on the underlying mechanisms and consequences of perineural invasion in colorectal cancer.
- Published
- 2018
- Full Text
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36. The neuroprotective effects of human bone marrow mesenchymal stem cells are dose-dependent in TNBS colitis
- Author
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Ainsley M. Robinson, Ahmed A. Rahman, Sarah Miller, Rhian Stavely, Samy Sakkal, and Kulmira Nurgali
- Subjects
Inflammatory bowel disease ,Intestinal inflammation ,Mesenchymal stem cells ,Enteric neurons ,Dose-dependence ,Medicine (General) ,R5-920 ,Biochemistry ,QD415-436 - Abstract
Abstract Background The incidence of inflammatory bowel diseases (IBD) is increasing worldwide with patients experiencing severe impacts on their quality of life. It is well accepted that intestinal inflammation associates with extensive damage to the enteric nervous system (ENS), which intrinsically innervates the gastrointestinal tract and regulates all gut functions. Hence, treatments targeting the enteric neurons are plausible for alleviating IBD and associated complications. Mesenchymal stem cells (MSCs) are gaining wide recognition as a potential therapy for many diseases due to their immunomodulatory and neuroprotective qualities. However, there is a large discrepancy regarding appropriate cell doses used in both clinical trials and experimental models of disease. We have previously demonstrated that human bone marrow MSCs exhibit neuroprotective and anti-inflammatory effects in a guinea-pig model of 2,4,6-trinitrobenzene-sulfonate (TNBS)-induced colitis; but an investigation into whether this response is dose-dependent has not been conducted. Methods Hartley guinea-pigs were administered TNBS or sham treatment intra-rectally. Animals in the MSC treatment groups received either 1 × 105, 1 × 106 or 3 × 106 MSCs by enema 3 hours after induction of colitis. Colon tissues were collected 72 hours after TNBS administration to assess the effects of MSC treatments on the level of inflammation and damage to the ENS by immunohistochemical and histological analyses. Results MSCs administered at a low dose, 1 × 105 cells, had little or no effect on the level of immune cell infiltrate and damage to the colonic innervation was similar to the TNBS group. Treatment with 1 × 106 MSCs decreased the quantity of immune infiltrate and damage to nerve processes in the colonic wall, prevented myenteric neuronal loss and changes in neuronal subpopulations. Treatment with 3 × 106 MSCs had similar effects to 1 × 106 MSC treatments. Conclusions The neuroprotective effect of MSCs in TNBS colitis is dose-dependent. Increasing doses higher than 1 × 106 MSCs demonstrates no further therapeutic benefit than 1 × 106 MSCs in preventing enteric neuropathy associated with intestinal inflammation. Furthermore, we have established an optimal dose of MSCs for future studies investigating intestinal inflammation, the enteric neurons and stem cell therapy in this model.
- Published
- 2017
- Full Text
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37. The effect of ageing on the innervation and total collagen content of human colon.
- Author
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Baidoo, Nicholas and Baidoo, Nicholas
- Abstract
This thesis addressed the enteric innervations and total collagen content and its distribution within the functional sublayers, namely: mucosa, submucosa and muscularis externa (circular muscle (CM) and taenia coli (TC)) in ageing human colon. Macroscopically normal ascending (AC) and descending (DC) colon was obtained at surgery from cancer patients without diagnosis of diverticular disease or inflammatory bowel disease. Masson’s trichrome and Picrosirius red stains were employed to identify the total collagen content and distribution within the colonic wall. A hydroxyproline assay evaluated the total collagen concentration in the formalin-fixed, paraffin-embedded human colonic samples. Assessment of the subtypes of enteric glial cells (EGCs) and calretinin- immunoreactive (IR) enteric neurons were demonstrated by immunohistochemical method. Standardized procedures were utilised to ensure unbiased counting and densitometric evaluation for further quantitative analysis. The results of the present study demonstrated that greater a collagen content was present in the submucosa and muscularis externa, particularly the TC in the elderly (≥ 65 years) samples compared to adult (< 65 years). The density of S100-IR EGCs declined among the elderly in the CM and within the myenteric plexus (MP) per ganglionic area. There was little or no GFAP-IR EGCs in both adult and elderly colon. Among the elderly, the density of calretinin-IR neurons and fibres were decreased in the submucosal plexus of AC but not clearly in the DC. In the mucosal layer of both AC and DC, the decrease in density of calretinin-IR fibres was greater in the AC compared to DC. Sex related differences were not found when data combined in both the AC and DC samples. Collectively, these results indicate that there are region and sublayer dependent changes in the distribution of total collagen fibres, EGCs and calretinin-IR enteric neurons in ageing human colon. This age-related structural change may d
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- 2023
38. Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction
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Rachel M. McQuade, Maryam Al Thaalibi, Aaron C. Petersen, Raquel Abalo, Joel C. Bornstein, Emma Rybalka, and Kulmira Nurgali
- Subjects
chemotherapy ,enteric neurons ,5-fluorouracil ,BGP-15 ,neuroprotection ,cytoprotection ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin.
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- 2019
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39. Co-treatment With BGP-15 Exacerbates 5-Fluorouracil-Induced Gastrointestinal Dysfunction.
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McQuade, Rachel M., Al Thaalibi, Maryam, Petersen, Aaron C., Abalo, Raquel, Bornstein, Joel C., Rybalka, Emma, and Nurgali, Kulmira
- Subjects
GASTROINTESTINAL diseases ,DISEASE exacerbation ,FLUOROURACIL ,CANCER chemotherapy ,CANCER treatment ,TREATMENT effectiveness - Abstract
Gastrointestinal (GI) side-effects of chemotherapy present a constant impediment to efficient and tolerable treatment of cancer. GI symptoms often lead to dose reduction, delays and cessation of treatment. Chemotherapy-induced nausea, bloating, vomiting, constipation, and/or diarrhea can persist up to 10 years post-treatment. We have previously reported that long-term 5-fluorouracil (5-FU) administration results in enteric neuronal loss, acute inflammation and intestinal dysfunction. In this study, we investigated whether the cytoprotectant, BGP-15, has a neuroprotective effect during 5-FU treatment. Balb/c mice received tri-weekly intraperitoneal 5-FU (23 mg/kg/d) administration with and without BGP-15 (15 mg/kg/d) for up to 14 days. GI transit was analyzed via in vivo serial X-ray imaging prior to and following 3, 7, and 14 days of treatment. On day 14, colons were collected for assessment of ex vivo colonic motility, neuronal mitochondrial superoxide, and cytochrome c levels as well as immunohistochemical analysis of myenteric neurons. BGP-15 did not inhibit 5-FU-induced neuronal loss, but significantly increased the number and proportion of choline acetyltransferase (ChAT)-immunoreactive (IR) and neuronal nitric oxide synthase (nNOS)-IR neurons in the myenteric plexus. BGP-15 co-administration significantly increased mitochondrial superoxide production, mitochondrial depolarization and cytochrome c release in myenteric plexus and exacerbated 5-FU-induced colonic inflammation. BGP-15 exacerbated 5-FU-induced colonic dysmotility by reducing the number and proportion of colonic migrating motor complexes and increasing the number and proportion of fragmented contractions and increased fecal water content indicative of diarrhea. Taken together, BGP-15 co-treatment aggravates 5-FU-induced GI side-effects, in contrast with our previous findings that BGP-15 alleviates GI side-effects of oxaliplatin. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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40. A novel role for the extracellular matrix glycoprotein‐Tenascin‐X in gastric function.
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Aktar, Rubina, Peiris, Madusha, Fikree, Asma, Eaton, Simon, Kritas, Stamatiki, Kentish, Stephen J., Araujo, Eduardo J. A., Bacarin, Cristiano, Page, Amanda J., Voermans, Nicol C., Aziz, Qasim, and Blackshaw, L. Ashley
- Subjects
- *
GASTROPARESIS , *EXTRACELLULAR matrix , *EHLERS-Danlos syndrome - Abstract
Key points: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architectureTNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively.TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity.Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice.TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology.TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. Tenascin‐X (TNX) is a glycoprotein that regulates tissue structure via anti‐adhesive interactions with collagen in the extracellular matrix. TNX deficiency causes a phenotype similar to hypermobility Ehlers–Danlos syndrome involving joint hypermobility, skin hyperelasticity, pain and gastrointestinal dysfunction. Previously, we have shown that TNX is required for neural control of the bowel by a specific subtype of mainly cholinergic enteric neurones and regulates sprouting and sensitivity of nociceptive sensory endings in mouse colon. These findings correlate with symptoms shown by TNX‐deficient patients and mice. We aimed to identify whether TNX is similarly present in neural structures found in mouse and human gastric tissue. We then determined whether TNX has a functional role, specifically in gastric motor and sensory function and nodose ganglia neurones. We report that TNX was present in calretinin‐immunoreactive extrinsic nerve endings in mouse and human stomach. TNX deficient mice had accelerated gastric emptying and markedly increased vagal afferent responses to gastric distension that could be rescued with GABAB receptor agonist. There were no changes in nodose ganglia excitability in TNX deficient mice, suggesting that vagal afferent responses are probably the result of altered peripheral mechanosensitivity. In TNXB‐deficient patients, significantly greater symptoms of reflux, indigestion and abdominal pain were reported. In the present study, we report the first role for TNX in gastric function. Further studies are required in TNX deficient patients to determine whether symptoms can be relieved using GABAB agonists. Key points: Tenascin X (TNX) functions in the extracellular matrix of skin and joints where it maintains correct intercellular connections and tissue architectureTNX is associated exclusively with vagal‐afferent endings and some myenteric neurones in mouse and human stomach, respectively.TNX‐deficient mice have accelerated gastric emptying and hypersensitivity of gastric vagal mechanoreceptors that can be normalized by an inhibitor of vagal‐afferent sensitivity.Cultured nodose ganglion neurones showed no changes in response to capsaicin, cholecystokinin and potassium chloride in TNX‐deficient mice.TNX‐deficient patients have upper gastric dysfunction consistent with those in a mouse model. Our translational studies suggest that abnormal gastric sensory function may explain the upper gut symptoms present in TNX deficient patients, thus making it important to study gastric physiology.TNX deficiency should be evaluated routinely in patients with connective tissue abnormalities, which will enable a better understanding of its role and allow targeted treatment. For example, inhibitors of vagal afferents‐baclofen could be beneficial in patients. These hypotheses need confirmation via targeted clinical trials. [ABSTRACT FROM AUTHOR]
- Published
- 2019
- Full Text
- View/download PDF
41. Role of MiR-215 in Hirschsprung's Disease Pathogenesis by Targeting SIGLEC-8
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Hao Lei, Hongxing Li, Hua Xie, Chunxia Du, Yankai Xia, and Weibing Tang
- Subjects
Host Gene ,Enteric Neurons ,MicroRNA ,Gene regulation ,Hirschsprung's disease ,Physiology ,QP1-981 ,Biochemistry ,QD415-436 - Abstract
Background/Aims: Hirschsprung's disease (HSCR), known as aganglionosis, is an infrequent congenital gut motility disorder characterized by absence of enteric neurons. In this study, we focus on the role of the intronic miR-215 and its host gene isoleucyl-tRNA synthetase 2 (IARS2) in the pathogenesis of HSCR. Methods: Quantitative real time PCR and Western blot were used to detect the miRNA, mRNAs, and proteins levels. The dual-luciferase reporter gene assay confirmed the direct regulation of the specific mRNA and miRNAs in cell lines. Transwell assays, CCK8 assay, and flow cytometry were used to measure cell function of the human 293T and SH-SY5Y cells. Results: Expression levels of miR-215 in HSCR patient colon tissues were outstandingly lower than controls, which was positively correlated with expression of the host gene IARS2 and negatively correlated with predicted target gene: sialic acid binding Ig-like lectin 8 (SIGLEC-8). The loss of miR-215 inhibited cell migration and proliferation, which was consistent with the reduction of IARS2. The dual-luciferase reporter gene assay confirmed that miR-215 resulted in the inhibition of SIGLEC-8 by directly binding to the 3'-UTR of SIGLEC-8. Moreover, knocking-down SIGLEC-8 rescued the extent of suppressed cell migration and proliferation that resulted from the diminishment of miR-215. Conclusions: Our findings indicate that miR-215 acts in concert with the host gene IARS2 to affect neuron migration and proliferation through the target gene SIGLEC-8. We infer that the IARS2-miR-215-SIGLEC-8 pathway may play a crucial role in the pathogenesis of HSCR.
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- 2016
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42. Acrylamide-Induced Changes in the Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Immunoreactivity in Small Intestinal Intramural Neurons in Pigs
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Aleksandra Karpiesiuk, Jarosław Całka, and Katarzyna Palus
- Subjects
pig ,Health, Toxicology and Mutagenesis ,Public Health, Environmental and Occupational Health ,acrylamide ,enteric neurons ,PACAP ,small intestine - Abstract
Background: A particularly pressing problem is determining consumer-safe doses of potentially health- and life-threatening substances, such as acrylamide. The aim of the study was to determine how acrylamide affects the pituitary adenylate cyclase-activating polypeptide (PACAP)-immunoreactive intramural neurons in the small intestine of sexually immature gilts. Methods: The study was conducted on 15 sexually immature Danish gilts receiving for 28 days empty gelatin capsules or acrylamide in low (0.5 µg/kg of body weight (b.w.)/day) and high (5 µg/kg b.w./day) doses. After euthanasia, intestinal sections were stained using the double immunofluorescence staining procedure. Results: Studies have shown that oral administration of acrylamide in both doses induced a response of intramural neurons expressed as an increase in the population of PACAP-immunoreactive neurons in the small intestine. In the duodenum, only in the myenteric plexus (MP) was an increase in the number of PACAP-immunoreactive (IR) neurons observed in both experimental groups, while in the outer submucous plexus (OSP) and inner submucous plexus (ISP), an increase was noted only in the high-dose group. In the jejunum, both doses of acrylamide led to an increase in the population of PACAP-IR neurons in each enteric plexus (MP, OSP, ISP), while in the ileum, only supplementation with the higher dose of acrylamide increased the number of PACAP-IR enteric neurons in the MP, OSP, and ISP. Conclusions: The obtained results suggest the participation of PACAP in acrylamide-induced plasticity of enteric neurons, which may be an important line of defence from the harmful action of acrylamide on the small intestines.
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- 2023
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43. Cocaine- and amphetamine-regulated transcript (CART) peptide in the enteric nervous system of the porcine esophagus.
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Makowska, Krystyna, Rytel, Liliana, Lech, Piotr, Osowski, Adam, Kruminis-Kaszkiel, Ewa, and Gonkowski, Slawomir
- Subjects
- *
COCAINE , *AMPHETAMINES , *PERIPHERAL nervous system , *APPETITE depressants , *ENTERIC nervous system - Abstract
Cocaine- and amphetamine-regulated transcript peptide (CART) is widely distributed within the central and peripheral nervous system. In the brain, CART is considered as the main anorectic peptide involved in the regulation of food intake. Contrary to the central nervous system, a lot of aspects connected with the distribution and functions of CART within the enteric nervous system (ENS) still remain unknown. The aim of the present study was to investigate, for the first time, the population of CART-like immunoreactive (CART-LI) neurons within the porcine esophagus and the denotation of their neurochemical coding. During this experiment, the distribution of CART-LI neurons and the colocalization of CART with other neuronal active substances were examined using standard double- and triple-immunofluorescence techniques in enteric plexuses of cervical, thoracic, and abdominal esophagus fragments. The obtained results showed that CART is present in a relatively high percentage of esophageal neurons (values fluctuated from 45.2 ± 0.9% in the submucous plexus of the thoracic esophagus to 58.1 ± 5.0% in the myenteric plexus of the same fragment of the esophagus). Moreover, CART colocalized with a wide range of other active neuronal substances, mainly with the vesicular acetylcholine transporter (VAChT, a marker of cholinergic neurons), neuronal isoform of nitric oxide synthase (nNOS, a marker of nitrergic neurons), vasoactive intestinal polypeptide (VIP) and galanin (GAL). The number of CART-positive neuronal cells and their neurochemical coding clearly depended on the fragment of esophagus studied and the type of enteric plexus. The obtained results suggest that CART may play important and multidirectional roles in the neuronal regulation of esophageal functions. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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- View/download PDF
44. Estrogen receptor β controls proliferation of enteric glia and differentiation of neurons in the myenteric plexus after damage.
- Author
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Di Leo, A., D'Errico, F., Dai, Y., Wu, W., Warner, M., Gustafsson, J. A., Goverse, G., Stakenborg, M., Labeeuw, E., De Simone, V., Verstockt, B., Gomez-Pinilla, P. J., and Matteoli, G.
- Subjects
- *
ESTROGEN , *DIETHYLSTILBESTROL , *CELL proliferation , *NEURONS , *MYENTERIC plexus , *INTESTINES - Abstract
Injury to the enteric nervous system (ENS) can cause several gastrointestinal (GI) disorders including achalasia, irritable bowel syndrome, and gastroparesis. Recently, a subpopulation of enteric glial cells with neuronal stem/progenitor properties (ENSCs) has been identified in the adult ENS. ENSCs have the ability of reconstituting the enteric neuronal pool after damage of the myenteric plexus. Since the estrogen receptor β (ERβ) is expressed in enteric glial cells and neurons, we investigated whether a selective ERβ agonist, LY3201, can influence neuronal and glial cell differentiation. Myenteric ganglia from the murine muscularis externa were isolated and cultured in either glial cell medium or neuronal medium. In glial cell medium, the number of glial progenitor cells (Sox10+) was increased by fourfold in the presence of LY3201. In the neuronal medium supplemented with an antimitotic agent to block glial cell proliferation, LY3201 elicited a 2.7-fold increase in the number of neurons (neurofilament+ or HuC/D+). In addition, the effect of LY3201 was evaluated in vivo in two murine models of enteric neuronal damage and loss, namely, high-fat diet and topical application of the cationic detergent benzalkonium chloride (BAC) on the intestinal serosa, respectively. In both models, treatment with LY3201 significantly increased the recovery of neurons after damage. Thus, LY3201 was able to stimulate glial-to-neuron cell differentiation in vitro and promoted neurogenesis in the damaged myenteric plexus in vivo. Overall, our study suggests that selective ERβ agonists may represent a therapeutic tool to treat patients suffering from GI disorders, caused by excessive neuronal/glial cell damage. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
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45. VIP is involved in peripheral CRF-induced stimulation of propulsive colonic motor function and diarrhea in male rats.
- Author
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Seiichi Yakabi, Lixin Wang, Hiroshi Karasawa, Pu-Qing Yuan, Kazuhiko Koike, Koji Yakabi, and Yvette Taché
- Abstract
We investigated whether vasoactive intestinal peptide (VIP) and/or prostaglandins contribute to peripheral corticotropin-releasing factor (CRF)-induced CRF1 receptor-mediated stimulation of colonic motor function and diarrhea in rats. The VIP antagonist, [4Cl-D-Phe6, Leu17]VIP injected intraperitoneally completely prevented CRF (10 µg/kg ip)-induced fecal output and diarrhea occurring within the first hour after injection, whereas pretreatment with the prostaglandins synthesis inhibitor, indomethacin, had no effect. In submucosal plexus neurons, CRF induced significant c-Fos expression most prominently in the terminal ileum compared with duodenum and jejunum, whereas no c-Fos was observed in the proximal colon. c-Fos expression in ileal submucosa was colocalized in 93.4% of VIP-positive neurons and 31.1% of non-VIP-labeled neurons. CRF1 receptor immunoreactivity was found on the VIP neurons. In myenteric neurons, CRF induced only a few c-Fos-positive neurons in the ileum and a robust expression in the proximal colon (17.5 ± 2.4 vs. 0.4 ± 0.3 cells/ganglion in vehicle). The VIP antagonist prevented intraperitoneal CRF-induced c-Fos induction in the ileal submucosal plexus and proximal colon myenteric plexus. At 60 min after injection, CRF decreased VIP levels in the terminal ileum compared with saline (0.8 ± 0.3 vs. 2.5 ± 0.7 ng/g), whereas VIP mRNA level detected by qPCR was not changed. These data indicate that intraperitoneal CRF activates intestinal submucosal VIP neurons most prominently in the ileum and myenteric neurons in the colon. It also implicates VIP signaling as part of underlying mechanisms driving the acute colonic secretomotor response to a peripheral injection of CRF, whereas prostaglandins do not play a role. NEW & NOTEWORTHY Corticotropin-releasing factor (CRF) in the gut plays a physiological role in the stimulation of lower gut secretomotor function induced by stress. We showed that vasoactive intestinal peptide (VIP)-immunoreactive neurons in the ileal submucosal plexus expressed CRF1 receptor and were prominently activated by CRF, unlike colonic submucosal neurons. VIP antagonist abrogated CRF-induced ileal submucosal and colonic myenteric activation along with functional responses (defecation and diarrhea). These data point to VIP signaling in ileum and colon as downstream effectors of CRF. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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46. The Influence of a Hyperglycemic Condition on the Population of Somatostatin Enteric Neurons in the Porcine Gastrointestinal Tract
- Author
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Michał Bulc, Katarzyna Palus, and Jarosław Całka
- Subjects
somatostatin ,hyperglycemia ,enteric neurons ,pig ,Veterinary medicine ,SF600-1100 ,Zoology ,QL1-991 - Abstract
Somatostatin (SOM) is the most common agent in the gastrointestinal (GI) tract that is involved in the regulation of several gastric functions, as well as in gastric disorders. Hyperglycemia, which develops as a consequence of improperly treated diabetes, can cause numerous disturbances in the appropriate functioning of the gastrointestinal tract. High glucose level is toxic to neurons. One of the lines of defense of neurons against this glucotoxicity are changes in their chemical coding. To better understood the role of SOM secreted by enteric neurons in neuronal response on elevated glucose level, pancreatic β cells were destroyed using streptozotocin. Due to the close similarity of the pig to humans, especially the GI tract, the current study used pigs as an animal model. The results revealed that the number of enteric neurons immunoreactive to SOM (SOM-IR) in a physiological state clearly depend on the part of the GI tract studied. In turn, experimentally induced diabetes caused changes in the number of SOM-IR neurons. The least visible changes were observed in the stomach, where an increase in SOM-IR neurons was observed, only in the submucosal plexus in the corpus. However, diabetes led to an increase in the population of myenteric and submucosal neurons immunoreactive to SOM in all segments of the small intestine. The opposite situation occurred in the descending colon, where a decrease in the number of SOM-IR neurons was visible. This study underlines the significant role of SOM expressed in enteric nervous system neurons during diabetes.
- Published
- 2020
- Full Text
- View/download PDF
47. Same hit, different gut punches.
- Subjects
- *
MORPHOLOGY , *ENTERIC nervous system , *SUBMUCOUS plexus , *IRRITABLE colon - Abstract
Of these, only the ENS showed sex-specific changes, suggesting that the way in which the ENS plexuses responded to the same early life stress was sex-biased. The sex-specific nature of alterations in ENS and in the female-specific nature of dysmotility simulates an important feature of DGBI, where women seem to be more prone to developing gastrointestinal dysmotility disorders. Keywords: DGBI; dysbiosis; early life; enteric neurons; gastrointestinal dysmotility; sex-biased EN DGBI dysbiosis early life enteric neurons gastrointestinal dysmotility sex-biased 4251 4252 2 10/04/22 20221001 NES 221001 Disorders of gut-brain interaction (DGBI) afflict large numbers of people and are associated with gut dysfunctions including gastrointestinal dysmotility and altered stool frequency (Schmulson & Drossman, 2017). [Extracted from the article]
- Published
- 2022
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48. The neuroprotective effects of human bone marrow mesenchymal stem cells are dose-dependent in TNBS colitis.
- Author
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Robinson, Ainsley M., Rahman, Ahmed A., Miller, Sarah, Stavely, Rhian, Sakkal, Samy, and Nurgali, Kulmira
- Subjects
MESENCHYMAL stem cells ,NEUROPROTECTIVE agents ,TRINITROBENZENE ,COLITIS ,INFLAMMATORY bowel diseases ,GUINEA pigs as laboratory animals - Abstract
Background: The incidence of inflammatory bowel diseases (IBD) is increasing worldwide with patients experiencing severe impacts on their quality of life. It is well accepted that intestinal inflammation associates with extensive damage to the enteric nervous system (ENS), which intrinsically innervates the gastrointestinal tract and regulates all gut functions. Hence, treatments targeting the enteric neurons are plausible for alleviating IBD and associated complications. Mesenchymal stem cells (MSCs) are gaining wide recognition as a potential therapy for many diseases due to their immunomodulatory and neuroprotective qualities. However, there is a large discrepancy regarding appropriate cell doses used in both clinical trials and experimental models of disease. We have previously demonstrated that human bone marrow MSCs exhibit neuroprotective and anti-inflammatory effects in a guinea-pig model of 2,4,6-trinitrobenzene-sulfonate (TNBS)-induced colitis; but an investigation into whether this response is dose-dependent has not been conducted. Methods: Hartley guinea-pigs were administered TNBS or sham treatment intra-rectally. Animals in the MSC treatment groups received either 1 × 10
5 , 1×106 or 3 × 106 MSCs by enema 3 hours after induction of colitis. Colon tissues were collected 72 hours after TNBS administration to assess the effects of MSC treatments on the level of inflammation and damage to the ENS by immunohistochemical and histological analyses. Results: MSCs administered at a low dose, 1 × 105 cells, had little or no effect on the level of immune cell infiltrate and damage to the colonic innervation was similar to the TNBS group. Treatment with 1 × 106 MSCs decreased the quantity of immune infiltrate and damage to nerve processes in the colonic wall, prevented myenteric neuronal loss and changes in neuronal subpopulations. Treatment with 3 × 106 MSCs had similar effects to 1 × 106 MSC treatments. Conclusions: The neuroprotective effect of MSCs in TNBS colitis is dose-dependent. Increasing doses higher than 1 × 106 MSCs demonstrates no further therapeutic benefit than 1 × 106 MSCs in preventing enteric neuropathy associated with intestinal inflammation. Furthermore, we have established an optimal dose of MSCs for future studies investigating intestinal inflammation, the enteric neurons and stem cell therapy in this model. [ABSTRACT FROM AUTHOR]- Published
- 2017
- Full Text
- View/download PDF
49. Effects of Quercetin-Supplementation in NADH-Diaphorase Positive Neurons Subpopulations in the Ileum of Rats with Experimental Diabetes Mellitus.
- Author
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Pereira Alves, Angela Maria, de Paula, Anderson Luiz, Rafael Moreira, Cassio, Ferrari, Fernanda, Coelho Leal, Jean Paulo, Saleh Hatoum, Ualid, Vieira Silva, Helaine Maruska, Belato Alves, Eder Paulo, de Miranda Neto, Marcilio Hubner, and Alexandre Galvanini, Paulo
- Subjects
- *
QUERCETIN , *NAD (Coenzyme) , *PEOPLE with diabetes , *QUANTITATIVE chemical analysis , *NEURAL physiology , *ILEUM physiology , *LABORATORY rats , *PHYSIOLOGY - Abstract
The effects of quercetin supplementation in NADH-diaphorase positive (NADH-d) neurons of streptozotocininduced diabetic rats was carried in this study. Fifteen male rats were divided into three groups: normoglycemic (N), diabetic (D) and diabetic supplemented with quercetin (DQ). Whole mount preparations of the muscular layer of the ileum underwent NADH-d histochemistry for evidencing the NADH-d neuronal subpopulation. Quantitative analyzes were performed on 30 random fields, and morphometric analyzes in 100 neuronal bodies and nuclei per animal. The supplementation promoted a 44% reduction in the neuronal density in D group when compared to N group (p <0.001); a 24.5% reduction was observed in the DQ group when compared to N (p <0.01). Animals in D group presented an 18.7% increase in the cell body areas of myenteric neurons when compared to N (p <0.001); DQ group showed a 14.2% decrease in neuronal areas when compared to D (p <0.01); the nuclear area were similar among the three groups. We conclude that quercetin supplementation was positive for animals with diabetes mellitus. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
50. The enteric nervous system relays psychological stress to intestinal inflammation.
- Author
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Schneider, Kai Markus, Blank, Niklas, Alvarez, Yelina, Thum, Katharina, Lundgren, Patrick, Litichevskiy, Lev, Sleeman, Madeleine, Bahnsen, Klaas, Kim, Jihee, Kardo, Simon, Patel, Shaan, Dohnalová, Lenka, Uhr, Giulia T., Descamps, Hélène C., Kircher, Susanna, McSween, Alana M., Ardabili, Ashkan Rezazadeh, Nemec, Kelsey M., Jimenez, Monica T., and Glotfelty, Lila G.
- Subjects
- *
ENTERIC nervous system , *PSYCHOLOGICAL stress , *INFLAMMATORY bowel diseases , *SUBMUCOUS plexus , *ENCEPHALITIS , *INFLAMMATION - Abstract
Mental health profoundly impacts inflammatory responses in the body. This is particularly apparent in inflammatory bowel disease (IBD), in which psychological stress is associated with exacerbated disease flares. Here, we discover a critical role for the enteric nervous system (ENS) in mediating the aggravating effect of chronic stress on intestinal inflammation. We find that chronically elevated levels of glucocorticoids drive the generation of an inflammatory subset of enteric glia that promotes monocyte- and TNF-mediated inflammation via CSF1. Additionally, glucocorticoids cause transcriptional immaturity in enteric neurons, acetylcholine deficiency, and dysmotility via TGF-β2. We verify the connection between the psychological state, intestinal inflammation, and dysmotility in three cohorts of IBD patients. Together, these findings offer a mechanistic explanation for the impact of the brain on peripheral inflammation, define the ENS as a relay between psychological stress and gut inflammation, and suggest that stress management could serve as a valuable component of IBD care. [Display omitted] • Psychological stress leads to monocyte-mediated exacerbation of gut inflammation • Chronic glucocorticoid signaling drives the effect of stress on IBD • Stress induces inflammatory enteric glia that promote monocyte recruitment via CSF1 • Stress provokes transcriptional immaturity in enteric neurons and dysmotility Psychological stress and chronically elevated glucocorticoid levels induce inflammatory enteric glia and transcriptional immaturity in enteric neurons, leading to dysmotility and predisposing the intestine to monocyte-mediated inflammation. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
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