Enteric nervous system and inflammatory bowel diseases: Correlated impacts and therapeutic approaches through the P2X7 receptor

Magalhães, Henrique Inhauser Riceti; Castelucci, Patrícia

doi:10.3748/wjg.v27.i46.7909

Cited by 16 publications

(7 citation statements)

References 172 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The quantitative analysis identified a reduction in the number of nNOS-ir, ChAT-ir, and GPR41-ir neurons in the Colitis group when compared to the Sham group. These results corroborate data from the literature that document the reduction of enteric neurons in IBD protocols [8][9][10]51]. In this study, after 7 days of acid injection, neuronal reduction was observed.…”

Section: Discussionsupporting

confidence: 92%

Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis

Caetano

Magalhães

Duarte

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferments dietary fibers and produces short-chain fatty acids, such as Butyrate, which bind to G protein–coupled receptors, such as GPR41, and contribute to maintaining intestinal health. This work aimed to study the GPR41 in myenteric neurons and analyze the effect of Butyrate in mice submitted to experimental ulcerative colitis. The 2, 4, 6 trinitrobenzene sulfonic acid (TNBS) was injected intrarectally in C57BL/6 mice (Colitis). Sham group received ethanol (vehicle). One group was treated with 100 mg/kg of Sodium Butyrate (Butyrate), and the other groups received saline. Animals were euthanized 7 days after colitis induction. Analyzes demonstrated colocalization of GPR41 with neurons immunoreactive (-ir) to nNOS and ChAT-ir and absence of colocalization of the GPR41 with GFAP-ir glia. Quantitative results demonstrated losses of nNOS-ir, ChAT-ir, and GPR41-ir neurons in the Colitis group and Butyrate treatment attenuated neuronal loss. The number of GFAP-ir glia increased in the Colitis group, whereas Butyrate reduced the number of these cells. In addition, morphological alterations observed in the Colitis group were attenuated in the Butyrate group. The presence of GPR41 in myenteric neurons was identified, and the treatment with Butyrate attenuated the damage caused by experimental ulcerative colitis.

show abstract

Section: Discussionsupporting

confidence: 92%

Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis

Caetano

Magalhães

Duarte

et al. 2023

Cells

Self Cite

View full text Add to dashboard Cite

show abstract

“…Indeed, recent evidence has indicated that colitis affects not only the intestinal mucosa but also the muscle layer and components of the ENS. Hence, gastrointestinal symptoms result from degenerative changes and a reduction in the number of enteric neurons and glial cells, sometimes induced by the P2X7 receptor[ 35 - 40 , 48 , 50 , 62 , 63 , 82 - 84 ]. However, little is known about the cellular signaling mechanisms responsible for the loss of enteric innervation in IBDs[ 85 ].…”

Section: Discussionmentioning

confidence: 99%

“…Thus, improving the understanding of the cellular and molecular basis of neuronal death can aid in the identification and development of specific therapeutic strategies[ 8 ]. However, studies on the mechanisms underlying the death of enteric neurons, especially the role of the P2X7 receptor as an inducer of the death of these neurons in inflammatory bowel diseases (IBDs), are still lacking[ 37 - 40 , 51 , 52 , 60 - 63 ].…”

Section: Introductionmentioning

confidence: 99%

Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis

Magalhães¹,

Machado²,

Souza³

et al. 2023

World J Gastroenterol

Self Cite

View full text Add to dashboard Cite

BACKGROUND The literature indicates that the enteric nervous system is affected in inflammatory bowel diseases (IBDs) and that the P2X7 receptor triggers neuronal death. However, the mechanism by which enteric neurons are lost in IBDs is unknown. AIM To study the role of the caspase-3 and nuclear factor kappa B (NF-κB) pathways in myenteric neurons in a P2X7 receptor knockout (KO) mouse model of IBDs. METHODS Forty male wild-type (WT) C57BL/6 and P2X7 receptor KO mice were euthanized 24 h or 4 d after colitis induction by 2,4,6-trinitrobenzene sulfonic acid (colitis group). Mice in the sham groups were injected with vehicle. The mice were divided into eight groups ( n = 5): The WT sham 24 h and 4 d groups, the WT colitis 24 h and 4 d groups, the KO sham 24 h and 4 d groups, and the KO colitis 24 h and 4 d groups. The disease activity index (DAI) was analyzed, the distal colon was collected for immunohistochemistry analyses, and immunofluorescence was performed to identify neurons immunoreactive (ir) for calretinin, P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, and total NF-κB. We analyzed the number of calretinin-ir and P2X7 receptor-ir neurons per ganglion, the neuronal profile area (µm²), and corrected total cell fluorescence (CTCF). RESULTS Cells double labeled for calretinin and P2X7 receptor, cleaved caspase-3, total caspase-3, phospho-NF-κB, or total NF-κB were observed in the WT colitis 24 h and 4 d groups. The number of calretinin-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (2.10 ± 0.13 vs 3.33 ± 0.17, P < 0.001; 2.92 ± 0.12 vs 3.70 ± 0.11, P < 0.05), but was not significantly different between the KO groups. The calretinin-ir neuronal profile area was increased in the WT colitis 24 h group compared to the WT sham 24 h group (312.60 ± 7.85 vs 278.41 ± 6.65, P < 0.05), and the nuclear profile area was decreased in the WT colitis 4 d group compared to the WT sham 4 d group (104.63 ± 2.49 vs 117.41 ± 1.14, P < 0.01). The number of P2X7 receptor-ir neurons per ganglion was decreased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d groups, respectively (19.49 ± 0.35 vs 22.21 ± 0.18, P < 0.001; 20.35 ± 0.14 vs 22.75 ± 0.51, P < 0.001), and no P2X7 receptor-ir neurons were observed in the KO groups. Myenteric neurons showed ultrastructural changes in the WT colitis 24 h and 4 d groups and in the KO colitis 24 h group. The cleaved caspase-3 CTCF was increased in the WT colitis 24 h and 4 d groups compared to the WT sham 24 h and 4 d...

show abstract

“…Thus, P2X7 receptors, which are shown in the present study to be expressed in the colonic epithelium, too (Figures 8–10), play a central role in a great spectrum of diseases. Consequently, inhibition of this ionotropic receptor may serve as approach for the treatment of inflammatory bowel diseases (Magalhães & Castelucci, 2021).…”

Section: Discussionmentioning

confidence: 99%

Ionotropic P2X4 and P2X7 receptors in the regulation of ion transport across rat colon

Ballout

Claßen

Richter

et al. 2022

British J Pharmacology

View full text Add to dashboard Cite

Background and purpose: ATP plays an important role as an extracellular messenger acting via different types of purinoceptors. Whereas most of the actions of ATP at intestinal epithelia are thought to be mediated by metabotropic P2Y receptors, the role of ionotropic P2X receptors remains unclear. Consequently, we investigated the role of P2X4 and P2X7 receptors on ion transport across rat colonic epithelia by using BzATP, a potent agonist at P2X7 (and weak agonist at P2X4).Experimental approach: Ussing chamber and Ca 2+ imaging experiments were performed on rat colonic epithelia, combined with P2X receptor expression studies.Key results: Ussing chamber experiments revealed that serosal BzATP induced a neuronally mediated increase in short-circuit current caused by Cl À secretion. In contrast, the effect of mucosal BzATP was smaller, insensitive to tetrodotoxin and Cl À -independent. When epithelia were basolaterally depolarized to measure currents across the apical membrane, BzATP stimulated a cation current consistent with the activation of apical nonselective cation channels. Experiments with isolated colonic crypts revealed a BzATP-induced increase in the cytosolic Ca 2+ concentration. Sensitivity to antagonists indicates stimulation of P2X4 and P2X7 receptors by serosal BzATP and of P2X7 receptors by mucosal BzATP. A similar pattern was observed with native ATP, which induced larger transepithelial currents in comparison to BzATP. RT-PCR and immunohistochemistry experiments confirmed the expression of P2X4 and P2X7 receptors in the colon localized in the epithelium and in submucosal ganglia. Conclusions and implications: Epithelial and neuronal ionotropic P2X receptors are involved in the regulation of intestinal ion transport.

show abstract

Enteric nervous system and inflammatory bowel diseases: Correlated impacts and therapeutic approaches through the P2X7 receptor

Cited by 16 publications

References 172 publications

Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis

Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis

Study of the roles of caspase-3 and nuclear factor kappa B in myenteric neurons in a P2X7 receptor knockout mouse model of ulcerative colitis

Ionotropic P2X4 and P2X7 receptors in the regulation of ion transport across rat colon

Contact Info

Product

Resources

About