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Electroacupuncture Attenuates Post-Inflammatory IBS-Associated Visceral and Somatic Hypersensitivity and Correlates With the Regulatory Mechanism of Epac1-Piezo2 Axis.

ABSTRACT: Electroacupuncture (EA) is considered to have a therapeutic effect in the relief of irritable bowel syndrome (IBS)-associated visceral hypersensitivity via the reduction of the level of 5-hydroxytryptamine (5-HT) and 5-HT₃ receptors (5-HT₃R). However, whether Epac1/Piezo2, as the upstream of 5-HT, is involved in this process remains unclear. We investigated whether EA at the ST36 and ST37 acupoints alleviated visceral and somatic hypersensitivity in a post-inflammatory IBS (PI-IBS) model mice via the Epac1-Piezo2 axis. In this study, we used 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced PI-IBS as a mouse model. Visceral sensitivity was assessed by the abdominal withdrawal reflex test. Somatic sensitivity was evaluated by the hind paw withdrawal threshold. Quantitative real-time PCR, immunofluorescence staining, ELISA, and Western blotting were performed to examine the expressions of Epac1, Piezo2, 5-HT, and 5-HT₃R from the mouse distal colon/L5-S2 dorsal root ganglia (DRG). Our results showed that EA improved the increased visceral sensation and peripheral mechanical hyperalgesia in PI-IBS model mice, and the effects of EA were superior to the sham EA. EA significantly decreased the protein and mRNA levels of Epac1 and Piezo2, and reduced 5-HT and 5-HT₃R expressions in the distal colon. Knockdown of colonic Piezo2 eliminated the effect of EA on somatic hypersensitivity. Combined knockdown of colonic Epac1 and Piezo2 synergized with EA in relieving visceral hypersensitivity and blocked the effect of EA on somatic hypersensitivity. Additionally, protein levels of Epac1 and Piezo2 were also found to be decreased in the L5-S2 DRGs after EA treatment. Taken together, our study suggested that EA at ST36 and ST37 can alleviate visceral and somatic hypersensitivity in PI-IBS model mice, which is closely related to the regulation of the Epac1-Piezo2 axis.

SUBMITTER: Guo J

PROVIDER: S-EPMC9294163 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Electroacupuncture Attenuates Post-Inflammatory IBS-Associated Visceral and Somatic Hypersensitivity and Correlates With the Regulatory Mechanism of Epac1-Piezo2 Axis.

Guo Jing J Chen Lu L Wang Yu-Hang YH Song Ya-Fang YF Zhao Zhan-Hao ZH Zhao Ting-Ting TT Lin Zhi-Ying ZY Gu Dong-Mei DM Liu Yun-Qi YQ Peng Yong-Jun YJ Pei Li-Xia LX Sun Jian-Hua JH

Frontiers in endocrinology 20220705

Electroacupuncture (EA) is considered to have a therapeutic effect in the relief of irritable bowel syndrome (IBS)-associated visceral hypersensitivity via the reduction of the level of 5-hydroxytryptamine (5-HT) and 5-HT3 receptors (5-HT3R). However, whether Epac1/Piezo2, as the upstream of 5-HT, is involved in this process remains unclear. We investigated whether EA at the ST36 and ST37 acupoints alleviated visceral and somatic hypersensitivity in a post-inflammato ...[more]

PMID: 35865309

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Project description:Background and objective: IBS-D is a common functional bowel disease with complex etiology and without biomarker. The pathological and physiological basis of IBS-D focuses on visceral hypersensitivity. However, its epigenetic mechanism remains elusive. Our study aimed to integrate the relationship between differentially expressed miRNAs, mRNAs and proteins in IBS-D patients in order to reveal epigenetic mechanism of visceral hypersensitivity from transcription and protein levels and provide the molecular basis for discovering biomarkers of IBS-D. Methods: The intestinal biopsies from IBS-D patients and healthy volunteers were obtained for high-throughput sequencing of miRNAs and mRNAs. The differential miRNAs were selected and verified by q-PCR experiment followed by target mRNA prediction. Biological functions were respectively analyzed for target mRNAs, differential mRNAs and the previously identified differential proteins in order to explore the characteristic involved visceral hypersensitivity. At last, interaction analysis of miRNAs, mRNAs and proteins was performed for the epigenetic regulation mechanism from transcription and protein levels. Results: Thirty-three miRNAs were found to be differentially expressed in IBS-D and five of them were further confirmed, including upregulated hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p and downregulated hsa-miR-219a-5p, hsa-miR-19b-1-5p. In addition, 3,812 differential mRNAs were identified. Thirty intersecting molecules were found from the analysis on the target mRNAs of miRNAs and mRNAs. Fourteen intersecting molecules were obtained from the analysis on the target mRNAs and proteins, and thirty-six intersecting molecules were identified from analysis on the proteins and different mRNAs. According to the integrated analysis of miRNA-mRNA-protein, we noticed two new molecules COPS2 regulated by hsa-miR-19b-1-5p and MARCKS regulated by hsa-miR-641. Meanwhile some critical signaling pathways in IBS-D were found such as MAPK, GABAergic synapse, Glutamatergic synapse, and Adherens junction. Conclusion: The expressions of hsa-miR-641, hsa-miR-1843, hsa-let-7d-3p, hsa-miR-219a-5p, and hsa-miR-19b-1-5p in the intestinal tissues of IBS-D patients were significantly different. Moreover, they could regulate a variety of molecules and signaling pathways, which were involved in the multifaceted and multilevel mechanism of visceral hypersensitivity of IBS-D.

Project description:AimsVisceral hypersensitivity in irritable bowel syndrome (IBS) is widespread, but effective therapies for it remain elusive. As a canonical anti-inflammatory protein, suppressor of cytokine signaling 3 (SOCS3) reportedly relays exchange protein 1 directly activated by cAMP (Epac1) signaling and inhibits the intracellular response to inflammatory cytokines. Despite the inhibitory effect of SOCS3 on the pro-inflammatory response and neuroinflammation in PVN, the systematic investigation of Epac1-SOCS3 signaling involved in visceral hypersensitivity remains unknown. This study aimed to explore Epac1-SOCS3 signaling in the activity of hypothalamic paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) neurons and visceral hypersensitivity in adult rats experiencing neonatal colorectal distension (CRD).MethodsRats were subjected to neonatal CRD to simulate visceral hypersensitivity to investigate the effect of Epac1-SOCS3 signaling on PVN CRF neurons. The expression and activity of Epac1 and SOCS3 in nociceptive hypersensitivity were determined by western blot, RT-PCR, immunofluorescence, radioimmunoassay, electrophysiology, and pharmacology.ResultsIn neonatal-CRD-induced visceral hypersensitivity model, Epac1 and SOCS3 expressions were downregulated and IL-6 levels elevated in PVN. However, infusion of Epac agonist 8-pCPT in PVN reduced CRF neuronal firing rates, and overexpression of SOCS3 in PVN by AAV-SOCS3 inhibited the activation of PVN neurons, reduced visceral hypersensitivity, and precluded pain precipitation. Intervention with IL-6 neutralizing antibody also alleviated the visceral hypersensitivity. In naïve rats, Epac antagonist ESI-09 in PVN increased CRF neuronal firing. Consistently, genetic knockdown of Epac1 or SOCS3 in PVN potentiated the firing rate of CRF neurons, functionality of HPA axis, and sensitivity of visceral nociception. Moreover, pharmacological intervention with exogenous IL-6 into PVN simulated the visceral hypersensitivity.ConclusionsInactivation of Epac1-SOCS3 pathway contributed to the neuroinflammation accompanied by the sensitization of CRF neurons in PVN, precipitating visceral hypersensitivity and pain in rats experiencing neonatal CRD.

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Dataset Information

Electroacupuncture Attenuates Post-Inflammatory IBS-Associated Visceral and Somatic Hypersensitivity and Correlates With the Regulatory Mechanism of Epac1-Piezo2 Axis.

Publications

Electroacupuncture Attenuates Post-Inflammatory IBS-Associated Visceral and Somatic Hypersensitivity and Correlates With the Regulatory Mechanism of Epac1-Piezo2 Axis.

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