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.

Acupuncture vs. antispasmodics in the treatment of irritable bowel syndrome: An adjusted indirect treatment comparison meta-analysis

“…However, due to the characteristics of multi-link and multi-target of acupuncture, there is still a lack of in-depth understanding of the mechanisms associated with acupuncture in the treatment of IBS. Relative studies had confirmed that acupuncture can improve visceral hypersensitivity and intestinal motility by regulating the Epac1-Piezo 2 axis and reducing 5-HT and 5-HTR expressions ( Zhao et al, 2016 ; Guo et al, 2022 ) and regulate the brain-gut axis and nervous system by affecting neurotransmitters including 5-HT, substance P, calcitonin gene-related peptide, nitric oxide, and norepinephrine. In addition, IL-18, IL-23, TNF-α, mast cells, and other immune cells and inflammatory factors may be also involved in the regulation of IBS by acupuncture ( Wu et al, 2008 ; Ma et al, 2014 ).…”

Piezo channels in the intestinal tract

“…IBS patients all experience 5-HT-induced nociceptive responses ( Keszthelyi et al, 2015 ), and Piezo2 channels can induce 5-HT release when activated by mechanical stimuli ( Alcaino et al, 2018 ). Therefore, Piezo2 in the colon is closely related to 5-HT ( Guo et al, 2022 ).…”

Acupuncture as multi-targeted therapy for the multifactorial disease obesity: a complex neuro-endocrine-immune interplay

“…Moreover, in adult patients with constipation dominant-IBS (IBS-C), an RCT comparing EA to mild-warm moxibustion treatment at ST25 and ST37 showed improvement of defecation frequency compared to baseline up to three months after treatment, and the effects of EA were proposed to be mediated through alleviation of visceral hypersensitivity and improved brain-gut function as visualised with fMRI ( 185 ). Additionally, several studies in animals and humans show altered levels of stress hormones such as cortisol and epinephrine, and changes in 5-HT associated with acupuncture, although mostly in the context of visceral pain management ( 186 – 189 ). In mice and rats with IBS-associated visceral hypersensitivity, treatment with EA significantly reduced 5-HT and 5-HT receptor mRNA expression levels compared to sham-treatment and was associated with attenuated visceral hypersensitivity ( 186 , 187 ).…”

“…Additionally, several studies in animals and humans show altered levels of stress hormones such as cortisol and epinephrine, and changes in 5-HT associated with acupuncture, although mostly in the context of visceral pain management ( 186 – 189 ). In mice and rats with IBS-associated visceral hypersensitivity, treatment with EA significantly reduced 5-HT and 5-HT receptor mRNA expression levels compared to sham-treatment and was associated with attenuated visceral hypersensitivity ( 186 , 187 ). In the context of obesity, a potential role for 5-HT on thermogenesis of brown adipose tissue in mice has been reported ( 189 ) and gut microbiota are directly implicated in the process of peripheral 5-HT biosynthesis in their host, both animals and human adults with obese phenotypes ( 122 , 190 , 191 ).…”