Sacral nerve stimulation ameliorates colonic barrier functions in a rodent model of colitis

Abstract

Background The mucosal barrier damage is recognized as one of the key factors in the pathogenesis of colitis. While sacral nerve stimulation (SNS) was reported to have therapeutic potential for colitis, its mechanisms of actions on colonic permeability remained largely unknown. Methods In this study, colitis was induced by intrarectal administration of TNBS in rats. Five days later, they were treated with SNS or sham‐SNS for 10 days. The effects of SNS on colonic permeability were assessed by measuring the expression of tight‐junction proteins involved in regulating permeability and the FITC‐dextran test. The mechanism of actions of SNS was investigated by studying the function of the enteric nervous system (ENS) cells and analyzing the autonomic nervous system. Key Results SNS decreased the disease activity index, microscopic and macroscopic scores, myeloperoxidase activity, and pro‐inflammatory cytokines (TNF‐α, IL‐6). SNS increased the expression of Zonula Occludens‐1, Occludin, Claudin‐1, and Junctional adhesion molecule‐A in the colon tissue. The FITC‐dextran test showed that the colonic permeability was lower with SCS than sham‐SNS. SNS increased ChAT, pancreatic polypeptide, and GDNF and reduced norepinephrine NGF, sub‐P, and mast cell overactivation in the colon tissue. Concurrently, SNS increased acetylcholine in colon tissues and elevated vagal efferent activity. Conclusions & Inferences SNS ameliorates colonic inflammation and enhances colonic barrier function with the proposed mechanisms involving the increase in parasympathetic activity and modulation of the activity of the ENS and immune system, including mast cells.

Neuro-Immune Modulation Effects of Sacral Nerve Stimulation for Visceral Hypersensitivity in Rats

“…Jiang et al (2019b) demonstrated that SNS with appropriate parameters could improve VH via the autonomic pathway. While we have also shown that SNS could ameliorate the colonic permeability in animal mode of IBD (Tu et al, 2020b), its mechanisms of action involved in the ameliorating effect of SNS on VH needs further investigation. Thus, in this study, we induced VH by administrating acetic acid (AA) in a neonatal stage, which is a widely accepted IBS animal model.…”

“…Therefore, in this study we used unilateral SNS on right sacral nerve of S3 to investigate the possible analgesic effects of SNS. Briefly, as we reported previously (Jiang et al, 2019b;Tu et al, 2020b), a dorsal midline incision was made to expose the right sacral nerve. One pair of electrodes (Cardiac pacing wire, A&E Medical, Farmingdale, NJ, United States) were placed around the right sacral nerve (S3) behind the sacral foramen and fixed by a surgical knot (oval cathode 2-3 mm in length in each electrode).…”

“…At the end of experiment, colonic acetylcholine (ACh) was measured as described previously (Tu et al, 2020b) in all rats, including the control rats. Briefly, the colonic tissues were dissected, and the mucosal layer was scarped on an ice-cold dish with clean tools as quickly as possible to prevent degradation by endogenous proteases.…”

“…Electrical stimulation of the peripheral nervous system has been proposed for reducing inflammation and pain in some GI diseases (Locke et al, 1997;Hungin et al, 2003;Whorwell, 2015;Pusceddu and Gareau, 2018), and as such sacral nerve stimulation (SNS) has been approved by the FDA for treating fecal incontinence and overactive bladder (Thin et al, 2013). In a series of animal studies, we have also shown that SNS with appropriate parameters could improve several other GI dysfunctions, such as delayed colonic transit (Peters et al, 2007) and bowel mucosal inflammation (Falletto et al, 2009;Lundby et al, 2011;Jiang et al, 2019b;Tu et al, 2020b). Few studies explored the potential of SNS for VH in animal models (Fassov et al, 2014;Langlois et al, 2015;Jiang et al, 2019a).…”

Bioelectronics in the brain–gut axis: focus on inflammatory bowel disease (IBD)

“…Electrical stimulation of the sacral nerve was also shown to improve mucosal integrity and DAI scores over an 18-month period in a single patient with proctitis (i.e. a condition in which the rectal mucosa is inflamed) ( 119 ), a finding which was confirmed in a rat model of TNBS colitis ( 120–123 ).…”