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* = Presenting author

P069 Sympathetic but not vagal intestinal innervation regulates murine dextran sodium sulphate-induced colitis

Willemze R.*1, Welting O.1, van Hamersveld P.1, Sridhar A.2, Vervoordeldonk M.2, Seppen J.1, de Jonge W.1

1Academic Medical Center (AMC), Tytgat Institute for Liver and Intestinal Research, Amsterdam, Netherlands 2Galvani, Bioelectronics, Stevenage, United Kingdom

Background

Targeted vagus nerve stimulation is currently evaluated as an alternative and medicine free treatment for inflammatory bowel disease (IBD). Because the vagus nerve does not directly innervate the spleen or the distal colon, it may not be the optimal peripheral nerve to target. Our first aim was to determine the effect of vagotomy (vx) of the right coeliac branch, or selective sympathectomy of the superior mesenteric nerve (SMNx), on dextran sodium sulphate (DSS)-induced colitis in mice. Secondly, we determined the effect of SMN stimulation (SMNstim) on DSS-induced colitis in rats.

Methods

To induce colitis, we exposed C57BL/6 mice to 2% DSS in the drinking water for 7 days. To determine the effect of vx, SMNx or a combination (cx), we measured the disease activity index (DAI) as a clinical parameter. In addition, we measured colonic cytokine expression by qPCR.

Changes in blood flow towards the intestine due to SMNstim were also determined. To test SMNstim in DSS-induced colitis, we implanted cuff electrodes around the SMN in Sprague Dawley rats with the wires connected to a head mount allowing non-invasive stimulation. 14 days after the surgery, we exposed the rats to 5% DSS in the drinking water for 9 days. At day 3 until day 9, we applied biphasic SMNstim twice a day for 5 minutes, 2 ms, 200 μA and 10 Hz. We assessed the DSS-induced colitis by measuring the DAI and colonic cytokines and assessing endoscopy and histology of the colon.

Results

Vx had no effect on the severity DSS-induced colitis in mice. However, SMNx as well as cx caused a significantly higher DAI (sham: 2.25±1.375; SMNx: 5±1; cx: 5±1.25; p<0.01) and a trend towards colonic IL-1β and IL-6 upregulation compared to a sham procedure. Given this worsening effect of SMNx, we performed SMNstim and determined the effect on DSS-induced colitis in rats. Noteworthy, the stimulus was well tolerated by the rats and there were no changes in blood flow towards the intestine. SMNstim led to a significantly improved DAI in rats compared to rats that underwent sham stimulation (sham: 6±4.13; SMNx: 2±1.88; p=0.04). However, colonic cytokines, endoscopy outcome and histological outcome did not change.

Conclusion

We conclude that the vagus nerve innervating the intestine does not affect DSS-induced colitis. Alternatively, our data imply that the SMN ameliorates colitis in our DSS-induced colitis models. Because we show that SMNstim can be executed safely and non-invasively in rats, our results also open an avenue to explore other nerves in experimental colitis. In the long run, our research contributes to the knowledge about nerve stimulation as an alternative treatment for IBD.