Introduction
Decreased vagus nerve activity and increased inflammatory immune cells are observed in ulcerative colitis (UC) (1, 2). Due to its anti-inflammatory and protective properties, vagus nerve stimulation (VNS) has garnered attention for UC therapy (3). Non-invasive transcutaneous auricular vagus nerve stimulation (NitaVNS), devoid of the side effects associated with invasive techniques, demonstrates protective anti-inflammatory effects in our mouse UC-like model of colitis (4), although the specific cellular mechanisms remain unclear.
Aims & Methods
To evaluate the effects of NitaVNS on the distribution of granulocytes, macrophages, natural killer (NK) cells, and CD4+ and CD8+ T cells in the colon tissue, spleen, and mesenteric lymph nodes of a UC-like colitis mouse model, NitaVNS was administered to C57BL/6 male mice daily for 10 min, beginning one day before colitis induction with 5% dextran sulfate sodium for 5 days in water (the control group received regular water). This continued until the end of the study, with no stimulation in sham mice. The daily disease activity index (DAI) was evaluated along with distal macroscopic scores at the time of sacrifice. The frequencies of granulocytes (Ly6G), macrophages (F4/80), NK cells (NK1.1), CD4+ T cells (CD3, CD4), and CD8+ T cells (CD3, CD8) were analyzed in the cecum, proximal, mid and distal colon, spleen, and mesenteric lymph nodes (MLNs) using flow cytometry.
Results
NitaVNS in colitic mice significantly improved the DAI and macroscopic scores related to rectal bleeding, colon bleeding, fecal consistency loss, and shortened colon length compared to sham-stimulated colitic mice. In contrast, no changes were observed in the non-colitic mice. While NitaVNS did not alter the frequency of Ly6G+ cells in the cecum, mid/distal colon, and MLNs, it significantly decreased the positivity of these cells in the proximal colon and spleen of mice with colitis without affecting non-colitic mice. NitaVNS significantly decreased the frequency of F4/80+ cells in the mid-colon but did not influence these cells in the cecum, proximal and distal colon, spleen, or MLNs. In colitic conditions, NitaVNS significantly increased NK cell frequency in the spleen without affecting non-colitic mice. Moreover, NitaVNS did not alter the frequency of NK cells in the colon or MLNs in colitic or non-colitic mice. Additionally, NitaVNS did not induce changes in CD4+ and CD8+ T cell distribution in the colon tissue, spleen, or mesenteric lymph nodes of colitic and non-colitic mice.
Conclusion
These results suggest that NitaVNS could potentially reduce inflammation in colitic mice, locally and systemically, by decreasing the frequency of granulocytes in the colon and spleen and colonic macrophages. Additionally, NitaVNS increased the number of splenic NK cells, potentially contributing to its systemic effects. These findings indicate promising therapeutic potential for NitaVNS.
References
1. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology. 2006;131(4):1122-30.
2. Wiese JJ, Manna S, Kühl AA, Fascì A, Elezkurtaj S, Sonnenberg E, Bubeck M, Atreya R, Becker C, Weixler B, Siegmund B, Patankar JV, Prüß MS, Schumann M. Myenteric Plexus Immune Cell Infiltrations and Neurotransmitter Expression in Crohn's Disease and Ulcerative Colitis. J Crohns Colitis. 2024 Jan 27;18(1):121-133.
3. Verma N, Mudge JD, Kasole M, Chen RC, Blanz SL, Trevathan JK, Lovett EG, Williams JC, Ludwig KA. Auricular Vagus Neuromodulation-A Systematic Review on Quality of Evidence and Clinical Effects. Front Neurosci. 2021 Apr 30;15:664740.
4. Hesampour F, Tshikudi D, Veysel Özden A, Bernstein CN, Ghia JE. A54 The impact of non-invasive transcutaneous auricular nerve stimulation (NitaVNS) on the development of experimental colitis in mice. J Can Assoc Gastroenterol. 2023 Mar 7;6(Suppl 1):30.
Disclosure
F. Hesampour: None Declared, D. Tshikudi: None Declared, A. Veysel Özden: The employee of the company providing the stimulator, C. N. Bernstein: None Declared, J-E. Ghia: None Declared.