Functional characterization of oxazolone-induced colitis and survival improvement by vagus nerve stimulation

• Published in: PloS one 2018-05, Vol.13 (5), p.e0197487-e0197487
• Main Authors: Meroni, Elisa, Stakenborg, Nathalie, Gomez-Pinilla, Pedro J, De Hertogh, Gert, Goverse, Gera, Matteoli, Gianluca, Verheijden, Simon, Boeckxstaens, Guy E
• Format: Article
• Language: English
• Subjects: Animal models; Anti-inflammatory agents; Antiinflammatory agents; Biology and Life Sciences; Body temperature; Care and treatment; Chronic illnesses; Colitis; Colon; Development and progression; Helper cells; HMGB1 protein; Immune response; Immune system; Infiltration; Inflammatory bowel disease; Inflammatory bowel diseases; Inflammatory response; Interleukin 6; Leukocytes (neutrophilic); Lymphocytes T; Medicine and Health Sciences; Methods; Mice; Monocytes; Mortality; mRNA; Mucosa; Oxazolone; Rodents; Sepsis; Stimulation; Survival; Tumor necrosis factor-α; Ulcerative colitis; Vagus nerve; Vagus nerve stimulation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0197487

Oxazolone-induced colitis has been frequently used in literature as a model of IBD, but insights into the underlying immune response and pathological features are surprisingly still very limited. Vagus nerve stimulation (VNS) has proven to be effective in innate and Th1/Th17 predominant inflammatory models, including pre-clinical models of colitis, however to what extent VNS is also effective in ameliorating Th2-driven colitis remains to be studied. In the present study, we therefore further characterized the immune response in oxazolone-induced colitis and investigated the potential therapeutic effect of VNS. Colitis was induced in Balb/c mice by cutaneous sensitization with 3% oxazolone followed by intracolonic administration of 1% oxazolone 7 days later. To evaluate the effect of VNS on the development of Th2-driven colitis, VNS and sham-treated mice were challenged with 1% oxazolone. Intracolonic oxazolone administration resulted in a severe destruction of the colonic mucosa and a rapid drop in body temperature leading to a 65% mortality rate at day 5. Severe infiltration of neutrophils and monocytes was detected 6h after oxazolone administration which was associated with a Th2-type inflammatory response. VNS significantly improved survival rate which correlated with decreased levels of HMGB1 and reduced colonic (il6 and cxcl1 mRNA) and serum cytokine levels (IL-6, TNFα and CXCL1) compared to sham treated mice. Oxazolone-induced colitis rather represents a model of sepsis and, at best, may resemble a severe type of ulcerative colitis, associated with early and severe mucosal damage and a high mortality rate. VNS reduces colonic inflammation and improves survival in this model, supporting the anti-inflammatory properties of VNS, even in an aggressive model as oxazolone-induced colitis.