Previous studies have identified a counter-inflammatory vagal reflex in the context of endotoxic shock. We have extended this observation to show that the vagus confers protection against acute (5 days) colitis induced by dextran sodium sulfate (DSS) or by dinitrobenzene sulfonic acid (DNBS). We have shown that this is mediated via macrophages and involves the suppression of pro-inflammatory cytokines. In this study, we have examined whether the vagal integrity confers long lasting protection by studying DNBS and DSS-induced inflammatory responses in the colon at 9 to 61 days post-vagotomy. The integrity of vagotomy was confirmed at all time points using CCK-induced satiety. As previously described in a DNBS and DSS-model, vagotomy associated with the pyloroplasty increased all indices of inflammation. Vagotomy increased the disease activity index, macroscopic and histological scores by 75% and 41% respectively. In addition, MPO activity, serum levels of CRP and colonic tissue levels of pro-inflammatory cytokine when colitis was induced 9 days post-vagotomy. However, these increases in inflammatory indices were substantially diminished in mice with colitis induced 21, 33 and 61 days post-vagotomy. This was accompanied by increased production of IL-10, TGF-beta, increased in FOXP3 staining in colonic tissue and increased serum corticosterone. These findings indicate that while vagal integrity is an important protective factor, other counter inflammatory mechanisms, come into play if vagal integrity is compromised beyond 2 weeks.