Vagus Nerve Mediates the Neural Stem Cell Response to Intestinal Injury

BACKGROUND: Intestinal ischemia and reperfusion injury results in damage to elements critical to maintaining intestinal barrier function, including neurons and glia cells, which are part of the enteric nervous system (ENS). To limit inflammation, the ENS must be restored or replaced, yet the process by which this occurs is poorly understood. Multipotent progenitor cells called enteric nervous stem cells (ENSC) can differentiate into neurons or glia when stimulated. The ability of this cell population to respond to intestinal injury is unknown. In this study, we hypothesized that resolution of intestinal barrier injury would be associated with vagus nerve-mediated expansion of ENSCs. STUDY DESIGN: Ischemia and reperfusion injury was reproduced in male mice by occluding the superior mesenteric artery for 30 minutes. Abdominal vagotomy was performed in a separate cohort to study the effects of the vagus nerve. Terminal ileum was harvested at various time points after reperfusion and analyzed with histology, flow cytometry, and immunohistochemistry. RESULTS: Enteric nervous stem cell expansion occurs at 2, 4, and 8 hours after injury compared with sham (4.6% vs 2.1%; p < 0.001) and correlated with increased glial fibrillary acidic protein on immunohistochemistry. Vagotomy prevented both ENSC expansion and increased glial fibrillary acidic protein staining after injury. Intestinal permeability was restored to baseline by 48 hours after injury, but remained elevated in the vagotomy group compared with sham and injury alone at 48 hours (3.25 mg/mL vs 0.57 mg/mL and 0.26 mg/mL, respectively; p < 0.05). CONCLUSIONS: Vagal-mediated expansion of ENSCs occurs after ischemia and reperfusion injury and results in improved kinetics of injury resolution. (C) 2015 by the American College of Surgeons