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The vagus nerve regulates immunometabolic homeostasis in the ovine fetus near term: impact on terminal ileum

The contribution of the vagus nerve to inflammation and glucosensing in the fetus is not understood. We hypothesized that vagotomy (Vx) will trigger a rise in systemic glucose levels and this will be enhanced during systemic and organ-specific inflammation. Efferent vagus nerve stimulation (VNS) should reverse this phenotype. Near-term fetal sheep (n=57) were surgically prepared with vascular catheters and ECG electrodes as control and treatment groups (lipopolysaccharide (LPS), Vx+LPS, Vx+LPS+selective efferent VNS). Fetal arterial blood samples were drawn for 7 days to profile inflammation (IL-6), insulin, blood gas and metabolism (glucose). At 54 h, a necropsy was performed; terminal ileum macrophages; CD11c (M1 phenotype) immunofluorescence was quantified to detect inflammation. Across the treatment groups, blood gas and cardiovascular changes indicated mild septicemia. At 3 h, in the LPS group IL-6 peaked; that peak was decreased in Vx+LPS400 and doubled in Vx+LPS800 group; the efferent VNS sped up the reduction of the inflammatory response profile over 54 h. M1 macrophage activity was increased in the LPS and Vx+LPS800 groups only. Glucose and insulin levels in the Vx+LPS group were respectively 1.3-fold and 2.3-fold higher vs. control at 3 h, and the efferent VNS normalized glucose levels. Complete withdrawal of vagal innervation results in a 72h delayed onset of sustained increase in glucose levels for at least 54h and intermittent hyperinsulinemia. Under conditions of moderate fetal inflammation, this is related to higher levels of gut inflammation; the efferent VNS reduces the systemic inflammatory response as well as restores both the levels of glucose and terminal ileum inflammation, but not the insulin levels. Our findings reveal a novel regulatory, hormetic, role of the vagus nerve in the immunometabolic response to endotoxin in near-term fetuses.