  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.
