The gut microbiota (GM) plays a beneficial role in host metabolism. In mammals, the GM ferments dietary fiber into short chain fatty acids (SCFA), like propionate, that improves glucose metabolism. Rats fed a propionate diet increased intestinal gluconeogenic (IGN) gene expression, which was blocked by treatment with the neurotoxin, capsaicin, suggesting a neuronal-dependent mechanism. We hypothesized that the gut neuropeptide, vasoactive intestinal peptide (VIP), links GM derived propionate to IGN expression. We fed VIP deficient mice a 5% propionate chow diet (n=60) for 2 weeks and measured mRNA levels for GN genes by dPCR. Basel intestinal and liver GN mRNA expression was dysregulated by the loss of VIP. GN mRNA levels in liver were differentially altered in males versus females fed a propionate diet in a VIP-dependent manner. We conclude that VIP regulates basal intestinal and hepatic GN mRNA expression and mediates propionate induced GN mRNA changes in liver.