The beneficial metabolic effects of soluble dietary fiber are thought to be owing to its fermentation by gut bacteria into short-chain fatty acids. Gilles Mithieux and his colleagues found that the healthful effects of these fatty acids depend on their stimulation of intestinal gluconeogenesis, in part through a gut-brain neural circuit (Cell, 156, 84–96, 2014).

Mice fed soluble fiber or either of two short-chain fatty acids—butyrate or proprionate—showed an improved metabolic profile, with increased glucose tolerance and insulin sensitivity. Both butyrate and proprionate stimulated intestinal gluconeogenesis, but they use different mechanisms. Whereas butyrate had direct effects on intestinal cells, proprionate acted indirectly, via the nervous system. In this neural circuit, proprionate seems to act through the fatty acid receptor FFAR3 on nerve fibers of the portal vein, resulting in activation of several regions in the brain and spinal cord.

Intestinal gluconeogenesis was needed for the beneficial effects of soluble fiber or short fatty acids, as neither dietary intervention improved the metabolic profile of mice with an intestine-specific deficiency of the key gluconeogenic enzyme glucose-6-phosphatase.