3-Hydroxybutyrate could serve as a principal energy substrate for human microbiota

3-Hydroxybutyrate (3HB) is a ketone body present in the lumen of the large intestine. Although the circulatory system regulates 3HB at around 0.1 mM, its concentration in the gut lumen is about 0.3 mM, possibly due to its high production by the gut epithelial cells. The mitochondrial rate-limiting enzyme, 3-hydroxy-3-methylglutarylCoA synthase 2 (HMGCS2), is responsible for 3HB production and was highly expressed in the epithelial cells. Thus, maintaining HMGCS2 expression is crucial for supplying 3HB to the microbiota. Herein, we proposed that the microbiota consumes 3HB produced by the gut epithelial cells by creating a physiological positive shuttle system called "Ketone Body-Butyrate Shuttle" between the gut epithelial cells and microbiota. Its decline may lead to aging of the gut environment. This shuttle might aid the mammals and microbiota to survive severe starvation by using 3HB. In addition, we propose that poly-beta-hydroxybutyrate (PHB), a ketone donor to microbiotas, may be a specific activator of the ketone body-butyrate shuttle since PHB can donate 3HB to microbiotas in the large intestine.