Impact of intestinal propionate metabolism on systemic metabolic homeostasis

Propionate is an abundant short-chain fatty acid largely derived from gut microbiota in mammals. Propionate metabolism is essential to maintain systemic homeostasis, and inborn errors of essential metabolic enzymes in this pathway cause severe illness. The juxtaposition of high concentrations of propionate with the intestinal epithelium suggests a need for propionate catabolism. To understand the requirement of propionate metabolism in intestinal epithelium, we generated mice with a conditional knockout of propionyl-CoA carboxylase A (Pcca) specifically in the intestine (Pcca^Vil-Cre). Male and female Pcca^Vil-Cre mice were born and weaned at the expected Mendelian ratio and gained weight normally on chow and high-fat diets. Liver metabolomics of Pcca^Vil-Cre mice suggest that propionate metabolism affects the gut-liver axis. However, the loss of Pcca in the intestine did not affect the colonic transcriptome. These data suggest that intestinal propionate metabolism is largely dispensable, and that hepatic capture and metabolism of propionate dominate systemic physiology.NEW & NOTEWORTHY Propionate generated by the microbiome is extremely high in the lumen of the gut. To determine the requirement of propionate metabolism in the gut, we generated and characterized mice with an intestine-specific knockout of propionyl-CoA carboxcylase alpha (PCCA), the first step in propionyl-CoA metabolism. Overall, mice that are unable to use propionate in the intestine are relatively normal with alterations in the gut-liver axis.