Gut microbiota-derived L-theanine promotes host branched-chain amino acid catabolism

Elevated levels of serum branched-chain amino acids (BCAA) are linked to various metabolic disorders such as obesity, insulin resistance and type 2 diabetes. Although gut microbiota can regulate circulating BCAA levels via direct transformation, here we uncover an indirect mechanism that influences host BCAA metabolism. Comparisons between the metabolome and gut microbiota of germ-free and wild-type mice and pigs revealed Lactobacillus reuteri and its metabolite L-theanine to be associated with increased BCAA catabolism. This effect was reproduced by monocolonization of the animals with Lactobacillus reuteri or treatment with L-theanine. Experiments with pig cell lines showed that L-theanine enhanced the expression of branched-chain aminotransferases (BCATs), host enzymes involved in BCAA catabolism. Specifically, L-theanine promoted the expression of BCAT2 mRNA by suppressing its histone methylation and stabilizing the BCAT2 protein by inhibiting ubiquitination of specific lysine residues. Our findings provide a potential avenue for development of therapies against disorders associated with elevated BCAA levels.