Alteration of gut bacteria and metabolomes after glucaro-1,4-lactone treatment contributes to the prevention of hypercholesterolemia.

ABSTRACT

D-Glucaro-1,4-lactone (1,4-GL) has been shown to have a hypocholesterolemic effect in rats and human subjects. However, little information is known concerning the alteration of metabolome associated with the effect. Here, we show that 1,4-GL delays the development of hypercholesterolemia with the coadministration of a high-fat, high-cholesterol diet (HFHC) in rats. Metabonomic results based on proton nuclear magnetic resonance indicate that urinary trimethylamine N-oxide, trimethylamine, lactate, acetate, formate, and creatinine are significantly altered after 1,4-GL and HFHC treatments. Colonic flora test results reveal that the quantity of Bifidobacterium and Lactobacillus in the intestines respectively increase by about 1.7- and 4.2-fold in rats treated with 1,4-GL compared with those in the control group. Rats that were coadministered with HFHC and 1,4-GL exhibit normal levels of lactate and acetate in serum and display urinary excretions of lactate and acetate that are 2 to 3 times higher compared with those treated with HFHC alone. The results imply that the increased probiotic quantities and urinary excretion of breakdown products of fat/cholesterol after 1,4-GL treatment contribute to the prevention of hypercholesterolemia. Our study offers insights into the model of action for 1,4-GL in preventing hypercholesterolemia.