Ursodeoxycholic acid for trans intestinal cholesterol excretion stimulation: a randomized placebo controlled cross-over study.

ObjectiveThe Trans Intestinal Cholesterol Excretion (TICE) pathway is a potential therapeutic target to reduce plasma low-density lipoprotein (LDL) cholesterol levels. TICE encompasses the direct excretion of cholesterol by enterocytes into feces. In mice TICE has been shown to be stimulated by a hydrophilic bile acid pool, resulting in increased fecal neutral sterols (FNS) loss and reduced plasma cholesterol levels. We investigated whether treatment with a hydrophilic bile acid - ursodeoxycholic acid (UDCA) - would increase FNS in humans as a proxy for TICE. Approach and resultsWe performed a randomized double-blind placebo controlled cross-over trial in 20 male participants aged >18 years, with plasma LDL cholesterol levels [&ge;]2.6mmol/L. After a run-in period of ezetimibe 20mg once daily for three weeks, patients were randomized to UDCA 600mg or placebo orally once daily for two weeks. After a three week wash-out, patients underwent the alternate treatment. At baseline, mean (SD) age, BMI, and plasma LDL cholesterol were 59{+/-}11.3 years, 26.4{+/-}3.1 kg/m2, and 3.9{+/-}0.8 mmol/L, respectively. After UDCA treatment, the plasma bile acid hydrophobicity index was reduced compared to placebo (-115.88% versus +1.85%, p<0.001). The FNS did not change (-5.8% versus +18.8%, p=0.51) and treatment with UDCA increased LDL cholesterol with 0.39 mmol/L (+10.95% versus -3.24%, p=0.002) when compared with placebo. ConclusionUDCA in combination with ezetimibe increased plasma bile acid hydrophilicity in hypercholesterolaemic subjects, but did not result in increased FNS or decreased LDL cholesterol. This suggests that TICE is not stimulated by an increase in the hydrophilicity of the bile acid pool in humans.