Differential effects of metformin on bile salt absorption from the jejunum and ileum

Aims: The antidiabetic drug metformin is often associated with a small reduction in total circulating cholesterol, but the mechanism responsible is unknown. As bile salts contribute significantly to cholesterol homeostasis, this study has investigated the effect of metformin on the absorption of bile salts by the jejunum and ileum, and their transfer into bile. Methods: Sodium-[1-¹⁴C]-glycocholate was administered into the jejunum or ileum of anaesthetized rats with and without metformin (250 mg/kg). Appearance of ¹⁴C-glycocholate in plasma and bile was followed for 150 min. Results: Absorption of ¹⁴C-glycocholate from the ileum, which is a high-capacity active process, was 10-fold greater than absorption from the jejunum, which is mainly a passive process. Metformin increased threefold the absorption of ¹⁴C-glycocholate from the jejunum. Metformin similarly increased the appearance of jejunal ¹⁴C-glycocholate in plasma and bile. In contrast to the jejunum, absorption of ¹⁴C-glycocholate from the ileum was suppressed by more than half with metformin. This was associated with corresponding reductions of ¹⁴C-glycocholate in plasma and bile. Discussion: Thus, metformin induced a large suppression of active bile salt absorption from the ileum compared with a small increase in passive absorption from the jejunum. This suggests that the ileal effect of metformin to reduce overall bile salt absorption could contribute to the modest cholesterol-lowering effect of this drug.