The gut microbiota contributes to the modulation of intestinal CYP3A1 and P-gp in streptozotocin-induced type 1 diabetic rats

Abstract

Hepatic and intestinal CYP3A and P-gp in diabetic rats exhibit opposite expression patterns. However, the underlying mechanisms remain unclear. In this study, CYP3A1 and P-gp protein and mRNA expression levels in liver and different intestinal segments (duodenum, jejunum, ileum and colon) were compared between diabetic and normal rats. The microbiota in the ileum and colon contents was analyzed via 16S rRNA high-throughput sequencing technology. Caco-2 cells were incubated with serum or culture supernatant of colon contents from diabetic and normal rats, and CYP3A4 and ABCB1 mRNA levels were measured. Compared with that in normal rats, hepatic CYP3A1 and P-gp protein expression in diabetic rats was increased. CYP3A1 and P-gp protein was not changed in the duodenum and jejunum but significantly decreased by 29-41% in the ileum and colon of diabetic rats. Cyp3a1 and Abcb1a mRNA expression results were similar to the protein expression results. The composition of some bacteria changed significantly in the ileum and colon of diabetic rats compared with normal rats. CYP3A1 and P-gp protein expression was positively correlated with Lachnoclostridium and unclassified_f_Ruminococcaceae but negatively correlated with Clostridium_sensu_stricto_1, Turicibacter, Ruminococcaceae_UCG-005 and several genera belonging to the family Prevotellaceae. In addition, in vitro cell culture experiments showed that serum from diabetic rats significantly induced CYP3A4 and ABCB1 mRNA expression, while the supernatant of colon contents of diabetic rats significantly reduced CYP3A4 and ABCB1 mRNA expression by 45% and 86% respectively in Caco-2 cells. In conclusion, diabetes exhibited synchronous and regional effects on CYP3A and P-gp expression in the intestinal tract, in which gut microbiota dysbiosis might play an important role.