Effect of Gestational Diabetes on Postpartum Depression-like Behavior in Rats and Its Mechanism

Abstract

Recent studies have reported a strong association between gestational diabetes mellitus (GDM) and postpartum depression (PPD), but little is known about the underlying physiological mechanism. In this study, a GDM rat model was used to evaluate the direct effect of GDM on PPD and to explore the mechanism. After parturition, the GDM dams were divided into two groups: blood glucose not recovered group (GH group) and blood glucose recovered group (GL group). Fasting plasma glucose (FPG), cortisol (COR) and serotonin (5-hydroxytryptamine, 5-HT) metabolism were continuously monitored during the lactation period, until postnatal day 21. PPD was evaluated by behavioral tests. At the endpoint, the expression of the key enzymes of Trp metabolic pathway in colon and brain tissues was analyzed by immunohistochemistry and western blot. The microbe composition of colonic contents was determined by 16S rDNA gene sequencing. The results showed that GDM induced postpartum depression-like behavior in rats. The HPA axis hormone did not show the typical stress state of depression, but the level of 5-HT decreased significantly in serum, prefrontal cortex and hippocampus, and the Kyn/Trp ratio increased significantly in serum and prefrontal cortex, implying the switch of the tryptophan (Trp) metabolism from the 5-HT pathway to the kynurenine (Kyn) pathway. The expression of Indoleamine 2,3-dioxygenase (IDO), a key rate-limiting enzyme in Kyn metabolism, was up-regulated in the colon and brain, which was an important reason for this switch. This switch was accelerated by a decrease in the expression of tryptophan hydroxylase (TPH), a key enzyme of the 5-HT production pathway, in the colon. GDM dams displayed significant changes in gut microbiome profiles, which were correlated with depression. The ratio of Firmicutes to Bacteroidetes decreased. Lactobacillus and Bacteroides were negatively correlated with 5-HT level and positively correlated with Kyn level, whereas Clostridium XlVa and Ruminococcus were positively correlated with 5-HT level. These results suggest that GDM disrupts both the Trp pathway and the composition of the gut microbiota, which provide a putative physiological basis for PPD.