Alterations in gut microbiota during remission and recurrence of diabetes after duodenal-jejunal bypass in rats

AIM: To observe the alterations in gut microbiota in high-fat diet(HFD)-induced diabetes recurrence after duodenal-jejunal bypass(DJB) in rats. METHODS: We assigned HDF- and low-dose streptozotocin-induced diabetic rats into two major groups to receive DJB and sham operation respectively. When the DJB was completed, we used HFD to induce diabetes recurrence. Then, we grouped the DJB-operated rats by blood glucose level into the DJB-remission(DJB-RM) group and the DJB-recurrence(DJB-RC) group. At a sequence of time points after operations, we compared calorie content in the food intake(calorie intake), oral glucose tolerance test, homeostasis model assessment of insulin resistance(HOMA-IR), concentrations of glucagon-like peptide 1(GLP-1), serum insulin, total bile acids(TBAs) and lipopolysaccharide(LPS) and alterations in colonic microbiota.RESULTS: The relative abundance of Firmicutes in the control(58.06% ± 11.12%; P < 0.05 vs sham; P < 0.05 vs DJB-RC) and DJB-RM(55.58% ± 6.16%; P < 0.05 vs sham; P < 0.05 vs DJB-RC) groups was higher than that in the sham(29.04% ± 1.36%) and DJB-RC(27.44% ± 2.17%) groups; but the relative abundance of Bacteroidetes was lower(control group: 33.46% ± 10.52%, P < 0.05 vs sham 46.88% ± 2.34%, P < 0.05 vs DJB-RC 47.41% ± 5.67%. DJB-RM group: 34.63% ± 3.37%, P < 0.05 vs sham; P < 0.05 vs DJB-RC). Escherichia coli was higher in the sham(15.72% ± 1.67%, P < 0.05 vs control, P < 0.05 vs DJB-RM) and DJB-RC(16.42% ± 3.00%; P < 0.05 vs control; P < 0.05 vs DJB-RM) groups than in the control(3.58% ± 3.67%) and DJB-RM(4.15% ± 2.76%) groups. Improved HOMA-IR(2.82 ± 0.73, P < 0.05 vs DJB-RC 4.23 ± 0.72), increased TBAs(27803.17 ± 4673.42 ng/m L; P < 0.05 vs DJB-RC 18744.00 ± 3047.26 ng/m L) and decreased LPS(0.12 ± 0.04 ng/m L, P < 0.05 vs DJBRC 0.19 ± 0.03 ng/m L) were observed the in DJB-RM group; however, these improvements were reversed in the DJB-RC group, with the exception of GLP-1(DJB-RM vs DJB-RC P > 0.05). CONCLUSION: Alterations in gut microbiota may be responsible for the diabetes remission and recurrence after DJB, possibly by influencing serum LPS and TBAs.

Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats

BACKGROUND The mechanisms underlying diabetes remission after duodenal-jejunal bypass(DJB) remain elusive. In DJB surgery, the duodenum is excluded. However, the duodenum has emerged as an important regulator of glucose homeostasis, and elevated duodenal SIRT1 leads to improved hepatic insulin sensitivity. After DJB, bile acids(BAs) in the duodenum are not mixed and diluted by the ingested food. And activation of BA receptors promotes SIRT1 expression in many tissues. We hypothesized that BA-mediated upregulation of SIRT1 may contribute to diabetic control after DJB.AIM To investigate the surgical effects of DJB on duodenal SIRT1 expression and uncover the potential crosslinks between BAs and SIRT1.METHODS Twenty diabetic rats were randomly allocated to the sham(n = 10) and DJB(n = 10) groups. Body weight, food intake, fasting blood glucose(FBG), serum and intraduodenal total BA(TBA) levels were measured accordingly. Oral glucose tolerance test(OGTT) and intraperitoneal pyruvate tolerance test(ip PTT) were performed to evaluate the effects of surgeries on systemic glucose disposal and hepatic gluconeogenesis. The key genes of BA signaling pathway in the duodenal mucosa, including farnesoid X receptor(FXR), small heterodimer partner(SHP), and Takeda G-protein-coupled receptor 5(TGR5) were evaluated by real-time quantitative polymerase chain reaction 8 wk postoperatively. The duodenal SIRT1, AMPK, and phosphorylated AMPK(p-AMPK) levels were evaluated by western blotting. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BAs on SIRT1 expression in enterocytes.RESULTS The DJB group exhibited body weight and food intake comparable to those of the sham group at all postoperative time points. The FBG level and area under the curve for the OGTT and ip PTT were significantly lower in the DJB group. The DJB group exhibited higher fasting and postprandial serum TBA levels than the sham group at both 2 and 8 wk postoperatively. At 8 wk after surgery, the DJB group showed higher intraluminal TBA concentration, upregulated m RNA expression of FXR and SHP, and elevated protein expression of SIRT1 and p-AMPK in the descending and horizontal segments of the duodenum. Activation of FXR and TGR5 receptors by GW4064 and INT-777 increased the m RNA and protein expression of SIRT1 and promoted the phosphorylation of AMPK in IEC-6 cells.CONCLUSION DJB elevates intraduodenal BA levels and activates the duodenal BA signaling pathway, which may upregulate duodenal SIRT1 and further contribute to improved glucose homeostasis after DJB.

Duodenal-jejunal bypass reduces serum ceramides via inhibiting intestinal bile acid-farnesoid X receptor pathway

BACKGROUND Bile acids play an important role in the amelioration of type 2 diabetes following duodenal-jejunal bypass(DJB).Serum bile acids are elevated postoperatively.However,the clinical relevance is not known.Bile acids in the peripheral circulation reflect the amount of bile acids in the gut.Therefore,a further investigation of luminal bile acids following DJB is of great significance.AIM To investigate changes of luminal bile acids following DJB.METHODS Salicylhydroxamic acid(SHAM),DJB,and DJB with oral chenodeoxycholic acid(CDCA)supplementation were performed in a high-fat-diet/streptozotocininduced diabetic rat model.Body weight,energy intake,oral glucose tolerance test,luminal bile acids,serum ceramides and intestinal ceramide synthesis were analyzed at week 12 postoperatively.RESULTS Compared to SHAM,DJB achieved rapid and durable improvement in glucose tolerance and led to increased total luminal bile acid concentrations with preferentially increased proportion of farnesoid X receptor(FXR)-inhibitory bile acids within the common limb.Intestinal ceramide synthesis was repressed with decreased serum ceramides,and this phenomenon could be partially antagonized by luminal supplementation of FXR activating bile acid CDCA.CONCLUSION DJB significantly changes luminal bile acid composition with increased proportion FXR-inhibitory bile acids and reduces serum ceramide levels.There observations suggest a novel mechanism of bile acids in metabolic regulation after DJB.

A high-fat diet reverses improvement in glucose tolerance induced by duodenal-jejunal bypass in type 2 diabetic rats

Background Bariatric surgery offers successful resolution of type 2 diabetes mellitus （T2DM）. However, recurrence of T2DM has been observed in a number of patients with initial resolution after bariatric surgery. This study aimed to induce reversal of the improvement of diabetes in T2DM rats after duodenal-jejunal bypass （DJB）, and identify the effects of weight changes and gut hormones that might be involved.

Duodenal-jejunal bypass surgery on type 2 diabetic rats reduces the expression of matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 in the thoracic aorta

Background Bariatric surgery offers a productive resolution of type 2 diabetes mellitus （T2DM）.The development of T2DM vasculopathy is due to chronic inflammation,which increases matrix metalloproteinase-9 （MMP-9） and tissue inhibitor of matrix metalloproteinase-1 （TIMP-1） expression.This study sought to examine MMP-9 and TIMP-1 expression in the thoracic aorta after duodenal-jejunal bypass （DJB） surgery on a T2DM rat model induced by a high-fat diet and low dose streptozotocin （STZ）.Methods Twenty-one T2DM Wistar rats induced by high-fat diet and low dose STZ were randomly divided into DJB and sham duodenal-jejunal bypass （S-DJB） groups.Ten Wistar rats were fed a normal diet as a control.Recovery of gastrointestinal function post-operation and resumption of a normal diet completed the experiment.Body weight,blood glucose,blood lipid levels,and MMP-9 and TIMP-1 expression levels in aortic endothelial cells were measured throughout.Results DJB rats showed significant weight loss 2 weeks post-operation compared with S-DJB rats.After surgery,DJB rats showed significant improvement and steady glycemic control with improved insulin sensitivity and glucose tolerance.They also exhibited improved lipid metabolism with a decrease in fasting free fatty acids （FFAs） and triglycerides （all P ＜0.05）.Immunohistochemistry showed decreased MMP-9 and TIMP-1 expression 12 weeks after surgery （P ＜ 0.01）.Conclusions DJB surgery on an induced T2DM rat model improves blood glucose levels and lipids,following a high-fat diet and low dose STZ treatment.In addition,DJB decreased MMP-9 and TIMP-1 expression in vascular endothelial cells,which may play an important role in delaying the development of T2DM vascular disease.