Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 21, 2022; 28(31): 4338-4350
Published online Aug 21, 2022. doi: 10.3748/wjg.v28.i31.4338
Duodenal-jejunal bypass increases intraduodenal bile acids and upregulates duodenal SIRT1 expression in high-fat diet and streptozotocin-induced diabetic rats
Hai-Feng Han, Shao-Zhuang Liu, Xiang Zhang, Meng Wei, Xin Huang, Wen-Bin Yu
Hai-Feng Han, Shao-Zhuang Liu, Xiang Zhang, Meng Wei, Xin Huang, Wen-Bin Yu, Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, Shandong Province, China
Author contributions: Han HF and Yu WB conceived of the experiments; Liu SZ and Yu WB designed the experiments; Han HF, Zhang X, Wei M, and Huang X carried out the experiments, performed the statistical analyses and wrote the manuscript; and all authors have commented on the initial and final drafts of the manuscript and approved the final version of the article.
Supported by the National Natural Science Foundation of China, No. 81600617, 81700708, 81702647 and 82100853; and the Natural Science Foundation of Shandong Province, No. ZR2020MH246, ZR2021LZL003 and ZR2021QH028.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care Committee of Cheeloo College of Medicine, Shandong University, (Protocol No. 19085).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wen-Bin Yu, MD, PhD, Chief Doctor, Professor, Department of General Surgery, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 107 West Wenhua Road, Jinan 250012, Shandong Province, China. wenbin_yu2003@163.com
Received: May 26, 2022
Peer-review started: May 26, 2022
First decision: June 19, 2022
Revised: June 28, 2022
Accepted: July 25, 2022
Article in press: July 25, 2022
Published online: August 21, 2022
Processing time: 82 Days and 2.6 Hours
ARTICLE HIGHLIGHTS
Research background

Duodenal-jejunal bypass (DJB) induces rapid and significant amelioration of type 2 diabetes mellitus in various diabetic rat models, while the mechanisms have not been fully elucidated. Duodenal SIRT1 regulates hepatic glucose production and hepatic insulin sensitivity through a gut-brain-liver axis, and activation of bile acid (BA) receptors promotes SIRT1 expression in many tissues. This study aimed at uncovering the roles of duodenal BAs and SIRT1 in the diabetic control after DJB.

Research motivation

To expand and deepen our understanding on the mechanisms underlying diabetes control after DJB, and to provide new ideas and targets for the non-surgical treatment of diabetes in the future.

Research objectives

To investigate the effects of DJB on the duodenal BA signaling pathway and SIRT1 expression in a diabetic rat model, and further reveal the roles of BAs in modulating SIRT1 expression in enterocytes.

Research methods

DJB and sham surgeries were performed on rats with diabetes induced by high-fat diet and low-dose streptozotocin. The effects of surgeries on metabolic parameters were compared accordingly. The intraduodenal BA concentration, the key genes of BA signaling pathway and SIRT1 in the duodenal mucosa were evaluated 8 wk postoperatively. Rat small intestine epithelial IEC-6 cells were treated with GW4064 and INT-777 to verify the effects of BA receptor activation on SIRT1 expression in enterocytes.

Research results

DJB rapidly and dramatically improved glucose homeostasis in the diabetic rats independently of body weight and food intake. DJB increased both systemic and intraduodenal total BAs, activated the BA signaling pathway and promoted SIRT1 expression in the duodenum mucosa. Activation of BA receptors including farnesoid X receptor and Takeda G-protein-coupled receptor 5 increased the mRNA and protein expression of SIRT1 in IEC-6 cells.

Research conclusions

DJB increases intraduodenal BA levels and activates the duodenal BA signaling pathway, which may further contribute to the improved hepatic insulin resistance and glucose homeostasis by upregulating SIRT1 expression in the duodenal mucosa.

Research perspectives

Our findings provide evidence that BA-mediated upregulation of SIRT1 in the duodenum contributes to the diabetic control after DJB. This study also implicates that duodenal BAs and SIRT1 might be potential targets for improving hepatic insulin sensitivity and systemic glucose homeostasis, which lays the groundwork for developing duodenal BA and SIRT1-specific treatments to alleviate diabetes.