Multi-omics Analysis Reveals the Crucial Mediators of DJB in the Treatment of Type 2 Diabetes

Purpose Duodenal-jejunal bypass (DJB) has a definite hypoglycemic effect; however, the intrinsic mechanisms remain unclear. The purpose of this study was to determine whether DJB may cause changes in the gut microbiota and metabolite of portal venous blood and to explore the effects of DJB on blood glucose metabolism. Methods T2DM was induced in rats with a high-fat diet and a low dose of streptozotocin, which were randomly divided into two groups: Sham operation and DJB. Results DJB significantly improved several diabetic parameters. 16S rRNA analyses showed that the compositions of the gut microbiota were significantly different between the two groups. The results of metabolomics showed that DJB could significantly regulate the metabolites, among which diaminopimelic acid and isovaleric acid had a significant down-regulation in the DJB group. Transcriptomic analysis showed that DJB can regulate the expression of hepatic genes related to abnormal glucose metabolism, such as Ltc4s, Alox15, Ggt1, Gpat3, and Cyp2c24. Correlation analyses showed that diaminopimelic acid was positively associated with Allobaculum , Serratia , and Turicibacter . There was a significant correlation between diaminopimelic acid and Gpat3, and its Spearman correlation coefficient was the highest among metabolite-DEG pairs ( ρ =0.97). Discussions These results suggest an important cue of the relation between the diaminopimelic acid, Gpat3, and gut microbiome in the mechanism by which DJB can improve glucose metabolism. Graphical Abstract