Influence of Roux-en-Y gastric bypass surgery on the gene expression and microRNA in the small intestine

H Bruckmueller1, S Oswald2, R Häsler1, K Ludwig3, W Siegmund2, I Cascorbi1. 1Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, Kiel, Germany, 2Department of Clinical Pharmacology, University of Greifswald, Greifwald, Germany, 3Department of Surgery, Clinic Südstadt, Rostock, Germany

Introduction: Obesity is an increasing global health problem, associated with numerous comorbidities including type 2 diabetes mellitus, hyperlipidemia, hypertension. Despite all preventive and therapeutic efforts, long-term weight loss often fails. Bariatric surgery procedures like Roux-en-Y gastric bypass (RYGB) are well accepted, causing a significant reduction of body weight and obesity-related comorbidity. RYGB leads to massif antatomical changes in the upper small intestine., In particular the jejunum is subjected to highly altered influences after surgery. The aim of our study was to investigate these changes in the small intestine as well as potential intestinal adaptation processes. To address this issue, we did a gene and microRNA expression profiling of duodenum and the jejunum before and of jejunum after RYGB. Furthermore, pathways involved in intestinal adaptation processes as well as microRNA- target gene interactions were studied.

Methods: Biopsies from twelve obese patients were obtained during RYGB (duodenum, jejunum) and one year later (only jejunum). mRNA expression was analyzed by Affymetrix Human Gene 1.0 ST chip while microRNA expression was analysed by TaqMan Low-Density Arrays Pool A+B. A selection of significant deregulated genes and microRNAs were confirmed in individual TaqMan gene expression or TaqMan microRNA assays. To define overrepresented pathways among the significant deregulated genes a gene ontology analysis was performed. MicroRNA target prediction was conducted using TargetScan, Diana and the miRanda algorithm. For studying microRNA-target gene 3’UTR interactions luciferase assays were performed.

Results: We found significant mRNA expression differences comparing duodenal and relocated jejunal tissue one year after RYGB and within jejunal tissue before and after RYGB. In particular genes related to cholesterol metabolism were significant deregulated (HMGCS2 FC=-5.57, INSIG1 FC04.17, LDLR FC=2.02; p<0.05). MicroRNA expression varied significantly between duodenal and jejunal tissue before surgery and within jejunal tissue before and after RYGB (has-miR-130a FC=-2.06, has-miR-454 FC=-2.38, p<0.05). Inverse correlation of microRNA and predicted target mRNA expression were found for cholesterol metabolism related genes like INSIG1 and LDLR.

Conclusion: RYGB leads to a strong change of the mucosal gene expression profile in the relocated jejunum during one year possibly due to altered external influences as evidenced by the change of the initial jejunal microRNA to the profile of the initial duodenum.