Gastric Bypass Elicits Persistent Gut Adaptation and Unique Diabetes Remission-Related Metabolic Gene Regulation

Abstract: Objective: We have previously shown that early intestinal adaptation precedes and relates to metabolic improvement in humans after Roux-en-Y gastric bypass surgery (RYGB). We hypothesized that intestinal adaptation would persist at the one-year postoperative timepoint, and that gene expression (GE) signatures would relate to Type 2 diabetes (T2D) remission, providing insight into potential mechanisms for intestinally-mediated metabolic improvement after RYGB. Methods: We determined GE by RNA-seq in jejunum (Roux limb, RL) collected from 28 patients before and 12 months after RYGB. Results: Global GE from paired baseline and 1-year jejunal samples did not separate according to clinical phenotype (T2D remission, sustained weight loss). In general, GE was consistent with persistent RL remodeling, and microvilli were elongated by 39%. Remodeling was not attenuated in patients with lack of diabetes remission or with weight regain. Patients with diabetes remission demonstrated greater jejunal activation of lipogenesis-related pathways driven by RXR, LXR and SREBP. Conclusions: RL adaptation is a key feature of RYGB in all patients, likely reflecting the dramatic alterations to gastrointestinal anatomy, but jejunal lipogenesis appears to be more strongly activated in those patients with diabetes remission. Further study is needed to understand whether these pathways may drive metabolic remission after RYGB.