Intestinal Epigenetic Reprogramming Relates to Glycemic Improvement after Roux-en-Y Gastric Bypass Surgery

Despite the remarkable, early remission of T2D after RYGB, the surgery’s key mechanisms have yet to be defined in a way that can be translated to less invasive therapies. Recently, we demonstrated that improved glucose homeostasis after RYGB in rodents is associated with intestinal metabolic reprogramming: the Roux Limb (RL) exhibits dramatic morphologic and metabolic remodeling, leading to augmented utilization of metabolic fuels to support the increased bioenergetic demand. To address whether this phenomenon is important for T2D remission in human patients after RYGB, RL biopsies were obtained at the time of surgery and at 1 and 6 months postoperatively. Differentially expressed genes (DEG) were determined using Affymetrix HTA 2.0 microarrays; morphology was examined via electron microscopy, revealing a significant increase in microvillus length over time (P<0.01). Enrichment analysis showed robust changes cellular proliferation, cell cycle regulation, and cytoskeletal remodeling pathways at both timepoints. DEG suggest a metabolic shift away from fatty acid oxidation, toward utilization of glucose and amino acids. Common DEG (FDR<0.05) at 1 and 6 months were strongly correlated (R²=0.899, P<0.0001), suggesting that RL signatures are established early and persist. Interestingly, 91% of the top 100 DEG at 6 months were downregulated; GSEA revealed significant enrichment of genes regulating epigenetic reprogramming (P<0.01), e.g., DNMT1 and DNMT3B at 1 and 6 months. Remarkably, change in DNMT1 expression at 1 month, controlling for baseline body weight, predicted 6-month HbA1c change (R²=0.744, P=0.002). This suggests a mechanistic role for methylation to underlie glycemic improvement, and points to a potential predictive role for early RL DEG. We hypothesize that post-RYGB T2D improvement may relate to RL remodeling including increased energy utilization, and that the stimulus may be epigenetic reprogramming as a result of altered intestinal nutrient flow.