Impaired Iron-Copper Metabolic Axis in Human Intestinal Mucosa After Roux-en-Y Gastric Bypass: A Prospective Transcriptomic Study Using Double-Balloon Enteroscopy

Abstract Background Roux-en-Y gastric bypass (RYGB) effectively leads to weight loss in patients with severe obesity but is often accompanied by refractory iron deficiency. The molecular mechanisms governing the human intestinal copper-iron metabolic axis post-surgery remain poorly defined. This study evaluated the longitudinal impact of RYGB on intestinal gene expression related to micronutrient homeostasis. Methods In a prospective study of 20 women (body mass index, BMI 46.5 ± 5.3 kg/m²), intestinal mucosa biopsies were collected via double-balloon enteroscopy (DBE) pre- and three months post-RYGB from anatomically marked sites in the duodenum, jejunum, and ileum. Gene expression was assessed using Affymetrix microarrays, with Ceruloplasmin (CP) validated by RT-qPCR. Results Three months post-RYGB, BMI significantly ( p < 0.05) decreased to 38.2 ± 4.2 kg/m². Microarray analysis revealed segment-specific adaptations. Divalent metal transporter 1 (DMT1) was significantly ( p < 0.05) upregulated in the bypassed duodenum (+ 0.421), indicating a local compensatory response to decreased iron availability. Conversely, CP expression was significantly downregulated across all segments, notably in the jejunum (− 1.017; p < 0.05). This downregulation, confirmed by RT-qPCR, suggests impaired iron oxidation and mobilization. Lysyl oxidase (LOX), a copper-dependent enzyme critical for mucosal structural integrity, was also significantly downregulated in the duodenum (− 0.333; p < 0.05) and jejunum (− 0.450; p < 0.05). Conclusion RYGB induces early and segment-specific transcriptional adaptations in the intestinal mucosa. The upregulation of DMT1 in the bypassed duodenum suggests a compensatory response, whereas the consistent downregulation of CP and LOX indicates a potential alteration in the copper–iron metabolic axis. These findings provide a biologically plausible framework for postoperative micronutrient disturbances; however, in the absence of functional and biochemical data, causal relationships cannot be established.