DOI: 10.37349/eemd.2026.101482 ISSN: 2998-2456

New avenues in metabolic disease treatment: duodenal mucosal resurfacing and gene therapy

Christina Dias, Smit Patel, Tanmay Gaglani, Nirav Thosani
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Metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD) are increasing rapidly worldwide and contribute substantially to morbidity, mortality, and healthcare costs. Current therapies, including glucagon-like peptide-1 receptor agonists (GLP-1RAs), have transformed metabolic disease management but remain limited by high costs, adverse effects, treatment discontinuation, and the need for chronic administration. Duodenal mucosal resurfacing (DMR) and gene therapy represent potential long-term strategies for metabolic disease modulation. DMR is a minimally invasive endoscopic procedure that ablates and regenerates the duodenal mucosa, with clinical studies demonstrating improvements in glycemic control, insulin sensitivity, and liver fibrosis markers in patients with T2DM and MASLD. Although the precise mechanisms remain incompletely understood, recent evidence suggests that DMR may induce significant genetic, enteroendocrine, and gut microbiota changes involving pathways associated with glucose uptake, intestinal differentiation, and metabolic signaling. In parallel, advances in gene therapy using adeno-associated viral (AAV) vectors and lipid nanoparticles (LNPs) have shown potential in sustained modulation of insulin secretion, GLP-1 signaling, and β-cell regeneration. These approaches may overcome several limitations of conventional pharmacotherapy by providing longer-lasting therapeutic effects with fewer pharmacokinetic fluctuations. This review highlights the biological rationale underlying DMR and gene therapy, evaluates current preclinical and clinical evidence, and discusses limitations related to safety, efficacy, delivery specificity, manufacturing scalability, and ethical accessibility. Additionally, it explores the potential intersection between DMR and gene therapy, proposing that genes identified through DMR-mediated metabolic remodeling may serve as future therapeutic targets. This review also hypothesizes how DMR and gene therapy could be used together to have long-lasting complementary effects. Together, these technologies represent promising and potentially complementary strategies that could reshape the therapeutic landscape for obesity, diabetes, and MASLD.

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