Reduced REG3α in obesity and type 2 diabetes is linked to altered intestinal barrier homeostasis and inflammation

The antimicrobial peptide regenerating family member 3α (REG3α) constitutes a critical component of epithelial immunity and microbial homeostasis, but its contribution to obesity-associated intestinal dysfunction remains unclear. We hypothesized that obesity impairs REG3α-mediated epithelial defense, promoting intestinal barrier disruption and inflammation. Circulating REG3α was analyzed in 84 individuals with normal-weight, obesity, and type 2 diabetes (T2D). Jejunal REG3A expression was assessed in a subgroup undergoing bariatric surgery. Additional studies were performed in rats with diet-induced obesity and after sleeve gastrectomy, and in HT-29 intestinal epithelial cells exposed to inflammatory and metabolic stimuli, recombinant REG3α, and REG3A silencing. Circulating REG3α concentrations were markedly reduced (P0.001) in obesity, independent of glycemic status, and positively associated with insulin sensitivity. Jejunal REG3A expression was decreased (P0.05) in individuals with obesity and T2D and correlated with circulating levels. In rats with obesity, jejunal Reg3g expression was suppressed (P0.05) and restored (P0.05) after weight loss induced by sleeve gastrectomy. In HT-29 cells, inflammatory cytokines (IL-33, IL-18), glucose, and lipopolysaccharide induced REG3A expression (P0.01). REG3α modulated epithelial homeostasis by suppressing NLRP3 inflammasome signaling and extracellular matrix remodeling genes (COL1A1, COL6A3, ELN, MMP9; P0.01) and enhancing acute inflammatory mediators (IL1B, IL6; P0.01), tight-junction proteins (CLDN1; P0.01), mucus (MUC2; P0.01), and anti-inflammatory markers (KLF4; P0.01). Conversely, REG3A silencing impaired epithelial repair pathways and CLDN1 expression. Reduced REG3α in obesity and T2D is linked to alterations in epithelial integrity and low-grade inflammation, suggesting that modulation of REG3α may represent a potential strategy to reinforce gut barrier function and metabolic homeostasis.