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 (P<0.001) in obesity, independent of glycemic status, and positively associated with insulin sensitivity. Jejunal REG3A expression was decreased (P<0.05) in individuals with obesity and T2D and correlated with circulating levels. In rats with obesity, jejunal Reg3g expression was suppressed (P<0.05) and restored (P<0.05) after weight loss induced by sleeve gastrectomy. In HT-29 cells, inflammatory cytokines (IL-33, IL-18), glucose, and lipopolysaccharide induced REG3A expression (P<0.01). REG3α modulated epithelial homeostasis by suppressing NLRP3 inflammasome signaling and extracellular matrix remodeling genes (COL1A1, COL6A3, ELN, MMP9; P<0.01) and enhancing acute inflammatory mediators (IL1B, IL6; P<0.01), tight-junction proteins (CLDN1; P<0.01), mucus (MUC2; P<0.01), and anti-inflammatory markers (KLF4; P<0.01). 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.