Calcitriol/Vitamin D receptor ameliorates fructose-induced enteritis-hepatitis axis dysregulation in mice

Emerging evidence associates excessive fructose consumption with intestinal inflammation and metabolic dysfunction-associated steatotic liver disease (MASLD), though the underlying mechanisms remain elusive. This preclinical study systematically investigated the therapeutic potential of calcitriol/vitamin D receptor (VDR) signaling in counteracting fructose-induced gut-liver axis dysregulation using female C57BL/6J mice. Experimental groups included: (1) Control (C), (2) Fructose (F; 20% w/v fructose water for 8 weeks), (3) Fructose+Calcitriol (F+V; 300 ng/kg calcitriol gavage during weeks 4-8), and (4) Calcitriol alone (V). Key findings revealed that chronic fructose exposure induced gut microbiota dysbiosis (characterized by decreased Firmicutes/Bacteroidetes ratio), compromised intestinal barrier integrity through downregulation of tight junction proteins, depleted secretory cells (Goblet/Paneth cells), and triggered apoptosis with concomitant elevation of pro-inflammatory cytokines (TNF-α, IL-6). These intestinal alterations culminated in endotoxemia-mediated hepatic inflammation and fibrogenesis, accompanied by persistent NF-κB pathway activation. Notably, calcitriol intervention significantly restored VDR expression, enhanced autophagic flux, stimulated mucin/antimicrobial peptide production, and suppressed NF-κB-mediated inflammatory responses. In vitro validation using Caco2 and RAW264.7 cells demonstrated that VDR activation effectively reversed fructose-impaired autophagy and NF-κB hyperactivation. Microbiome analysis further indicated calcitriol's partial normalization of fructose-induced microbial shifts, suggesting microbiota-mediated mechanisms. Collectively, these findings establish that calcitriol/VDR signaling mitigates fructose-driven gut-liver axis dysfunction through coordinated regulation of autophagy, mucosal defense systems, and inflammatory pathways. This mechanistic framework positions the VDR pathway as a promising therapeutic target for enteritis-hepatitis axis disorders, warranting further clinical investigation.