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<p>Vitamin D3 has been shown to exert a protective effect on intestinal barrier function in sepsis. TLR4 may be a key link in this process. However, the precise mechanism of action in intestinal epithelial cells during sepsis remains unclear. A rat sepsis model was established by CLP.VD3 was administered via intraperitoneal injection at 50&#xa0;µg/kg. IHC was employed to detect TLR4 and Lgr5 + cells. AB-PAS staining identified goblet cells. HE staining evaluated Paneth cells. LYZ and DEF-5 expression was performed to assess the function of Paneth cells. RT-PCR detected MUC1, MUC2 and VDR expression. Western blotting detected intestinal tight junction proteins and ER stress biomarkers.16S rRNA gene sequencing characterized gut microbiota composition, and functional potential was predicted using KEGG pathway analysis. Following VD3 intervention, TLR4 expression in the intestinal tissue of septic rats was significantly reduced. Histological improvements included less intestinal epithelial degeneration and shedding, repaired mucosa, villus hyperplasia, and a more ordered villous arrangement. Paneth cell and goblet cell numbers significantly increased, along with their restoration of secretory function. Tight junction protein expression was improved, and overactivated IRE1/sXBP1-mediated ER stress was markedly inhibited. Interestingly, Lgr5 + intestinal stem cell numbers were paradoxically elevated in the sepsis group and were reduced following VD3 intervention, suggesting a shift from excessive proliferation toward differentiation that facilitates mucosal repair. VD3 treatment also improved gut microbiota diversity, partially restored the Firmicutes/Proteobacteria ratio, and specifically enriched Dubosiella as identified by LEfSe analysis. Our results suggest that VD3 ameliorates sepsis-induced intestinal epithelial cell injury by suppressing TLR4-mediated IRE1/sXBP1 ER stress, restoring Paneth and goblet cell number and secretory function, improving intestinal mechanical barrier integrity, and reshaping gut microbiota toward a more eubiotic configuration. The reduction in Lgr5 + ISC numbers following VD3 intervention likely reflects a shift from excessive self-proliferation toward differentiation, facilitated by normalization of the inflammatory stem cell niche, restoration of balanced Wnt/Notch signals from recovered Paneth and goblet cells, and VD3-induced microbiota changes that promote epithelial maturation. </p>

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Vitamin D3 reverses intestinal epithelial cell injury in septic rats by alleviating toll-like receptor 4 mediated endoplasmic reticulum stress

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月21日

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  • Ting Li,
  • Dapeng Zhang,
  • Xue Wu,
  • Lihong Dong,
  • Yijie Wang

摘要

Vitamin D3 has been shown to exert a protective effect on intestinal barrier function in sepsis. TLR4 may be a key link in this process. However, the precise mechanism of action in intestinal epithelial cells during sepsis remains unclear. A rat sepsis model was established by CLP.VD3 was administered via intraperitoneal injection at 50 µg/kg. IHC was employed to detect TLR4 and Lgr5 + cells. AB-PAS staining identified goblet cells. HE staining evaluated Paneth cells. LYZ and DEF-5 expression was performed to assess the function of Paneth cells. RT-PCR detected MUC1, MUC2 and VDR expression. Western blotting detected intestinal tight junction proteins and ER stress biomarkers.16S rRNA gene sequencing characterized gut microbiota composition, and functional potential was predicted using KEGG pathway analysis. Following VD3 intervention, TLR4 expression in the intestinal tissue of septic rats was significantly reduced. Histological improvements included less intestinal epithelial degeneration and shedding, repaired mucosa, villus hyperplasia, and a more ordered villous arrangement. Paneth cell and goblet cell numbers significantly increased, along with their restoration of secretory function. Tight junction protein expression was improved, and overactivated IRE1/sXBP1-mediated ER stress was markedly inhibited. Interestingly, Lgr5 + intestinal stem cell numbers were paradoxically elevated in the sepsis group and were reduced following VD3 intervention, suggesting a shift from excessive proliferation toward differentiation that facilitates mucosal repair. VD3 treatment also improved gut microbiota diversity, partially restored the Firmicutes/Proteobacteria ratio, and specifically enriched Dubosiella as identified by LEfSe analysis. Our results suggest that VD3 ameliorates sepsis-induced intestinal epithelial cell injury by suppressing TLR4-mediated IRE1/sXBP1 ER stress, restoring Paneth and goblet cell number and secretory function, improving intestinal mechanical barrier integrity, and reshaping gut microbiota toward a more eubiotic configuration. The reduction in Lgr5 + ISC numbers following VD3 intervention likely reflects a shift from excessive self-proliferation toward differentiation, facilitated by normalization of the inflammatory stem cell niche, restoration of balanced Wnt/Notch signals from recovered Paneth and goblet cells, and VD3-induced microbiota changes that promote epithelial maturation.