1,25(OH)2D3 supplementation alleviates gut–vascular barrier disruption via inhibition of S100B/ADAM10 pathway

ABSTRACT

Gut–vascular barrier (GVB) is the second barrier in mucosa to control systemic dissemination of gut bacteria. Severe burns induce enteroglial cells to produce S100B and endothelial cells to generate ADAM10 and cause vitamin D3 insufficiency/deficiency and GVB disruption. It is not clear whether vitamin D3 supplementation attenuates GVB damage via regulation of S100B/ADAM10 pathway. Here, GVB disruption was induced by 30% of total body surface area scalds. Rats were treated with 1,25(OH)2D3 (0.05, 0.5 or 5 μg/kg) or S100B monoclonal antibody (S100BmAb, 10 μg/kg) or GI254023X (ADAM10 inhibitor, 100 mg/kg). Rat enteric glial cell-line CRL2690 and rat intestinal microvascular endothelial cells (RIMECs) were treated with S100B (5 μM) or plus 1,25(OH)2D3 (0.05, 0.5 or 5 μM) or GI254023X (5 μM). S100B, TNF-α, 25(OH)D3 and 1,25(OH)2D3 in serum and gut mucosa were determined by enzyme-linked immunosorbent assay. The endothelial permeability was measured using FITC-dextran 70 kDa. ADAM10 and β-catenin expression was assayed by Western blot. The results showed that 1,25(OH)2D3 and 25(OH)D3 concentration in serum reduced whereas TNF-α and S100B in serum and gut mucosa increased in burned rats. S100BmAb, GI254023X and 1,25(OH)2D3 treatment lowered burns-increased GVB permeability. 1,25(OH)2D3 also decreased S100B concentration in serum and gut mucosa. 1,25(OH)2D3 inhibited S100B release from TNF-α-treated CRL2690 and raised β-catenin while decreasing ADAM10 protein in S100B-treated RIMECs. 1,25(OH)2D3 and GI254023X also decreased the endothelial permeability of S100B-treated RIMECs. Collectively, these findings provide evidence that severe burns lower serum 25(OH)D3 and 1,25(OH)2D3 concentration. 1,25(OH)2D3 supplementation alleviates burns-elicited GVB disruption via inhibition of S100B/ADAM10 signaling.

KEYWORDS:

• 1
• 25(OH)2D3
• 25(OH)D3
• ADAM10
• burn injury
• enteric glial cells
• gut barrier
• S100B

Acknowledgments

We thank Guangrong Zhou, the Affiliated First Huai’an Hospital, Nanjing Medical University, Jiangsu, China, for the critical reading of the manuscript and Bin Chen, Maoming People’s Hospital, Southern Medical University, China, his technical assistance.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

A. Feng conceived and designed the experiments, provided funding acquisition, and reviewed the writing. C. Li, S. Su and Y. Liu performed the experiments and analyzed the data and contributed to the writing of the manuscript. The final form of the article has been approved by all of the authors.

Additional information

Funding

This research was supported by “Medical Science and Technology Foundation of Guangdong Province“ [A2021087, A2022453], “Special Fund for Science and Technology of Maoming City” [2020KJZX010], “High-level Hospital Construction Research Project of Maoming People’s Hospital” [ZX2020019].