Vitamin D mitigates intestinal inflammation through modulation of oxidative stress, autophagy and intestinal permeability in <i>Cftr</i> ‐null mice

Background The gut is the earliest organ affected by cystic fibrosis (CF), often in utero. Besides maldigestion and malabsorption, the other common intestinal manifestation is chronic inflammation, which exerts a negative impact on the nutrition, lung health and quality of life of these individuals. To date, few treatments exist to alleviate CF intestinal inflammation. Vitamin D plays anti‐inflammatory roles in the intestine through autocrine and/or paracrine actions, but its potential has been poorly investigated in the context of CF disease. Due to its anatomic location, the gut is the tissue exposed to the largest amount of vitamin D from external sources, making this vitamin an attractive therapeutic option. We previously showed that intestinal mucosa from CF mice exhibited increased eosinophilic infiltration compared to non‐CF mice, an effect that was reversed by the administration of a high‐vitamin D 3 diet. We thus postulate that vitamin D mitigates CF intestinal inflammation through regulation of critical processes involved in inflammatory responses, such as permeability, oxidative stress and autophagy. Methods Twelve‐week old BALB/c CF ( Cftr−/− ) and non‐CF ( Cftr+/+ ) mice were fed ad libitum a normal vitamin D 3 diet (1,500 IU/kg diet) or a high‐vitamin D 3 diet (5,000 IU/kg diet) for 8 weeks. Intestinal sections were harvested and assessed for the expression of markers of oxidative stress (e.g. deoxyguanidine), intestinal permeability (e.g. zonulin‐1) and autophagy (e.g.LC3, p62) by means of quantitative PCR, immunofluorescence and Western blotting. Results Deoxyguanidine (a marker of oxidative DNA damage) and zonulin‐1 duodenal immunostaining was increased in Cftr−/− mice fed with the normal vitamin D 3 diet compared to diet‐matched Cftr+/ + mice. Protein ratio of LC3‐II to LC3‐I was higher whereas p62 expression was lower in the duodena of Cftr−/− mice, suggesting enhanced baseline autophagy. Cftr−/− mice fed the high vitamin D 3 diet showed a decreased expression of deoxyguanidine, zonulin‐1 and LC3‐II to LC3‐I ratio and an increased p62 expression to levels of Cftr+/+ mice. Of note, the high‐vitamin D 3 diet did not have any measurable impact on the intestinal mucosa of Cftr+/+ mice, which was comparable to that of Cftr+/+ mice fed the normal vitamin D 3 diet. Conclusions Together, our findings show that the Cftr−/− duodenal mucosa exhibits increased permeability, autophagy and oxidative damage that may all contribute to the chronic inflammatory state. A high vitamin D 3 diet given for 8 weeks reverses those alterations, making this vitamin a potential therapeutic option for CF intestinal inflammation. Support or Funding Information This work was supported by a grant from Cystic Fibrosis Canada

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