Vitamin D supplementation mitigates inflammation in eosinophilic esophagitis
Click Here to Manage Email Alerts
Key takeaways:
- The vitamin D receptor is enriched in the vicinity of genes that are activated in the esophagus of patients with eosinophilic esophagitis.
- Vitamin D is a natural antagonist for IL-13, which governs epithelial tissue inflammation in eosinophilic esophagitis.
- When vitamin D levels are low, the effects of IL-13 are more prominent, active and strong.
Supplementation with vitamin D may alleviate allergic inflammation in the esophagus, whereas a deficiency in vitamin D may lead to a higher risk for eosinophilic esophagitis and other allergic states, according to a study published in Gut.
Half of the population in the West is deficient in vitamin D, Marc E. Rothenberg, MD, PhD, director of the division of allergy and immunology at the Center for Eosinophilic Diseases at Cincinnati Children’s Hospital Medical Center and a Healio Allergy/Asthma Peer Perspective Board Member, and colleagues wrote in the study.
“We asked what regulates the esophagus in terms of what turns on genes in the esophagus, and we were struck to find that the No. 1 transcriptional regulator that showed an extraordinarily high level of statistical significance was the vitamin D receptor,” Rothenberg told Healio.
As a lipid soluble vitamin, vitamin D can pass through all cell membranes and bind with the intracellular vitamin D receptor, which regulates gene expression. By examining thousands of data sets, Rothenberg explained, he and colleagues found that the vitamin D receptor, which is a transcriptional regulator (by acting as a transcription factor), is enriched in the human genome particularly at the sites of esophageal genes involved in eosinophilic esophagitis.
“When we found a strong interplay of the eosinophilic esophagitis transcriptome and the vitamin D receptor. I got excited as a physician scientist, because I know that vitamin D is linked with allergies,” Rothenberg said. “Also, the availability of vitamin D-based drugs provides a potential opportunity for quick clinical translation of these findings.”
Using histology, molecular imaging, motif discovery and metagenomic analysis, the researchers determined that the vitamin D receptor interacts with and is a natural antagonist for IL-13, a Th2 cytokine that governs epithelial tissue inflammation in asthma, atopic dermatitis, rhinosinusitis and other allergic diseases including eosinophilic esophagitis.
Specifically, metagenomic analysis revealed that supplementation with vitamin D reversed dysregulation of up to 70% of the transcriptome and epigenetic modifications induced by IL-13 in cells exposed to vitamin D deficient conditions. The researchers found that the interactome between vitamin D receptors and signal transducer and activator of transcription 6 (STAT6) may govern epithelial tissue responses to IL-13 signaling.
“The vitamin D receptor is a known transcription factor. Our findings show that the transcription factor engaged by IL-13, STAT6, and the vitamin D receptor, are actually regulating the same genes, and they regulate those genes mainly in opposite directions,” Rothenberg said.
“We showed that vitamin D antagonizes the effect of IL-13 in-vitro and in-vivo, so if you think about it, vitamin D has activity similar to blocking IL-13,” he added. “It has a physiological role in terms of regulating the IL-13 response, which is very critical in eliciting type 2 inflammatory responses.”
When the researchers examined a cohort of patients with EoE, they found that many of these patients had a vitamin D deficiency, Rothenberg said. Biopsies revealed that the severity of their disease, including eosinophil levels, histological changes and other features, were inversely proportional to vitamin D levels.
“That provided clinical significance that the murine findings were operational in humans,” Rothenberg said.
When the researchers manipulated vitamin D levels in mice and in human samples, IL-13 had a particularly remarkable effect when vitamin D levels were low.
“Low vitamin D made the IL-13 effect much more prominent, active and strong,” Rothenberg said.
Vitamin D, however, reversed the responses induced by IL-13 that are considered germane to EoE, such as epithelial hyperproliferation, dilated intercellular spaces and improving barrier function in mice with experimental eosinophilic esophagitis.
“When we normalized the vitamin D level, the EoE model became much milder,” Rothenberg said.
These findings provide a novel therapeutic entry point for type 2 immunity-related diseases in preventive and restorative medicine and therapies, according to the researchers.
IL-13 blockers now are in clinical use, the researchers continued, and vitamin D can be delivered in oral and topical forms. But translation to clinical use will require more research, Rothenberg cautioned.
“At this stage, I’m not recommending that people take high doses of vitamin D or anything like that. But there might be good reasons to check your vitamin D if you have EoE,” he said.
Reference:
- Vitamin D supplementation alleviates IL-13-induced esophageal inflammation. https://scienceblog.cincinnatichildrens.org/vitamin-d-supplementation-alleviates-il-13-induced-esophageal-inflammation/. Published Aug. 2, 2022. Accessed Sept. 7, 2022.
For more information:
Marc E. Rothenberg, MD, PhD, can be reached at marc.rothenberg@cchmc.org.