Researchers at Case Western Reserve University School of Medicine in Cleveland, Ohio, have discovered a link between uncontrolled vitamin A metabolism and damaging inflammation in the gut. The discovery adds key details regarding the relationship between diet and inflammatory diseases, such as inflammatory bowel disease (IBD), and could help doctors target nutritional strategies for patients.
Vitamin A metabolism starts with beta-carotene. Beta-carotene is the red-orange pigment nutrient in plants and fruits that gives certain foods their characteristic color, such as carrots and pumpkins.
Beta-carotene, also known as provitamin A, is transformed into vitamin A in the small intestine. Vitamin A is then mostly transported to other tissues to support many functions, such as healthy vision.
However, part of the vitamin A stays in the gut. Here, this nutrient is used to produce a growth factor, or hormone, for immune cells. This hormone triggers immune cells to proliferate and makes them active, causing inflammation in the gut when too much vitamin A is present.
In the study, “Transcription factor ISX mediates the cross talk between diet and immunity,” published in the journal Proceedings of the National Academy of Sciences, researchers described an important branching point in the metabolic pathway for vitamin A. This branching point hinges on a single protein called ISX. By studying mice genetically modified to lack ISX, the team found that this protein helps the body maintain a balanced process between beta-carotene and gut inflammation.
“Vitamin A exists in the diet as beta-carotene, which is enzymatically converted by cells lining the intestine. The content of beta-carotene in natural foods is variable and subject to seasonal fluctuations,” Ni Made Airanthi (Ila) Widjaja-Adhi, PhD, lead author of the study and post-doctoral fellow, and Marcin Golczak, PhD, co-author and assistant professor of pharmacology at Case Western Reserve School of Medicine, said in a press release.
“We describe in this study a mechanism for coping with this fluctuation, to maintain immunity at the intestinal barrier,” Widjaja-Adhi added.
The researchers showed that ISX turns on and off genes involved in beta-carotene-vitamin A metabolism. Specifically, ISX turns off a gene that expresses the enzyme Bco1, which is key to converting beta-carotene into vitamin A.
The ISX protein senses the uptake of beta-carotene by the small intestine after a meal by switching off the gene that codes Bco1. In this way, ISX “turns off” the transformation of the ingested beta-carotene into vitamin A. In other words, ISX makes the right amount of beta-carotene to be shuttled into the body for its vitamin A needs. As a consequence, most of the beta-carotene is removed from the gut.
The mice without ISX overproduced vitamin A. Unable to switch off the gene that codes Bco1, vitamin A remained in the small intestine in large quantities.
This triggered nearby immune cells in the small intestine. As a result, activated and multiplying immune cells were drawn into the gut, resulting in inflammation. The mice lacking ISX had severe inflammation in the small intestine, which then spread to the nearby pancreas.
The authors showed that immune cells in the small intestine can overreact to beta-carotene-rich diets when ISX is absent. The findings implicate ISX as a key link between diet and gut immunity.
“Too much vitamin A can promote inflammatory disease,” said Johannes von Lintig, PhD, associate professor of pharmacology at Case Western Reserve School of Medicine and lead author of the study. “In future studies, the ISX-deficient mouse will be a versatile model to study the molecular details of the intriguing interplay between diet and gastrointestinal immunity.”
Alterations in the “ISX gene have been associated with inflammatory disorders such as Crohn’s disease. A better understanding of the molecular factors that control gut immunity will aid the development of nutritional intervention strategies to improve health,” Von Lintig added.
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