Vitamin A deficiency in mice results in a hypermetabolic state, dysbiosis and alterations in bacterial metabolism

Vitamin A deficiency (A−) is the leading cause of preventable childhood blindness in developing countries and is associated with decreased ability to fight infection. A− mice are susceptible to Citrobacter rodentium infection and surviving mice fail to clear the infection. To better understand how vitamin A status influences the metabolome and gut microbiota, we systematically analyzed biological samples from vitamin A sufficient (A+, n = 6) and vitamin A deficient (A−, n = 6) mice using 1 H NMR-based metabolomics and 16S rRNA gene sequencing. 1 H NMR analyses showed that A− mice had disturbances in multiple metabolic pathways including alterations in energy metabolism (hyperglycemia, glycogenesis, TCA cycle, and lipoprotein biosynthesis) and the A− host showed overall signs of a hypermetabolic state. 16S rRNA gene sequencing indicated that the microbiota in A− mice had phenotypic as well as functional shifts (based on PICRUSt). Evaluation of bacterial metabolism showed enhanced amino acid metabolism, carbohydrate metabolism, DNA replication and repair, and signal transduction in A− mice. In addition, the A− microbiota had lower amino acid biosynthesis, vitamin metabolism, and cell motility. These findings suggest that vitamin A deficiency is associated with hyperglycemia, liver disease, and dysbiosis of the gut microbial communities. Bacteria do not express receptors for vitamin A and therefore it seems likely that the changes in bacterial communities and bacterial metabolism are indirectly regulated by vitamin A. How these changes might compromise the ability of the A− mice to clear a gastrointestinal infection with C. rodentium is an area of continuing investigation.