Imbalance of the intestinal virome and altered viral-bacterial interactions caused by a conditional deletion of the vitamin D receptor

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ABSTRACT Vitamin D receptor (VDR) deficiency is associated with cancer, infection, and chronic inflammation. Prior research has demonstrated VDR regulation of bacteria; however, little is known regarding VDR and viruses. We hypothesize that VDR deficiency impacts on the intestinal virome and viral-bacterial interactions. We specifically deleted VDR from intestinal epithelial cells (VDRΔIEC), Paneth cells (VDRΔPC), and myeloid cells (VDRΔLyz) in mice. Feces were collected for shotgun metagenomic sequencing and metabolite profiling. To test the functional changes, we evaluated pattern recognition receptors (PRRs) and analyzed microbial metabolites. Vibrio phages, Lactobacillus phages, and Escherichia coli typing phages were significantly enriched in all three conditional VDR-knockout mice. In the VDRΔLyz mice, the levels of eight more virus species (2 enriched, 6 depleted) were significantly changed. Altered virus species were primarily observed in female VDRΔLyz (2 enriched, 3 depleted) versus male VDRΔLyz (1 enriched, 1 depleted). Altered alpha and beta diversity (family to species) were found in VDRΔLyz. In VDRΔIEC mice, bovine viral diarrhea virus 1 was significantly enriched. A significant correlation between viral and bacterial alterations was found in conditional VDR knockout mice. There was a positive correlation between Vibrio phage JSF5 and Cutibacterium acnes in VDRΔPC and VDRΔLyz mice. Also, there were more altered viral species in female conditional VDR knockout mice. Notably, there were significant changes in PRRs: upregulated TLR3, TLR7, and NOD2 in VDRΔLyz mice and increased CLEC4L expression in VDRΔIEC and VDRΔPC mice. Furthermore, we identified metabolites related to virus infection: decreased glucose in VDRΔIEC mice, increased ribulose/xylulose and xylose in VDRΔLyz mice, and increased long-chain fatty acids in VDRΔIEC and VDRΔLyz female mice. Tissue-specific deletion of VDR changes the virome and functionally changes viral receptors, which leads to dysbiosis, metabolic dysfunction, and infection risk. This study helps to elucidate VDR regulating the virome in a tissue-specific and sex-specific manner.