Imbalance of the intestinal virome caused by a conditional deletion of the vitamin D receptor from epithelial cells, Paneth cells, or myeloid cells in murine models

Abstract Background Vitamin D receptor (VDR) is highly conserved in mammals, and its deficiency is associated with various diseases (e.g., cancer, infection, and chronic inflammation). Prior research has described the effect of VDR on bacteria; however, little is known regarding the effects of VDR on viruses. We hypothesize that VDR is a regulator of the virome and virus-bacterial interactions. We conditionally 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. Results Vibrio phages, Lactobacillus phages and Escherichia coli typing phages were significantly enriched in all three conditional VDR-knockout mice compared to VDRLoxP mice. In the VDRΔLyz mice, the levels of eight more virus species (2 enriched, 6 depleted) were significantly changed. These significantly 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 were found in VDRΔLyz (family to species). In VDRΔIEC mice, bovine viral diarrhea virus 1 was significantly enriched. Overall, these significantly altered virus species were more often observed in female VDRΔIEC mice (2 enriched, 5 depleted) versus male mice (none). 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. Conclusion 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 regulation of the virome in a tissue-specific and sex-specific manner.