Conditional Vitamin D Receptor Deletion Induces Fungal and Archaeal Dysbiosis and Altered Metabolites

A vitamin D receptor (VDR) deficiency leads to the dysbiosis of intestinal bacteria and is associated with various diseases, including cancer, infections, and inflammatory bowel disease. However, the impact of a VDR deficiency on fungi and archaea is unknown. We conditionally deleted the VDR in Paneth cells (VDR^ΔPC), intestinal epithelial cells (VDR^ΔIEC), or myeloid cells (VDR^ΔLyz) in mice and collected feces for shotgun metagenomic sequencing and untargeted metabolomics. We found that fungi were significantly altered in each knockout (KO) group compared to the VDR^Loxp control. The VDR^ΔLyz mice had the most altered fungi species (three depleted and seven enriched), followed by the VDR^ΔPC mice (six depleted and two enriched), and the VDR^ΔIEC mice (one depleted and one enriched). The methanogen Methanofollis liminatans was enriched in the VDR^ΔPC and VDR^ΔLyz mice and two further archaeal species (Thermococcus piezophilus and Sulfolobus acidocaldarius) were enriched in the VDR^ΔLyz mice compared to the Loxp group. Significant correlations existed among altered fungi, archaea, bacteria, and viruses in the KO mice. Functional metagenomics showed changes in several biologic functions, including decreased sulfate reduction and increased biosynthesis of cobalamin (vitamin B12) in VDR^ΔLyz mice relative to VDR^Loxp mice. Fecal metabolites were analyzed to examine the involvement of sulfate reduction and other pathways. In conclusion, a VDR deficiency caused the formation of altered fungi and archaea in a tissue- and sex-dependent manner. These results provide a foundation about the impact of a host factor (e.g., VDR deficiency) on fungi and archaea. It opens the door for further studies to determine how mycobiome and cross-kingdom interactions in the microbiome community and metabolites contribute to the risk of certain diseases.