Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA.
Gut Microbes. 2021 Jan-Dec;13(1):1957408. doi: 10.1080/19490976.2021.1957408.
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 (VDR), Paneth cells (VDR), and myeloid cells (VDR) 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. phages, phages, and typing phages were significantly enriched in all three conditional VDR-knockout mice. In the VDR mice, the levels of eight more virus species (2 enriched, 6 depleted) were significantly changed. Altered virus species were primarily observed in female VDR (2 enriched, 3 depleted) versus male VDR (1 enriched, 1 depleted). Altered alpha and beta diversity (family to species) were found in VDR. In VDR 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 phage JSF5 and in VDR and VDR 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 VDR mice and increased CLEC4L expression in VDR and VDR mice. Furthermore, we identified metabolites related to virus infection: decreased glucose in VDR mice, increased ribulose/xylulose and xylose in VDR mice, and increased long-chain fatty acids in VDR and VDR 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.
维生素 D 受体 (VDR) 缺乏与癌症、感染和慢性炎症有关。先前的研究表明 VDR 可以调节细菌；然而，对于 VDR 和病毒之间的关系知之甚少。我们假设 VDR 缺乏会影响肠道病毒组和病毒-细菌相互作用。我们分别从小鼠的肠上皮细胞（VDR）、潘氏细胞（VDR）和髓样细胞（VDR）中敲除了 VDR。收集粪便进行 shotgun 宏基因组测序和代谢产物分析。为了测试功能变化，我们评估了模式识别受体（PRR）并分析了微生物代谢产物。所有三种条件性 VDR 敲除小鼠的噬菌体、噬菌体和噬菌体都显著富集。在 VDR 小鼠中，8 种更多病毒物种（2 种富集，6 种耗尽）的水平显著改变。在雌性 VDR（2 种富集，3 种耗尽）而非雄性 VDR（1 种富集，1 种耗尽）中观察到改变的病毒物种。在 VDR 中发现了改变的 alpha 和 beta 多样性（从科到种）。在 VDR 小鼠中，牛病毒性腹泻病毒 1 显著富集。在条件性 VDR 敲除小鼠中发现病毒和细菌改变之间存在显著相关性。在 VDR 和 VDR 小鼠中，噬菌体 JSF5 和噬菌体呈正相关。此外，在雌性条件性 VDR 敲除小鼠中发现更多改变的病毒物种。值得注意的是，PRR 发生显著变化：VDR 小鼠中 TLR3、TLR7 和 NOD2 上调，VDR 和 VDR 小鼠中 CLEC4L 表达增加。此外，我们还鉴定出与病毒感染相关的代谢物：VDR 小鼠中葡萄糖减少，VDR 小鼠中核糖醇/木酮糖和木糖增加，VDR 和 VDR 雌性小鼠中长链脂肪酸增加。组织特异性敲除 VDR 会改变病毒组，并在功能上改变病毒受体，从而导致菌群失调、代谢功能障碍和感染风险。这项研究有助于阐明 VDR 以组织特异性和性别特异性方式调节病毒组。
