Regulation of Microbiota by Vitamin D Receptor: A Nuclear Weapon in Metabolic Diseases

Abstract

Metabolic syndrome is a multi-faceted disease. The microbiota, as a newly discovered organ, contributes to the pathogenesis and progression of metabolic syndrome. Recent studies have demonstrated that nuclear receptors play critical roles in metabolic diseases. In the current review, we discuss the general role of the microbiome in health and metabolic syndrome. We summarize the functions of the nuclear receptor vitamin D receptor (VDR) in metabolism. The focus of this review is the novel roles of vitamin D/VDR signaling in regulating inflammation and the microbiome, especially in obesity. Furthermore, we extend our discussion of potential gut-liver axis mediated by VDR signaling and microbiota in obesity. Finally, we discuss the potential clinical application of probiotics and fecal microbiota transplantation in prevention and treatment of metabolic syndrome. Insights into nuclear receptors in metabolism and metabolic diseases will allow us to develop new strategies for fighting metabolic diseases.

Keywords: FMT; Inflammation; bacteria; infection; microbiome; nuclear receptor; probiotics.

Figure 1:. VDR regulates the liver-gut axis:

In the liver, after VDR is activated by l,25(OH)2D or LCA, it then heterodimerizes with FXR/RXR and binds to VDR responsive element (VDRE) region of DNA. Active VDR directly increases CYP3A4 transcription, which in turn degrades LCA. VDR activation also induces negative regulation of CYP7A1, which decreases bile acid synthesis. Thus, VDR acts as a bile acid sensor. In the intestine, VDR regulates the intestinal barrier functions by regulating epithelial tight junction proteins and blocking inflammation and bacterial infection. Thus, VDR plays a major role in linking the signaling pathways that moderate the liver-gut axis. Dysregulation of this axis might lead to increased gut permeability, bacterial translocation, and obesity.

Figure 2:. Vitamin D receptor in regulating various cellular and molecular functions:

VDR regulates many vital physiological functions including immuno-modulation, proliferation, and autophagy via distinct effector molecules (as mentioned in the respective box). It directly influences the gut-microbiome and is involved in epigenetic modulation of the host. VDR is also known to block pathogen infection by regulating Paneth cells and anti-microbial peptides, such as defensins.