Vitamin D Receptor Protects Against Dysbiosis and Tumorigenesis via the JAK/STAT Pathway in Intestine

Abstract

Vitamin D/vitamin D receptor (VDR) deficiency causes a high risk of colon cancer, but how VDR is involved in tumorigenesis through microbiota remains unknown. We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis, indicating a new target: microbiome and VDR for the prevention of cancer. BACKGROUND & AIMS: Vitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in tumorigenesis. METHODS: To test our hypothesis, we used an azoxymethane/ dextran sulfate sodium-induced cancer model in intestinal VDR conditional knockout (VDR DIEC) mice, cell cultures, stem cell-derived colonoids, and human colon cancer samples. RESULTS: VDR DIEC mice have higher numbers of tumors, with the location shifted from the distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to a bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDR DIEC mice showed increased secondary bile acids, consistent with observations in human CRC. We further identified that VDR protein bound to the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/ STAT pathway is critical in intestinal and microbial homeostasis. Fecal samples from VDR DIEC mice activate the STAT3 signaling in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in response to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3. CONCLUSIONS: We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target: microbiome and VDR for the prevention of cancer.

Prognostic role of vitamin D receptor in breast cancer: a systematic review and meta-analysis

“…Results of the subgroup analysis showed that only the total VDR expression in nucleus and cytoplasm was related to BC patients’ survival. VDR mainly functions as a nuclear receptor [ 32 , 33 ], but it is widely distributed on multiple subcellular structures, including the nucleus, nuclear membrane, cytoplasm, and cell membrane [ 17 ]. Our results indicate that VDR in the cytoplasm also exerts specific biological functions in the progression of BC cells.…”

Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

“…The VDR bounded to 1,25-(OH) 2 D forms a heterodimer with the retinoic acid receptor (RXR), which migrates to the cell nucleus and binds to the vitamin D-response element (VDRE) in the promoter regions of target genes, acting as a nuclear transcription regulator [ 57 , 58 , 59 ] ( Figure 2 ). The VDRE is found in many genes, explaining the mechanisms associated with vitamin D, like autophagy [ 30 ], cell proliferation [ 60 ], intestinal barrier function [ 61 , 62 ], gut microbiota modulation [ 30 , 63 , 64 ], and immune functions [ 65 , 66 ], besides the most well-known mechanism, regarding calcium homeostasis and bone health [ 58 , 59 , 63 ].…”

Mechanistic Understanding of the Symbiotic Relationship Between the Gut Microbiota and the Host

“…Results from a large cohort suggest that higher level of VDR expression is associated with longer survival after surgical resection in patients with colorectal cancer. 6 This clinical evidence is supported by studies from Zhang et al 7 to elucidate a previously unrecognized mechanism through which the intestinal epithelial VDR regulates the homeostasis of the gut microbiome for preventing development of inflammation-associated colorectal cancer. Through a series of elegant in vivo and in vitro studies using human samples and mouse models of colorectal cancer, they report that the absence of VDR in intestinal epithelial cells results in shifting the gut bacterial profile toward that with high risk for colorectal cancer.…”