| Summary: | 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 (VDRΔIEC) mice, cell cultures, stem cell–derived colonoids, and human colon cancer samples. Results: VDRΔIEC 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 VDRΔIEC 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 VDRΔIEC 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.
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