TY - JOUR T1 - Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine JF - bioRxiv DO - 10.1101/2020.02.18.946335 SP - 2020.02.18.946335 AU - Yong-Guo Zhang AU - Rong Lu AU - Shaoping Wu AU - Ishita Chatterjee AU - David Zhou AU - Yinglin Xia AU - Jun Sun Y1 - 2020/01/01 UR - http://biorxiv.org/content/early/2020/02/19/2020.02.18.946335.abstract N2 - Background 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 JAK/STAT pathway in tumorigenesis. 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 location shifted from distal to proximal colon. Fecal microbiota analysis showed that VDR deletion leads to bacterial profile shift from normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human tumors. Microbial metabolites from VDRΔIEC mice showed elevated secondary bile acids, consistent with the 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 activation in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in respond to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced activation of STAT3.Conclusion We provide insights into the mechanism of VDR dysfunction leading to dysbiosis and tumorigenesis. It indicates a new target — microbiome and VDR for prevention of cancer.1,25(OH)2D31α,25-dihydroxy vitamin D3AOMazoxymethaneBrdUbromodeoxyuridineCHIPChromatin immunoprecipitationCRCcolon rectal cancerDSSdextran sodium sulfateFISHFluorescent in situ hybridizationIECsIntestinal epithelial cellsLcn-2Lipocalin 2IL10Interleukin 10JakJanus kinasesLPSLipopolysaccharidesPCNAProliferating cell nuclear antigenSTAT3Signal transducer and activator of transcription 3TUNELterminal transferase-mediated dUTP nick end labelingVDRvitamin D receptor ER -