Vitamin D receptor protects against dysbiosis and tumorigenesis via the JAK/STAT pathway in intestine

Abstract

26Background: Vitamin D exerts regulatory roles via vitamin D receptor (VDR) in mucosal 27 immunity, host defense, and inflammation involving host factors and microbiome. Human Vdr 28 gene variation shapes the microbiome and VDR deletion leads to dysbiosis. Low VDR expression 29 and diminished vitamin D/VDR signaling are observed in colon cancer. Nevertheless, how 30 intestinal epithelial VDR is involved in tumorigenesis through gut microbiota remains unknown. 31We hypothesized that intestinal VDR protects mice against dysbiosis via modulating the 32 JAK/STAT pathway in tumorigenesis. To test our hypothesis, we used an azoxymethane/Dextran 33 Sulfate Sodium-induced cancer model in intestinal VDR conditional knockout (VDR ΔIEC ) mice, cell 34 cultures, stem-cell derived colonoids, and human colon cancer samples. 35Results: VDR ΔIEC mice have higher numbers of tumors with location shifted from distal to proximal 36 colon. Fecal microbiota analysis showed that VDR deletion leads to bacterial profile shift from 37 normal to susceptible carcinogenesis. We found enhanced bacterial staining in mouse and human 38 tumors. Microbial metabolites from VDR ΔIEC mice showed elevated secondary bile acids, 39 consistent with the observations in human CRC. We further identified that VDR protein bound to 40 the Jak2 promoter, suggesting that VDR transcriptionally regulated Jak2. The JAK/STAT pathway 41 is critical in intestinal and microbial homeostasis. Fecal samples from VDR ΔIEC mice activate the 42 STAT3 activation in human and mouse organoids. Lack of VDR led to hyperfunction of Jak2 in 43 respond to intestinal dysbiosis. A JAK/STAT inhibitor abolished the microbiome-induced 44 activation of STAT3.45 Conclusion: We provide insights into the mechanism of VDR dysfunction leading to dysbiosis 46 and tumorigenesis. It indicates a new targetmicrobiome and VDR for prevention of cancer.47 48 Background 52 Current research has implicated vitamin D deficiency as a critical factor in the pathology and 53 clinical outcome of colon rectal cancer (CRC) [1, 2]. Low plasma vitamin D is associated with 54 adverse CRC survival after surgical resection [3, 4]. Vitamin D receptor (VDR) is a nuclear 55 receptor that mediates functions of 1,25-dihydroxyvitamin D (1,25(OH)2D3), the biological active 56 form of vitamin D [5]. Higher VDR expression in tumor stromal fibroblast is associated with longer 57 survival in a large cohort of CRC patients [2]. The parallel appreciation of a role for the VDR in58 cancer biology began approximately 3 decades ago and subsequently a remarkable increase has 59 occurred in the understanding of its actions in normal and malignant systems [6]. 61The VDR regulation of gut microbiome in human and animal studies represents a newly identified 62 and highly significant activity for VDR [7][8][9]. Human Vdr gene variation shapes gut microbiome 63 and Vdr deletion leads to dysbiosis [8]. Our study on VDR and bacteria establishes a 64 microorganism-induced program of epithelial cell homeostasis and repair in the intestine [...

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.…”

“…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. 7 They further demonstrate that dysbiosis in mice with VDR deletion in intestinal epithelial cells promotes tumorigenesis through stimulating antiinflammatory JAK/STAT3 signaling in intestinal epithelial cells. 7 It has been reported that alterations in the composition, distribution, or metabolism of the gut microbiota may produce an environment in the colon that promotes inflammation, dysplasia, and cancer.…”

“…7 They further demonstrate that dysbiosis in mice with VDR deletion in intestinal epithelial cells promotes tumorigenesis through stimulating antiinflammatory JAK/STAT3 signaling in intestinal epithelial cells. 7 It has been reported that alterations in the composition, distribution, or metabolism of the gut microbiota may produce an environment in the colon that promotes inflammation, dysplasia, and cancer. 8 Studies from Sun's group provide an encouraging base from which to further seek host factors that contribute to regulate the symbiotic relationship between gut microbial community and the host for maintaining intestinal homeostasis and protecting against diseases.…”

“…11 Discovery from Sun's work identifies the involvement of VDR in intestinal epithelial cells in maintaining homeostasis of the gut microbiome. 7 Studies from the same group have revealed that VDR deletion in intestinal epithelial cells leads to abnormal Paneth cells and reduced antimicrobial peptides. 12 Thus, VDR-dependent antimicrobial peptide production in the intestinal tract may contribute to regulating the composition of the gut microbiota, and deficiency of VDR may induce the observed dysbiosis, leading to altered bacteria accumulated in tumors.…”