In the development of colon cancer, the intestinal dysbiosis and disruption of barrier function are common manifestations. In the current study, we hypothesized that host factors, e.g., vitamin D receptor deficiency or adenomatous polyposis coli (APC) mutation, contribute to the enhanced dysbiosis and disrupted barrier in the pathogenesis of colorectal cancer (CRC). Using the human CRC database, we found enhanced tumor-invading bacteria and reduced colonic VDR expression, which was correlated with a reduction of Claudin-10 mRNA and protein. In the colon of VDRΔIEC mice, deletion of intestinal epithelial VDR led to lower protein of tight junction protein Claudin-10. Lacking VDR and a reduction of Claudin-10 are associated with an increased number of tumors in the mice without myeloid VDR. Intestinal permeability was significantly increased in the mice with myeloid VDR conditional deletion. Further, mice with conditional colonic APC mutation showed reduced mucus layer, enhanced bacteria in tumors, and loss of Claudin-10. Our data from human samples and colon cancer models provided solid evidence- on the host factor regulation of bacterial translocation and dysfunction on barriers in colonic tumorigenesis. Studies on the host factor regulation of microbiome and barriers could be potentially applied to risk assessment, early detection, and prevention of colon cancer.
Keywords: Adenomatous polyposis coli (APC); Barrier function; Claudin; Colon cancer; Inflammation; Microbiome; Mucin; Myeloid cells; Tight junction; Vitamin D; Vitamin D receptor.
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