Bacterial translocation and barrier dysfunction enhance colonic tumorigenesis

Area of Science:

• Gastroenterology
• Oncology
• Microbiology

Background:

• Intestinal dysbiosis and disrupted barrier function are key in colon cancer development.
• Host factors like vitamin D receptor (VDR) deficiency and adenomatous polyposis coli (APC) mutations may exacerbate these conditions in colorectal cancer (CRC).

Purpose of the Study:

• To investigate the role of host factors, specifically VDR and APC, in regulating gut microbiome and barrier integrity during colorectal cancer pathogenesis.
• To determine the impact of VDR deficiency and APC mutation on bacterial translocation and barrier dysfunction in CRC models.

Main Methods:

• Analysis of human CRC database for bacterial presence and VDR expression.
• Utilizing VDR-deficient (VDRΔIEC) and myeloid VDR conditional knockout mice models.
• Employing APC-conditional mutant mouse models to assess mucus layer, bacterial invasion, and Claudin-10 expression.
• Measuring intestinal permeability in relevant mouse models.

Main Results:

• Human CRC samples showed increased tumor-invading bacteria and reduced colonic VDR, correlating with decreased Claudin-10.
• VDR deletion in intestinal epithelium reduced Claudin-10 protein levels.
• Absence of VDR and reduced Claudin-10 correlated with increased tumor numbers in specific mouse models.
• Myeloid VDR deficiency significantly increased intestinal permeability.
• APC mutation in colon led to mucus layer reduction, increased tumor bacteria, and Claudin-10 loss.

Conclusions:

• Host factors, including VDR and APC, significantly regulate bacterial translocation and barrier function in colorectal cancer.
• VDR deficiency and APC mutations contribute to gut dysbiosis and barrier disruption, promoting colon tumorigenesis.
• Understanding these host-microbiome-barrier interactions offers potential for CRC risk assessment, early detection, and prevention strategies.