Toll‐like receptor 13‐mediated signaling protects against the development of colon cancer

Abstract

AbstractAppropriate host‐microbiota interactions are essential for maintaining intestinal homeostasis; hence, an imbalance in these interactions leads to inflammation‐associated intestinal diseases. Toll‐like receptors (TLRs) recognize microbial ligands and play a key role in host–microbe interactions in health and disease. TLR13 has a well‐established function in enhancing host defenses against pathogenic bacteria. However, its role in maintaining intestinal homeostasis and controlling colitis‐associated colon cancer (CAC) is largely unknown. This study aimed to investigate the involvement of TLR13‐mediated signaling in intestinal homeostasis and colonic tumorigenesis using ex vivo cell and in vivo CAC animal model. Tlr13‐deficient mice were prone to dextran sodium sulfate (DSS)‐induced colitis. During the early stages of the CAC regimen (AOM/DSS‐treated), Tlr13 deficiency led to severe ulcerative colitis. Moreover, Tlr13‐deficient mice exhibited increased intestinal permeability, as evidenced by elevated levels of fluorescein isothiocyanate (FITC)‐dextran, endotoxins, and bacterial translocation. Enhanced cell survival and proliferation of colonic intestinal cells were observed in Tlr13‐deficient mice. A transcriptome analysis revealed that Tlr13 deficiency is associated with substantial changes in gene expression profile of colonic tumor tissue. Tlr13‐deficient mice were more susceptible to CAC, with increased production of interleukin (IL)‐6, IL‐12, and TNF‐α cytokines and enhanced STAT3, NF‐κB, and MAPK signaling in colon tissues. These findings suggest that TLR13 plays a protective role in maintaining intestinal homeostasis and controlling CAC. Our study provides a novel perspective on intestinal health via TLR13‐mediated signaling, which is crucial for deciphering the role of host‐microbiota interactions in health and disease.