Regulation of Inflammation and Dysbiosis during Colon Carcinogenesis by a Commensal-derived TLR6 Ligand

Colorectal cancer (CRC) is the 3^rd most common cancer in the US and a role for the microbiota has been suggested. Dysbiosis of the microbiota has been shown to involve the direct expansion of DNA-damaging bacteria or communities that aggravate inflammation, yet the molecular signals contributing to dysbiosis remain elusive. The proximity of the intestinal epithelium with the microbial world suggests that signaling via toll-like receptors (TLR), which sense conserved microbial motifs, may be likely players in regulating the composition of the microbiota. Recently, we observed that polymorphisms in TLR6 are associated with predictive outcomes in CRC patients and that Ulcerative colitis patients with the same polymorphism in TLR6 had worse inflammation and more extensive disease, two highest reported risk factors for later developing CRC. These human phenotypes lead us to hypothesize that TLR6 signaling regulates inflammation and CRC. Indeed, we found that TLR6 signaling in a mouse model of carcinogenesis limited tumor size, number and location compared to TLR6-deficient (6KO) mice. TLR6 signaling also had profound effects on commensal dysbiosis. Despite a more severe cancer phenotype, the microbiota from 6KO mice was protective when transferred to commensal-depleted WT but not 6KO mice. Further, co-housing of 6KO and WT mice resulted in protection from tumorigenesis in the TLR6-sufficient WT mice only. Our data indicates that TLR6 signaling is critical for restraining tumorigenesis, however the dysbiosis that occurs in the absence of TLR6 signals allows for the maintenance of protective commensal bacteria that mediate anti-tumor responses in a TLR6-dependent manner.