Microbiota-induced activation of epithelial IL-6 signaling links inflammasome-driven inflammation with transmissible cancer

Abstract

The microbiota is pivotal in the pathogenesis of inflammatory bowel disease (IBD)-associated inflammation-induced colorectal cancer (CRC), yet mechanisms for these effects remain poorly characterized. Here, we demonstrate that aberrant inflammasome-induced microbiota plays a critical role in CRC development, where mice deficient in the NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome feature enhanced inflammation-induced CRC formation. Intriguingly, WT mice cohoused either with inflammasome-deficient mice or with mice lacking IL-18 feature exacerbated inflammation-induced CRC compared with singly housed WT mice. Enhanced tumorigenesis is dependent on microbiota-induced chemokine (C-C motif) ligand 5 (CCL5)-driven inflammation, which in turn promotes epithelial cell proliferation through local activation of the IL-6 pathway, leading to cancer formation. Altogether, our results mechanistically link the altered microbiota with the pathogenesis of inflammation-induced CRC and suggest that in some conditions, microbiota components may transfer CRC susceptibility between individuals.

Inflammasomes make the case for littermate-controlled experimental design in studying host-microbiota interactions

“…12 , 13 , 15-17 However, each of these earlier reports was based on fecal microbiota comparisons between non-littermate or externally sourced WT and KO mice that were separately housed for multiple generations. Several studies demonstrated animal facility-dependent microbiota differences in otherwise genetically identical mice, 7 , 18-20 indicating that the gut microbiota composition can be influenced by multiple non-genetic factors.…”

NOD-Like Receptors: Versatile Cytosolic Sentinels

“…Studies on animal models of colitis and colorectal tumorigenesis showed that animals deficient in NLRP12 are more susceptible to colon inflammation and tumor development, which is associated with increased production of inflammatory cytokines and failure to control NF-B and ERK activation in macrophages (295). Altered inflammatory pathway also seems to be the underlying mechanism by which animals lacking NLRP6 are more susceptible to inflammation-induced colon cancer (35,114). The precise mechanism by which NLRP6 protects against colon tumorigenesis remains unclear.…”

New insights from animal models of colon cancer: inflammation control as a new facet on the tumor suppressor APC gem

“…Remarkably, cohousing these NLRP6-mutant mice with wildtype mice results in development of colitis and colon tumors in the wild-type mice, consistent with transmissible tumor promoter. 192,193 A similar transmissible, tumor-promoter has been described in mice with mutations in other components of the innate immune response, NOD2 and RIP2. 194 Furthermore, expression of the secreted anti-inflammation mediator/antimicrobial, Pla2g2a in intestinal epithelial cells reduces the incidence of intestinal polyps in Apc Min/+ mice and in orthotopic xenografts of human colon cancer cells.…”