Abstract

Colorectal cancer (CRC) is one of the most prevalent and deadly forms of cancer in Western countries. Inflammation is a well-known driver of colonic carcinogenesis; however, its role in CRC extends beyond colitis-associated cancer. Over the last decades, numerous associations between intestinal dysbiosis and CRC have been identified, with more recent studies providing mechanistic evidence of a causative relationship. Nonetheless, much remains to be discovered regarding the precise implications of microbiome alterations in the pathogenesis of CRC. Research confirms the importance of a bidirectional crosstalk between the gut microbiome and the mucosal immune system in which inflammasomes, multiprotein complexes that can sense “danger signals,” serve as conduits by detecting microbial signals and activating innate immune responses, including the induction of microbicidal activities that can alter microbiome composition. Current evidence strongly supports an active role for this “inflammasome–microbiome axis” in the initiation and development of CRC. Furthermore, the gasdermin (GSDM) family of proteins, which are downstream effectors of the inflammasome that are primarily known for their role in pyroptosis, have been recently linked to CRC pathogenesis. These findings, however, do not come without controversy, as pyroptosis is reported to exert both anti- and protumorigenic functions. Furthermore, the multi-faceted interactions between GSDMs and the gut microbiome, as well as their importance in CRC, have only been superficially investigated. In this review, we summarize the existing literature supporting the importance of the inflammasome–microbiota axis, as well as the activation and function of GSDMs, to gain a better mechanistic understanding of CRC pathogenesis.

Highlights

  • Colorectal cancer (CRC) represents the third most prevalent malignancy and the second cause of cancer-related deaths worldwide (Arnold et al, 2017)

  • The following sections will summarize current findings regarding the impact of reciprocal interactions between the gut microbiome and the inflammasome, the so-called “microbiome– inflammasome axis,” and highlight the role of downstream gasdermins toward the pathogenesis of CRC

  • It is worth mentioning that a recent study demonstrates that GSDMD activation within intestinal epithelial cells (IEC) is mediated by the overgrowth of commensal flora in dextran sodium sulfate (DSS) colitic mice (Gao et al, 2021), suggesting that intestinal dysbiosis may potentially affect GSDM function(s) in inflammation-driven cancers

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Summary

INTRODUCTION

Colorectal cancer (CRC) represents the third most prevalent malignancy and the second cause of cancer-related deaths worldwide (Arnold et al, 2017). The interplay and bidirectional relationship between the gut microbiome and mucosal immune system are crucial factors in maintaining homeostasis under normal, healthy conditions; once this balance is disrupted, alterations in their respective functions can feed upon each other in a vicious cycle, promoting the development of intestinal pathologies, including CRC. Cytosolic PRRs— nucleotide-binding oligomerization domain-like receptors (NLRs)—are gaining increased attention following the discovery of the inflammasome, which can influence host– microbiome interactions, and when dysregulated, contributes to the development and progression of certain malignancies (Man, 2018). Recent evidence implicates GSDM activation in non-pyroptotic functions, including differentiation, proliferation, migration, and non-lytic release of inflammatory mediators, suggesting that the contribution of GSDMs in CRC might extend beyond pyroptosis (Zou et al, 2021; Rana et al, 2022). The following sections will summarize current findings regarding the impact of reciprocal interactions between the gut microbiome and the inflammasome, the so-called “microbiome– inflammasome axis,” and highlight the role of downstream gasdermins toward the pathogenesis of CRC

ROLE OF THE INFLAMMASOME
Influence of the Microbiome
CONCLUSIONS AND FUTURE DIRECTIONS

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