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.
Keywords:
ASC; colon cancer; microflora.
Publication types
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Chemokine CCL5 / deficiency
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Chemokine CCL5 / genetics
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Chemokine CCL5 / immunology
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Colitis / genetics
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Colitis / immunology
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Colitis / metabolism
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Colonoscopy
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / metabolism
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Epithelium / immunology
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Epithelium / metabolism
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Epithelium / microbiology
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Female
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Inflammasomes / immunology*
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Inflammasomes / metabolism
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Inflammation / genetics
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Inflammation / immunology*
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Inflammation / metabolism
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Interleukin-18 / deficiency
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Interleukin-18 / genetics
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Interleukin-18 / immunology
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Interleukin-6 / genetics
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Interleukin-6 / immunology*
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Interleukin-6 / metabolism
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Male
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Metagenome / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Neoplasms / genetics
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Neoplasms / immunology*
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Neoplasms / metabolism
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Receptors, Cell Surface / deficiency
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / immunology
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Signal Transduction / immunology
Substances
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Chemokine CCL5
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Inflammasomes
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Interleukin-18
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Interleukin-6
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Nod-like receptor pyrin domain-containing protein 6, mouse
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Receptors, Cell Surface