title: 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.
authors.affiliation: Departments of Immunobiology, Laboratory Medicine, and Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Eran
authors.initials: E
authors.lastname: Elinav
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.forename: Till
authors.initials: T
authors.lastname: Strowig
authors.forename: Liming
authors.initials: L
authors.lastname: Hao
authors.forename: Anja
authors.initials: A
authors.lastname: Hafemann
authors.forename: Chengcheng
authors.initials: C
authors.lastname: Jin
authors.forename: Claudia
authors.initials: C
authors.lastname: Wunderlich
authors.forename: Thomas
authors.initials: T
authors.lastname: Wunderlich
authors.forename: Stephanie C
authors.initials: SC
authors.lastname: Eisenbarth
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000818:Animals; D018946:Chemokine CCL5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003092:Colitis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003113:Colonoscopy; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004848:Epithelium / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D005260:Female; D058847:Inflammasomes / Q000276:immunology* / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008297:Male; D054892:Metagenome / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology
chemical_list: D018946:Chemokine CCL5; D058847:Inflammasomes; D020382:Interleukin-18; D015850:Interleukin-6; C559901:Nod-like receptor pyrin domain-containing protein 6, mouse; D011956:Receptors, Cell Surface
keywords: ASC; colon cancer; microflora