A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses
By Shaoguang Wu, Ki-Jong Rhee, E. Albesiano, S. Rabizadeh, Xinqun Wu, Hung-Rong Yen, D. Huso, F. Brancati, E. Wick, F. McAllister and 3 more. Nature Medicine, 2009
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The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (TH17) response distributed between CD4+ T cell receptor-αβ (TCRαβ)+ and CD4–8–TCRγδ+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying TH17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and TH17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.
Subfields: Epidemiology, Surgery
View Paper: https://www.semanticscholar.org/paper/f53fb553932bfddb15967220b2ff66f1a9118b7f
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Citations in the corpus
- The immune system and the gut microbiota: friends or foes? (2010, background): “fragilis (ETBF), which can stimulate colonic inflammation and tumorigenesis in predisposed multiple intestinal neoplasia (MIN) mic”
- Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. (2012, background): “The root cause of CRC is unclear, but inflammation is a well-rec- ognized risk factor (Wu et al. 2009; McLean et al. 2011).”
- Intestinal homeostasis and its breakdown in inflammatory bowel disease (2011, background): “T H 17 responses were also recently implicated in a model of colitis-associated cancer, because IL-17A depletion reduced colitis and tumour developmen”
- The Microbiome in Infectious Disease and Inflammation (2012, positive): “ETBF also induce Th17 cells through STAT3 activation in the colon (168).”
- Activation of the receptor (Gpr109a) for niacin and the commensal metabolite butyrate suppresses colonic inflammation and carcinogenesis (2014, neutral): “Bacteroides fragilis toxin (BFT) and Bacteroides vulgatus increases inflammation and colon cancer in Apc and Il10 / mice, respectively (Uronis et al., 2009; Wu et al., 2009).”
- Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers (2011, background): “In contrast, the common colonic commensal, enterotoxigenic B. fragilis was reported to trigger cellular proliferation, colonic colitis and strongly induce colonic tumors in multiple intestinal neoplasia (Min) mice (Wu et al., 2009).”
- Microbiome and Malignancy (2011, background): “Conclusions The examples provided are not comprehensive, but rather indicate several conserved and paradigmatic mechanisms; microbiome constituents likely will have roles in other human cancers (Garrett et al., 2009; Wu et al., 2009).”
- Helicobacter pylori and Gastric Cancer: Factors That Modulate Disease Risk (2010, background): “In addition to the Th1/Th2 paradigm, a third class of CD4 cells has been discovered (126) and is linked to the etiopathogenesis of inflammatory bowel disease (191) and colon carcinogenesis (348).”