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Link to original content: https://pubmed.ncbi.nlm.nih.gov/19701202/
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. 2009 Sep;15(9):1016-22.
doi: 10.1038/nm.2015. Epub 2009 Aug 23.

A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

Shaoguang Wu  1 , Ki-Jong Rhee, Emilia Albesiano, Shervin Rabizadeh, Xinqun Wu, Hung-Rong Yen, David L Huso, Frederick L Brancati, Elizabeth Wick, Florencia McAllister, Franck Housseau, Drew M Pardoll, Cynthia L Sears
Affiliations

A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses

Shaoguang Wu et al. Nat Med. 2009 Sep.

Abstract

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 (T(H)17) response distributed between CD4+ T cell receptor-alphabeta (TCRalphabeta)+ and CD4-8-TCRgammadelta+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying T(H)17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and T(H)17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.

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Figures

Figure 1
Figure 1
ETBF stimulates colonic inflammation and enhances colonic tumor formation in Min mice. (a) Methylene blue–stained representative samples of distal colons of sham control, NTBF-colonized and ETBF-colonized mice showing thickened mucosal folds and excess tumors, visualized in mice colonized with ETBF for 1–2 months. (b) Distribution of visible tumor numbers detected in sham control, NTBF- or ETBF-colonized mice at 4–6 weeks after inoculation. Tumor distributions are shown as box-and-whisker plots. n = 14, 10 or 75 for sham control, NTBF or ETBF, respectively. (c) Distal colon histopathology of sham control and NTBF-colonized mice at 4 weeks and ETBF-colonized mice at 1 week and 4 weeks after inoculation. Insets show GIN foci in sham and ETBF-colonized mice. (d) Linear regression analysis of histological scores of ETBF-colonized colons for inflammation and hyperplasia versus visible colon tumor formation or GIN foci. Error bars represent means ± s.e.m.
Figure 2
Figure 2
ETBF specifically activates Stat3 in the colons of Min mice. (a) Western blot analysis for activated Stat3 (pStat3) in colon samples of sham control Min mice or Min mice colonized with NTBF or ETBF for 2 d. Three individual mice are shown for each experimental condition. β-actin serves as a protein benchmark; protein concentrations per sample were equivalent (4.3–4.9 μg μl−1). The break in the gel (proximal colon) indicates that samples were run on separate gels analyzed in parallel for the same experiment. Data are representative of five sham-inoculated, six NTBF-colonized and six ETBF-colonized Min mice. (b) Western blot analysis for pStat proteins in colons of three ETBF-colonized Min mice. Positive controls for each pStat antibody are shown. β-actin served as a protein loading control. (c) Immunohistochemistry for pStat3 in distal colon of ETBF-colonized mice 4 weeks after inoculation compared to sham or NTBF-colonized mice. Arrows depict a subset of inflammatory cells in the lamina propria of ETBF-colonized mice that show pStat3 staining (see also Supplementary Fig. 1b). Representative of two sham, four NTBF-colonized and seven ETBF-colonized Min mice. (d) Immunohistochemistry for pStat3 in a large colon tumor from an eight-week-old, sham-inoculated Min mouse and a similar-sized colon tumor in a Min mouse colonized with ETBF for 4 weeks. Arrows designate pStat3 staining of inflammatory cells in the interstitium.
Figure 3
Figure 3
ETBF, but not NTBF, induces IL-17–producing CD3+CD4+ T lymphocytes and γδ T lymphocytes in the colon lamina propria of Min and WT mice 1 week after NTBF or ETBF inoculation. (a) ICS for IL-17, IFN-γ and IL-4 in CD3+CD4+ T lymphocytes of Min mice. Dot plots are derived from the CD3+CD4+ gate. (b) ICS for IL-17 in CD3+CD4+ and CD3+CD4− lymphocytes from the lamina propria of ETBF-colonized Min mice. Dot plots are derived from CD3+ gate. (c) ICS for IL-17 and IFN-γ in CD3+CD4+ and CD3+CD4− T lymphocytes of C57BL/6 mice. Dot plots are derived from CD3+CD4+ and CD3+ gates. (d) ICS for IL-17 in γδ T cells from the lamina propria of ETBF-colonized Min mice. Dot plots are derived from CD3+CD4− gate. (e) ICS staining in CD3+CD4+ and CD3+CD4− lymphocytes from WT and CD4 Stat3-KO C57BL/6 mice. Dot plots are derived from the CD3+ gate. Each panel is representative of at least three independent experiments except e (two independent experiments). The numbers inside the plots indicate the percentage of the cell population showing the quadrant characteristic.
Figure 4
Figure 4
Blockade of IL-17 and IL-23R, but not IFN-γ, inhibits ETBF-induced colonic tumor formation in Min mice. (a) Methylene blue–stained representative samples of distal colons of mice colonized with ETBF for 5 weeks and treated with IL-17 and IL-23R blocking antibodies or isotype control antibodies. (b) Depiction of tumor number distribution by box-and-whisker plots in ETBF-colonized mice treated with isotype-matched antibodies (IgG + ET; experimental positive control) and ETBF-colonized mice treated with IL-17– (IL-17A + ET), IL-17– and IL-23R– (IL-17 + IL-23R + ET) or IFN-γ– (IFN-γ + ET) blocking antibodies after 5 weeks. Sham-inoculated mice served as an experimental negative control. Top, n = 24 for IgG + ET, 8 for IL-17 + ET, 14 for IL-17 + IL-23R + ET and 7 for sham. Bottom, n = 9 for IgG + ET and 11 for IFN-γ + ET. (c) Histopathology of distal colon tumors in Min mice colonized with ETBF for 5 weeks and treated with isotype control antibodies (left) or IL-17– and IL-23R–blocking antibodies (right). Two representative mice of 24 (isotype control) or 14 (IL-17–blocking and IL-23R–blocking antibody treated) per treatment group are shown. (d) Histopathology of distal colon of Min mice colonized with ETBF for 1 week and treated with isotype control antibody (center) or IL-17– and IL-23R–blocking antibodies (right). Left image shows the distal colon of a sham control Min mouse. Micrographs are representative of three sham control, five ETBF and isotype control antibody–treated and four ETBF, IL-17– and IL-23R–neutralizing antibody–treated mice.
Figure 5
Figure 5
CD4+, but not γδ+, T cell depletion inhibits tumor formation in ETBF-colonized Min mice. CD4+ T cells (CD4 + ET) or γδ T cells (TCRγδ + ET) were depleted in ETBF-colonized mice using specific monoclonal antibodies and compared to ETBF-colonized mice treated in parallel with IgG isotype control antibodies (IgG + ET). Distribution of tumor numbers is shown using box-and-whisker plots. Left, n = 22 for IgG + ET and 24 for CD4 + ET. Right, n = 9 for IgG + ET and 11 for TCRγδ + ET.
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