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Amending microbiota by targeting intestinal inflammation with TNF blockade attenuates development of colorectal cancer

Abstract

Intestinal inflammation and microbiota are two important components of colorectal cancer (CRC) etiology. However, it is not clear how tuning inflammation using clinically relevant anti-inflammatory treatment impacts microbiota or whether this consequently influences CRC outcome. Here, using chemically induced (DSS/Apcmin/+) and spontaneous (Apcmin/+;Il10−/−) mouse CRC models colonized by colibactin-producing Escherichia coli, we established the role of microbiota in mediating the antitumorigenic effect of anti–tumor necrosis factor (TNF) therapy. We found that TNF blockade attenuated colitis and CRC development. Microbiota community structure and gene activities significantly changed with disease development, which was prevented by TNF blockade. Several microbiota functional pathways underwent similar changes in patients following anti-TNF therapy. Under cohousing condition, TNF blockade failed to prevent colitis, cancer development and disease-associated microbiota structural changes. Finally, microbiota transplantation showed reduced carcinogenic activity of microbiota from anti-TNF-treated mice. Together, our data demonstrate the plasticity of microbiota, which could be reverted to noncarcinogenic status by targeting inflammation.

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Fig. 1: E. coli NC101 promotes CRC development via colibactin activity in mice harboring a complex microbiota.
Fig. 2: TNF blockade attenuates NC101-mediated CRC development.
Fig. 3: TNF blockade alters microbiota composition in DSS/Apcmin/+ mice.
Fig. 4: TNF blockade alters microbiota activity in DSS/Apcmin/+ mice.
Fig. 5: Cohousing abrogates TNF blockade effect on microbiota, inflammation and CRC.
Fig. 6: TNF blockade-associated microbiota show reduced carcinogenic activity.

Data availability

The sequencing data generated in this study were deposited in the National Center for Biotechnology Information Sequence Read Archive under the following accessions: PRJNA564272 (transplant 16S rDNA sequences), PRJNA564144 (cohousing 16S rDNA sequences), PRJNA564137 (main experiment 16S rDNA sequences), PRJNA564115 (microbial RNA-seq) and PRJNA610017 (metagenome shotgun sequences). The human metatranscriptome and metagenome data were derived from the IBDMDB (https://ibdmdb.org/), and the unique ‘External ID’ for individual samples included in our analysis was listed in Supplementary Table 5. Data supporting the findings of this study are available from the corresponding author on reasonable request. Source data are provided with this paper.

Code availability

The Leica Application Suite X (https://www.leica-microsystems.com/products/microscope-software/p/leica-las-x-ls/) was used for histology and immunohistochemistry visualization and imaging. The following open-source code was used in the analyses performed in this research: QIIME v.1.9.1 (ref. 51), Trimmomatic v.0.36 (ref. 57), KneadData v.0.6.1 (http://huttenhower.sph.harvard.edu/kneaddata), Bowtie2 v.2.3.5 (ref. 58), featureCounts v.1.5.3 (ref. 59), HUMAnN2 v.2.8.1 (ref. 60), edgeR v.3.26, GAGE v.2.34 (ref. 61), Diamond v.0.9.24 (ref. 63), R statistical framework v.3.5.1, R phyloseq package v.1.26, R nlme package v.3.1-140 and R ggplot2 package v.3.2. In addition, the following commercial code was used for data analyses: COSMOSID (https://www.cosmosid.com/) and GraphPad Prism 8 (https://www.graphpad.com/scientific-software/prism/). Preprocessing steps were done using in-house scripts that are available upon request.

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Acknowledgements

This research was supported by NIH grant R01DK073338, the University of Florida Health Cancer Center Funds and the University of Florida Department of Medicine Gatorade Fund (all to C.J.). Y.Y. was supported by the Crohn’s & Colitis Foundation of America research fellowship award (ref. no. 409472). R.Z.G. was supported by UF Health Cancer Center Funds. R.C.N. was supported by an NIH TL1 training grant (TL1TR001428). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We are grateful to the Germ-Free Services division of UF Animal Care Services for assistance with gnotobiotic experiments, the UF Molecular Pathology Core for assistance with tissue processing and staining, the UF Interdisciplinary Center for Biotechnology Research Core for assistance with shotgun metagenome and microbial RNA sequencing and J. Gauthier for assistance with 16S rRNA gene sequencing.

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Y.Y. and C.J. conceived and designed the study. Y.Y. and R.C.N. acquired data. Y.Y. and R.Z.G. analyzed data. Y.Y., R.Z.G. and C.J. drafted the manuscript. C.J. supervised the study. All authors reviewed and approved the manuscript.

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Correspondence to Christian Jobin.

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Extended data

Extended Data Fig. 1 TNF blockade attenuates colonic inflammation and DNA damage response.

a, Timeline for short-term TNF blockade in NC101-colonized DSS/Apcmin/+ mice. Experiment was done once. b, Representative pictures of H&E stained colon Swiss roll section (distal). Scale bars = 500 μm. c, Distal colon histological scores. d, Representative pictures of colon Swiss roll sections stained for γH2AX. Scale bars = 100 μm. e, Association between treatment and incidence of γH2AX+ regenerating crypts. Fisher’s exact test was used to determine association. f, Fecal NC101 relative abundance in PBS- and anti-TNF-treated mice at day 14. g, Cytokine expression in distal colon snips of NC101-colonized Apcmin/+;Il10-/- mice treated with PBS or anti-TNF antibody (related to Fig. 2h). Data are mean ± s.d. Two-tailed Mann-Whitney U test was performed for paired comparisons. The number of animals (n) used for each graph was indicated.

Source data

Extended Data Fig. 2 Fecal microbiota and NC101 changes in DSS/Apcmin/+ mice treated with PBS or anti-TNF antibody.

a, Alpha diversity (Chao1) and beta diversity (PCoA) comparison of microbiota in PBS-treated mice between indicated time points. The box horizontal lines are the 25th (lower) and 75th (upper) percentile. The middle line is the 50th percentile (the median). The lower whisker is 25th percentile - 1.5 times the interquartile range and the upper whisker is 75th percentile + 1.5 times the interquartile range. b, Alpha diversity (Chao1) and beta diversity (PCoA) comparison of microbiota in anti-TNF-treated mice between indicated time points. Sequencing data analysis was described in details in Methods. The box horizontal lines are the 25th (lower) and 75th (upper) percentile. The middle line is the 50th percentile (the median). The lower whisker is 25th percentile - 1.5 times the interquartile range and the upper whisker is 75th percentile + 1.5 times the interquartile range. c, NC101 abundance by metagenome analysis. One-way ANOVA followed by Holm-Sidak’s multiple comparisons test was performed for multi-group comparisons. d, Normalized counts of transcripts aligned to clb genes. Two-tailed Mann-Whitney U test was performed for paired comparisons. Data are mean ± s.d. The number of animals (n) used for each graph was indicated.

Source data

Extended Data Fig. 3 Microbiota community structure changes in NC101-colonized Apcmin/+;Il10-/- mice treated with PBS or anti-TNF antibody.

a, Alpha diversity (Chao1) and beta diversity (PCoA) comparison of microbiota in PBS-treated mice between indicated time points. The box horizontal lines are the 25th (lower) and 75th (upper) percentile. The middle line is the 50th percentile (the median). The lower whisker is 25th percentile - 1.5 times the interquartile range and the upper whisker is 75th percentile + 1.5 times the interquartile range. b, Alpha diversity (Chao1) and beta diversity (PCoA) comparison of microbiota in anti-TNF-treated mice between indicated time points. The box horizontal lines are the 25th (lower) and 75th (upper) percentile. The middle line is the 50th percentile (the median). The lower whisker is 25th percentile - 1.5 times the interquartile range and the upper whisker is 75th percentile + 1.5 times the interquartile range. c, Alpha diversity (Chao1) and beta diversity (PCoA) comparison between PBS- and anti-TNF-treated mice in longitudinal stool samples and endpoint colon tissues. The box horizontal lines are the 25th (lower) and 75th (upper) percentile. The middle line is the 50th percentile (the median). The lower whisker is 25th percentile - 1.5 times the interquartile range and the upper whisker is 75th percentile + 1.5 times the interquartile range. ns, not significant. Sequencing data analysis was described in details in Methods. The number of animals (n) used for each graph was indicated.

Source data

Extended Data Fig. 4 Cohousing abolishes CRC-preventive effect of TNF blockade in NC101-colonized Apcmin/+;Il10-/- mice.

a, Schematic diagram for TNF blockade under cohousing condition. b, Macroscopic colon tumor counts. c, Distal colon histological scores. d, Fecal NC101 relative abundance in cohoused PBS- and anti-TNF-treated mice. Data are mean ± s.d. Two-tailed Mann-Whitney U test was performed for paired comparisons. Experiment was done once. The number of animals (n) used for each graph was indicated.

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Yang, Y., Gharaibeh, R.Z., Newsome, R.C. et al. Amending microbiota by targeting intestinal inflammation with TNF blockade attenuates development of colorectal cancer. Nat Cancer 1, 723–734 (2020). https://doi.org/10.1038/s43018-020-0078-7

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