Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic
Sarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, Cynthia L. Sears
Sarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, Cynthia L. Sears
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Research Article Microbiology Oncology

Human colon mucosal biofilms from healthy or colon cancer hosts are carcinogenic

Abstract

Mucus-invasive bacterial biofilms are identified on the colon mucosa of approximately 50% of colorectal cancer (CRC) patients and approximately 13% of healthy subjects. Here, we test the hypothesis that human colon biofilms comprise microbial communities that are carcinogenic in CRC mouse models. Homogenates of human biofilm-positive colon mucosa were prepared from tumor patients (tumor and paired normal tissues from surgical resections) or biofilm-positive biopsies from healthy individuals undergoing screening colonoscopy; homogenates of biofilm-negative colon biopsies from healthy individuals undergoing screening colonoscopy served as controls. After 12 weeks, biofilm-positive, but not biofilm-negative, human colon mucosal homogenates induced colon tumor formation in 3 mouse colon tumor models (germ-free ApcMinΔ850/+;Il10–/– or ApcMinΔ850/+ and specific pathogen–free ApcMinΔ716/+ mice). Remarkably, biofilm-positive communities from healthy colonoscopy biopsies induced colon inflammation and tumors similarly to biofilm-positive tumor tissues. By 1 week, biofilm-positive human tumor homogenates, but not healthy biopsies, displayed consistent bacterial mucus invasion and biofilm formation in mouse colons. 16S rRNA gene sequencing and RNA-Seq analyses identified compositional and functional microbiota differences between mice colonized with biofilm-positive and biofilm-negative communities. These results suggest human colon mucosal biofilms, whether from tumor hosts or healthy individuals undergoing screening colonoscopy, are carcinogenic in murine models of CRC.

Authors

Sarah Tomkovich, Christine M. Dejea, Kathryn Winglee, Julia L. Drewes, Liam Chung, Franck Housseau, Jillian L. Pope, Josee Gauthier, Xiaolun Sun, Marcus Mühlbauer, Xiuli Liu, Payam Fathi, Robert A. Anders, Sepideh Besharati, Ernesto Perez-Chanona, Ye Yang, Hua Ding, Xinqun Wu, Shaoguang Wu, James R. White, Raad Z. Gharaibeh, Anthony A. Fodor, Hao Wang, Drew M. Pardoll, Christian Jobin, Cynthia L. Sears

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Figure 3

Colon inflammation induced by BF+ and BF– human colon mucosal tissue inocula in GF ApcMinΔ850/+;Il10–/– and ApcMinΔ850/+ mouse models.

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Colon inflammation induced by BF+ and BF– human colon mucosal tissue ino...
(A) Distal colon inflammation scoring (see Methods) for GF ApcMinΔ850/+;Il10–/– and ApcMinΔ850/+ mice inoculated with BF+ or BF– human colon mucosal tissues. Both panels show BF– human colonoscopy biopsies (BF-bx, n = 12 mice are shown). In the left panel, 3 BF+ groups (BF+bx, BF+NF, and BF+T) are combined into 1 group (BF+, n = 42 mice), and in the right panel, BF+ colon tumor (BF+T, n = 25 mice), BF+ normal flanking tissue from CRC patients (BF+NF, n = 8 mice), and BF+ colonoscopy biopsies from healthy subjects (BF+bx, n = 9 mice) are shown separately. Data displayed as mean ± SEM analyzed by Mann-Whitney U test. (B) Distal colon inflammation scoring analyzed by mouse genotype for GF ApcMinΔ850/+;Il10–/– and ApcMinΔ850/+ mice inoculated with BF+ or BF– human colon mucosal tissues. Distal colon inflammation is displayed for inoculated ApcMinΔ850/+;Il10–/– mice (left panel) and ApcMinΔ850/+ (middle panel) only and is compared across the ApcMinΔ850/+;Il10–/– and ApcMinΔ850/+ mice genotypes (right panel). Data are displayed as mean ± SEM and were analyzed by Mann-Whitney U test. For the left panel, P < 0.0167 was considered statistically significant using Bonferroni’s correction. (C) Analysis of correlation between distal colon inflammation score and tumor numbers in ApcMinΔ850/+;Il10–/– and ApcMinΔ850/+ mice inoculated with BF+ or BF– human colon mucosal tissues. Both mouse genotypes (left panel); ApcMinΔ850/+;Il10–/– mice only (middle panel); ApcMinΔ850/+ mice only (right panel). Colon tumor induction is increased in BF+ tissue types and correlates with distal colon inflammation only in ApcMinΔ850/+;Il10–/– mice (middle panel). Black circles represent mice analyzed at 12 weeks after inoculation. White circles represent mice harvested at 13–20 weeks after inoculation (n = 9 mice). Analyzed by Spearman’s rank order correlation.