Inflammation is Essential for Microbial-Induced Carcinogenic Properties in the Intestine
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1 Inflammation is Essential for Microbial-Induced Carcinogenic Properties in the Intestine Department of Medicine and Department of Infectious Diseases & Pathology University of Florida, Gainesville
2 Microbiome: A bystander to the carcinogenic process? ~100 trillion >1000 species
3 Colorectal cancer Host Genetics microbiota? Inflammation Diet colitis-associated CRC 60% increased rate of CRC in IBD patients compared to healthy population? L. J. Herrinton et al., Gastroenterology 143, (2012
4 IBD: Clinical presentation Normal Mild ~100 trillion >1000 species Moderate Severe Is inflammation important for microbial carcinogenic activities?
5 Inflammation shapes microbial composition which affects tumorigenesis Genotoxic Microbiota polyketide synthase (pks) Host microbial compartment Host inflammatory compartment NF-κB, EGFR, STAT3, TGF, IL-6, TNF, IL-17 Arthur et al 2012 Science Oct 5;338(6103):120-3.
6 Presence of the genotoxin island polyketide synthases (pks) in E.coli NC101 Guerra, L., Guidi, R., & Frisan, T. (2011). FEBS Journal, 278(23), Comet Assay: ctl E.coli pks E.coli pks
7 E.coli NC101 mediates colitis independently of the pks island in Il10 -/- mice Inflammation wk n.s. NC101 pks Inflammation wk+AOM n.s. NC101 pks Inflammation wk+AOM n.s. NC101 pks
8 E.coli NC101 pks island mediates tumor progression in Il10 -/- mice
9 Higher prevalence of pks island in clinical isolates obtained from IBD and CRC patients Disease # Patients 1 ClbB+ Pks+ % ClbB+Pks+ p value 2 CRC IBD Control p<0.001 p< Mucosa-associated E. coli was isolated from colon tissue specimens 2 Differences in # Clb+Pks+ patients vs controls were assessed using the binomial test 3 Control = non-crc, non-ibd patients (see Table S3)
10 How do we get there? Illumina HiSeq2000 WT Germ-free 16S V6 Microbiome analysis mucosal tissues Stools IL-10 -/- mild Colitis/HGD spontaneous chronic inflammation -/+AOM Colitis/invasive tumor
11 Differential luminal microbial community assembly in Il10 -/- compared to WT mice WT mice Il10 -/- mice R=0.760 p=0.008 R=0.067 p=0.199
12 Enhanced enterobacteriaceae/escherichia resilience in inflamed Il10 -/- compared to WT mice
13 Could increase abundance of genotoxic bacteria promote CRC in absence of inflammation? Germ-free Il10 -/- Il10 -/- ; Rag2 -/- + AOM E.coli NC weeks Inflammation/Tumors?
14 E.coli NC101 failed to induce intestinal inflammation in Il10 -/- ; Rag2 -/- mice 5 p< Inflammation score AOM Il10 -/- AOM Il10 -/- ;Rag2 -/-
15 Inflammation is essential for E.coli NC101 mediated CRC in Il10 -/- mice Tumors/dysplasia per mouse * Il10 -/- Il10 -/- ; Rag2 -/-
16 Could increase abundance of genotoxic bacteria promote CRC in absence of inflammation? No Then what?
17 E.coli transcriptomic response to inflammation? Germ-free Il10 -/ E.coli NC101 + AOM 20 weeks Il10 -/- ; Rag2 -/ weeks Microbial RNAseq What is inflammation doing to microbial genes?
18 Environmental adaptation drives E.coli transcriptomic response Fatty acid oxidation/degradation/biosynthesis, Sucrose/ lactose metabolism, Mn 2+ /Fe 2+ ABC transporters, Rhamnose metabolism, Glycerol related metabolism, Nitrate regulation Il-10 -/- Il-10 -/- ;Rag2 -/- Il-10 -/- Il-10 -/- ;Rag2 -/- Il-10 -/- Il-10 -/- ;Rag2 -/- 2w 2w 12w 12w 20w 20w
19 The pks island is transcriptionally active during inflammation/cancer ribosomals pks island P-value 3.4x10-5 P-value P-value 0.09 Why should one care about a mouse E.coli strain causing CRC? Arthur et al 2014 Nature Comm Resubmitted
20 Harnesting the microbiome for CRC prevention/therapy? Prebiotics-Probiotics-antibiotics Dietary manipulation Bacteriotherapy Rx targeting microbial inflammatory genes Rx targeting microbial cancer genes Genotoxic Microbiota Cancer Schwabe, R. F., & Jobin, C. (2013). The microbiome and cancer. Nat Rev Cancer Nov;13(11):800-12
21 Jobin Lab Josh Uronis Janelle Arthur Jason Goldsmith Xiaolun Sun Marcus Mühlbauer Javier Rivera Brigitte Allard Ernesto Chanona Sarah Tomkovich UNC-CH Tepitope Keku Jon Hansen Ting-Jia Fan University Ottawa Alain Stinzi Turki Abujamel UNC-Charlotte Anthony Fodor Raad Gharaibeh Cornell University Kenny Simpson Belgin Dogan University Liverpool John Rhodes Barry Campbell Fundings: R01 DK73338 R01 DK47700 R21 AI UCRF Core Facility Pilot Award American Institute of Cancer Research UNC/NCSU Gnotobiotic Facilities Balfour Sartor Maureen Bower Cynthia Spivey Miriam Vizcaya Sue Tonkonogy
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