Abstract The human intestinal microbiota is a community of 1013-1014 microorganisms that reside in the intestine and normally participate in a symbiotic relationship with their eukaryotic host. The microbiome contains a wealth of information, encompassing 150 fold as many genes as the human genome. Recent studies have hinted that a core human microbiome exists at the gene level, with a large number of microbial genes and pathways shared among individuals. Deviations from this core microbiome could potentially affect human health and promote disease state. Thus characterizing the vast intestinal microbial community present in healthy as well as pathologic conditions will likely revolutionize our conception of bacteria/host interactions and identify new physiological processes influenced by the microbiota. Already the microbiota has been linked to cardiac development, angiogenesis, innate and adaptive immunity, metabolism, nutrient acquisition, and gastrointestinal development and homeostasis. Furthermore, alterations in the microbial community are associated with multiple diseases, including obesity, fatty liver disease, type 1 and type 2 diabetes, kidney disease, arthritis and inflammatory bowel diseases (IBD). Eukaryotes are equipped with an elegant repertoire of innate receptors each recognizing specific conserved microbial patterns present on various microorganisms, such as components of bacterial cell walls, locomotion system or nucleic acids. These microbial sensors are termed pattern recognition receptors (PRR) and include retinoic acid inducible gene-I like RNA helicases (RLH), C-type lectin receptors (CLR), Nucleotide-binding domain leucine-rich repeat proteins (NLR; also known as Nod-like receptors), and Toll-like receptors (TLR). Although the etiology of colitis-associated colorectal cancer remains elusive, innate host sensors have been shown to modulate the pathogenesis. Indeed, using mice exposed to the colon-specific carcinogen azoxymethane (AOM) compound and to the mucosal-damaging agent dextran sulfate sodium (DSS), numerous studies have revealed the differential contribution of innate sensors to CAC. For example, the NLR protein NOD1, a close relative of the IBD susceptible gene NOD2 protects against the development of colitis and colorectal cancer. Similarly, the adaptor protein MyD88 frequently utilized by TLR family members is protective in the context of AOM/DSS-induced colorectal cancer. Furthermore, the intracellular sensor NLRP3 also appears protective against colitis and CAC. In contrast, TLR4 signaling promotes the development of colorectal cancer in the AOM/DSS model. Although informative, these studies only capture the impact of various innate host responses on the development of colorectal cancer. The true impact of the microbiota could only be investigated using germ-free mice and gnotobiotic technology. To avoid the use of a chronic injury model (DSS), our laboratory has substituted the spontaneous IL-10−/− mouse model of intestinal inflammation for the AOM/DSS model. We have focused our attention on the role of microbial community on the development of colitis-associated colorectal cancer. Using this AOM/Il10−/− model of colorectal cancer in combination with gnotobiotic techniques, we observed a clear role for the microbiota in the development and progression of the pathology. Using metagenomic approaches, we observed a shift in bacterial community composition in mice bearing tumors compared to healthy controls. Interestingly, introduction of the probiotic VSL#3 changed microbial community structure and promoted the development of colorectal cancer in Il10−/− mice. Gnotobiotic experiments showed that bacteria-induced intestinal inflammation is not sufficient to promote colorectal cancer. Indeed, although the severity of colitis at the clinical and molecular levels is similar between Escherichia coli NC101 (E. coli) and Enterococcus faecalis (E. faecalis) monoassociated Il10−/− mice, tumor numbers were enhanced by more than 40 fold by the former commensal bacterium. We will present evidence that microbial composition and its associated genome/transcriptome plays a key role in the development of CAC. These findings would suggest that although chronic inflammation is a part of the pathology, microbial community and associated microbial genome is at the forefront of CAC susceptibility. Altering the composition of the microbiota may represent a novel means by which to modulate development of colorectal cancer in IBD patients. Citation Information: Cancer Prev Res 2010;3(12 Suppl):ED06-04.
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Open Access
Jan 1, 2015
Ammar Hassanzadeh Keshteli 
