The oral-gut axis in colorectal cancer

PROJECT SUMMARY/ABSTRACT: Microbes have been implicated in colorectal cancer (CRC) pathogenesis, but definitive knowledge awaits of the identities of contributing microbes and their biologic effects. There is a critical need to fill this knowledge gap, because advances in understanding the roles of microbes in CRC pathogenesis will offer new insights into how CRCs arise and progress along highlighting potential new approaches to prevent and treat CRC by targeting microbial pathways. It has been reported that selected oral microbes are enriched in the “gut” of patients with CRC. This finding implicates a potential “oral-gut axis” in CRC. We previously found that oral inflammation, such as periodontitis, induces aberrant expansion of oral pathobionts, which can translocate to the distal gastrointestinal tract and ectopically colonize. Consistent with the potential pathogenic role of oral inflammation in gastrointestinal disease phenotypes, a large human cohort study revealed that periodontal disease is a risk factor for CRC. A key long-term goal of this project is to define specific oral microbes associated with CRC and inhibit their contributions to CRC. We have examined the influence of periodontal inflammation on the development of CRC, using mouse models addressing both periodontitis and CRC. Our preliminary results demonstrate the following: (i) periodontitis facilitates colonic tumorigenesis in the AOM/DSS colitis-associated CRC model; (ii) periodontitis leads to the aberrant accumulation of genotoxic bacteria (colibactin-producing pks+ Escherichia coli) in the oral cavity; (iii) amassed oral genotoxic pks+ E. coli may translocate to the gut and ectopically colonize; (iv) gut colonization by oral pks+ E. coli promotes the development of CRC through colibactin; and (v) oral Streptococcus species that co-expand with pks+ E. coli during periodontal inflammation promote gut colonization by oral pks+ E. coli. Based on these preliminary results, the overarching hypothesis for this project is that poly-microbial interaction between oral microbes promotes colonic tumorigenesis. We plan to further explore this hypothesis by pursuing the following two specific aims: In Aim 1, we will determine the mechanisms by which oral bacteria associated with periodontal inflammation cooperatively promote tumorigenesis in the colon. We hypothesize oral Streptococcus species promote the colonization of pks+ E. coli in the colonic epithelium, thereby leading to enhanced tumorigenesis. In Aim 2, we will clarify the role of colibactin in ectopic gut colonization by oral pks+ E. coli. We hypothesize colibactin is required to maximize the fitness of E. coli during oral inflammation, stability of the bacterium during niche relocation, and ectopic gut colonization of the bacterium. The completion of the proposed research will yield impactful insights into how oral pathobionts contribute to CRC pathogenesis and the findings will clarify how to develop new therapies for CRC prevention and treatment by targeting the oral-gut axis.