The microbiota and colon cancer risk: cause or consequence?

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Keane, Jonathan
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University College Cork
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Background: Colorectal cancer (CRC) has a complex aetiology involving both genetic and environmental factors. Recently, attention has turned to the influence of the gut microbiota upon the development of CRC. The human gut microbiota is altered in CRC and certain microbial patterns are associated with increased cancer risk, but definitive identification of mechanisms and specific bacteria involved has proven elusive as species associated with human CRC are not consistent across studies. Moreover, research into the role of the microbiota in CRC has primarily focussed on changes that exist in and around tumour sites at a single point in time. This has made it difficult to differentiate between changes that promote cancer initiation in healthy tissue from changes that are a result of tumour development. We therefore tracked changes in the host and microbiota throughout the course of colon cancer development in mouse models of sporadic and familial CRC to elucidate their contribution to disease. Our aim was to identify changes in each of these criteria and establish their temporal relationships in order to generate a timeline of alterations and define causative and consequential events. One possible mechanism by which the gut microbiota may affect host processes leading to the development of CRC is the production of bacterial metabolites. We furthermore investigated the role of one of these metabolic pathways; in particular changes in free bile acids formed by the enzyme bile salt hydrolase (bsh), which is widespread in the microbiota. Results: We observed pro-tumorigenic changes in the microbial composition of our model of sporadic CRC prior to detection of host neoplastic transformation. The microbiota present in the gut of our familial model also differs prior to the onset of disease with the potential to contribute to disease initiation. Our longitudinal studies also identified a distinct set of microbial alterations associated with disease progression. This included a reduction of taxa associated with suppression of inflammation prior to the onset of pro-inflammatory signalling in our sporadic model, followed by enrichment for cancer-associated taxa later. In our intervention study, mice administered a research strain of E. coli overexpressing bsh displayed significantly fewer intestinal polyps compared to E. coli or PBS controls, possibly mediated by an enrichment of hydrophilic bile acid tauro-ursodeoxycholic acid and bile acid signalling. Conclusion: These results suggest that the microbiota is dynamic over time and may act as an instigating factor in CRC development. Moreover, it highlights prophylactic treatment of the gut microbiota as a potential avenue to reduce cancer risk. This could be explored by administration of probiotics, for example bsh-expressing species, to human subjects in a prospective clinical trial of CRC risk
Gut , Microbiome , Microbiota , Colon , Cancer , Colorectal , AOM , APCmin
Keane, J. 2019. The microbiota and colon cancer risk: cause or consequence? PhD Thesis, University College Cork.