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Identifying genetic and microbial factors that promote intestinal inflammation and cancer using Drosophila

Final Report Summary - INFECTIONCANCER (Identifying genetic and microbial factors that promote intestinal inflammation and cancer using Drosophila)

During the last two decades, pioneering work led to the identification of innate immunity signalling pathways in Drosophila melanogaster and uncovered their integral, evolutionarily conserved role in the host defense against microbes. In addition, processes linked to human carcinogenesis, such as cell polarity and inflammatory and compensatory cell proliferation, have conserved roles in epithelial homeostasis, and their role was revealed with the use of relevant Drosophila experimental models. Given that pathogenic microbes often perturb epithelial homeostasis towards inflammation, impairments in the innate immune response or perturbations in cell integrity and proliferation can lead to cancer. The molecular nature of the relationship between microbial infection and cancer, although very important, remains elusive and can be effectively explored in simple, genetically tractable model systems of inflammation and carcinogenesis in Drosophila.
Our previous work on Drosophila midgut has shown that virulent bacteria induce enterocyte apoptosis leading to stem cell-mediated compensatory proliferation that works for the benefit of the host in order to replenish the dying cells. This process, which shares conserved components with human inflammation, can be diverted in the presence of a tumorigenic genetic background in order to induce tumor formation and growth; the primary steps of cancer. Thus, we aimed to identify genes that are required for the detrimental interaction between infection and tumor development. We found a wealth of genes to be genetically variant or differentially expressed in intestinal dysplasia-prone infected flies. In addition we found that intestinal bacteria and dietary factors also affect subsequent steps of cancer i.e. the tumor cell migration and metastasis.
Our studies show that P. aeruginosa and other intestinal bacteria, such as Escherichia coli, interact with themselves and with the host to induce or even inhibit inflammation. We uncovered microbiota compositions that affect intestinal inflammation. It has long been postulated that intestinal bacteria play a key role in human health and disease. A number of studies have clearly shown a correlation between particular disease states and changes in the composition of the intestinal bacteria. For example, current studies show that inflammatory bowel disease is linked to a relative increase in the population of some bacterial species versus others. Yet it remains unknown if these alterations are a cause or a result of intestinal inflammation. Thus, we assessed the potential of a big array of human intestinal bacteria combinations to induce or inhibit intestinal inflammation and disease. We found that among others P. aeruginosa and Escherichia coli excreted metabolites can directly induce inflammation but they may also affect bacterial colonization and growth in the intestine.
We have already published some of our findings in high impact scientific journals (as part of our 14 publications produced since the beginning of this program). Additional findings provide the basis of ensuing publications.