Healthy gut microbiota, the complex consortia of resident microbes colonizing the human GI tract, influence aspects of health and normal development. An altered, or dysbiotic, microbial community can promote pathologic inflammation or hyperplasia, which can lead to a variety of diseases including cancer. Cancer-causing pathogens, such as Helicobacter pylori, can be associated with dysbiotic microbiota; however, whether dysbiotic communities contribute to H. pylori pathogenesis is unknown. Currently, many aspects of H. pylori-associated pathology are thought to be due to the action of the virulence protein CagA. CagA is translocated into host epithelial cells where it mimics a mammalian scaffold protein, alters cellular polarity, and manipulates host-signaling pathways that promote cell proliferation. We hypothesize that CagA also contributes to H. pylori pathogenesis by inducing microbial dysbiosis that contributes to cell proliferation and altered immune signaling.
Current animal models of H. pylori pathogenesis rely on infection with CagA positive strains to investigate the effects of CagA on host cell proliferation and disease progression. These models are limited because they cannot accurately disentangle the effects of the virulence protein from that of H. pylori or other microbes in the community. Using a transgenic Drosophila model of CagA expression within the gut epithelium we can genetically dissect the effects of CagA on the host epithelium from that of the pathogen or other microbial contributions. We have found that expression of CagA within host intestinal stem cells causes high rates of cell proliferation in the midgut epithelium. Our transgenic model also revealed that the gut microbiota promotes some of the pathological proliferation, as flies derived germ free have lower levels of cell proliferation than conventionally reared flies. Notably, the gut microbiota in CagA transgenic flies differs from that of wild-type flies, such that the microbiota is sufficient to induce both overexpression of an anti-microbial peptide and cell proliferation in wild-type flies. This demonstrates the pro-proliferative capacity of the CagA transgenic fly microbiota.
This model of CagA expression establishes that a bacterial virulence factor alters the gut microbial community, which exacerbates cell proliferation and immune phenotypes previously associated with H. pylori infection. This reveals a previously unrecognized role for the surrounding gut microbes in H. pylori pathogenesis, which provides valuable new insights into the mechanisms by which interactions between a pathogen, its host, and the microbiota contribute to disease.