Marine invertebrates are colonized by a plethora of microbes - some of which are benevelant (mutualist), while others can turn out to be detrimental (pathogen) depending on environmental conditions. Bacteria of the genus Vibrio colonizing marine bivalves like oysters are a prime example for adapting such different symbiont strategies. For one, the hemolymph of oysters shows a strong enrichment of diverse Vibrio strains, but oysters are also subject to recurrent disease episodes caused by shifts of these Vibrio populations to dominance of pathogenic strains. Here, we can show that Vibrio colonization is dependent on other components of the hosts microbiome. Despite of this larger microbiome perspective, we can identify decisive genetic factors differentiating virulence profiles of only distantly related Vibrio strains on different oyster host populations and show that these strains responded to similar selection pressures. Gene knock-outs further demonstrated that these genes are utilized both by host resistance/tolerance evolution but also function as colonization factors enabling Vibrios to grow in the hemolymph environment of their local host population.