Perhaps 8472 could go back to its original characterization. They come back from fluidic space to kill off all the other species (it seemed like this telepathic species couldn't cope mentally with the mere existence of an other and perceived it as an affront by an inferior?) But to be safe, they come back in Gamma Quadrant and start annihilating Dominion planets.
Enterprise as the flagship and DS9 as the gateway come in obviously. And Janeway et al. come in as experienced with 8472. If you want to go dark and gritty Janeway can do the crazy admiral and make another alliance with the Borg. (Cue Seven of Nine!)