That is quite a tough choice there... I'm usually more partial to Macro as opposed to having other characters be micro. But just thinking of story possibilities, normal main character/s interacting with micro's is a lot easier to keep going for a story what with the issues of;
A) With the degree of size some prefer there Macro's at, interaction with almost anyone is an issue (save for multi size Macro's I suppose)
B) The amount of attention a Macro would draw and all the calamity that would ensue would probably make it difficult to have that 'only slightly removed' from life feeling's a lot of comics strive for. That feeling there is usually something I feel keeps the comic in the 'one shot' comic genre rather than building a universe setting that running series or multiple comics from authors have. Sort of like how Karbo's pics all take place in Felarya, he's built a world.
But with all things there are ways to do them, like having a backstory as to how a character became a Macro. Explaining that it's not easy/normal being a Macro like you did in the Truffle story. (and having Gen being able to 'fix' things to her pleasing could help XD)
Even having the setting being on a massive planet that has cities/civilizations/continents of creatures that vary in size, or technology that can change size(*cough* ManiScience *cough*) would make things fit into a world rather than a one shot.
I'm probably just ranting about things you've already considered with how much thought you put into doing your comics though so I'll curtail it here. XD
nah, i know what you mean. it's tricky to build any kind of ongoing story around it c.c it's hard for me to even invent a whole story to begin with XD; which is why the things i've written have been so fragmented c.c