"All of the Rock Band and Guitar Hero games have the option to switch into 'lefty mode', for those of us of the sinister persuasion"
Erm, yes, but we're talking about the "real" guitar, which won't allow for that. You'd have to restring the guitar (probably with new ones due to the different lengths required), flip the string guide (if it's not fixed in place), adjust the bridge and the tuners, and hope the pickups aren't tuned to the expected strings. In electric models, the guitar is now upside down, and usually rather uncomfortable, not to mention the machine heads are on the underside now.
And that's before even getting into the complications of the midi pickup interface, or hoping the game copes with it.