Basically, you'd have to do at least one of the guild storylines to start the main quest. However you can completely lay off the main quest and do as many guild storylines as you want. Depending on which ones you do and how many will alter the characters, the events, and such in the main quest.
So let's say a warrior does the Companions and then the main quest. Events that occurred in the Companions' quests will affect the storyline over all. But assume this same warrior has also completed the Legion quests and the Blades quests, that will further alter the storyline, introducing more characters, changing events, and so on.
This would allow so much more different possibilities in the main quest. Each playthrough would literally be different, as there would be several outcomes that would change. Also, the character's build would be more fit for the main quest (being an Assassin, completing the Dark Brotherhood, makes it more assassin-oriented).
Think of Mass Effect, but replace Mass Effect's side-quests with guild quests like in Skyrim, and imagine bigger and better consequences for completing them.