I searched this out when I first unlocked it, and most posts I found said they really didn't notice a difference, but the consensus seemed to be that you can get harder rooms, with more difficult enemies, earlier.
In my case, I definitely noticed it. Honestly, I feel like the game has never been the same again- stronger enemies do show up where they didn't used to. But more than that, the architecture in the enemy rooms seems much harsher. I'd be amazed if Everything's Terrible didn't affect room layouts, too.
drexl235: wow....... not even achievements. whats the point
The main thing that happens that I've seen is that you get different variations on bosses after you get this ending.
Before you get it, Monstro, Larry Jr, Duke of Flies, all of them, only have one variation, the standard colour standard boss.
But after I got this ending I began finding bosses with different variations. For example, Monstro was smaller, and there were two of him. Larry Jr was bigger and faster, OR Larry Jr had the ability to shoot from his mouth. Duke of Flies had the ability to shoot a circle of blood OR shot a bunch of the splitting fly variants at you. I've also seen a variant of Fistula that dropped Fly Bombs when a piece of him dies instead of the standard Grubs.
Every boss seems to get variations except for Mum, Mum's Heart and Satan.
Typically it's harder room lay-outs and stronger enemys (like the knights, and their upgraded brethren) spawning in earlier levels, and usually more of em. however difficulty wise I barely noticed any difference in how hard the game is.