Simply put, the Colts know how to win. The Lions don't. 
Indy is coming off its bye. The Colts are much better coached than the Lions and own a far superior defense ranking in the top four in many of the major categories. 
The Colts are fresh and should control the trenches. The Lions rank 26th in run defense. Jonathan Taylor is lined up for success, which in turn takes the pressure off Philip Rivers. 
The expected return of superstar linebacker Darius Leonard makes the Colts' defense even stronger. Opposing QB's have just a 7-to-10 touchdown-to-interception ratio versus the Colts. 
The Lions have failed to cover nine of the last 13 times they've been underdogs.