De Bruyne has been troubled by a foot problem in recent weeks, whilst Ake came off in the midweek win over Brighton after twisting his ankle.
The Belgian midfielder completed 57 minutes as City thrashed Watford 5-1, providing a sublime cross for Gabriel Jesus’ second goal and Ake replaced Aymeric Laporte for the final 27 minutes despite not having fully recovered after Wednesday’s 3-0 win against the Seagulls.
With the first leg of our Champions League semi-final against Real Madrid to follow on Tuesday, Guardiola admitted those issues played a part in his selection and substitution decisions.
“I have 14/15 players fit and the last few games Kevin and Aymer play a lot of minutes,” he said at his post-match press conference.
“Kevin, it doesn’t look like it, but he is playing with some disturbing niggles in his ankles for the kicks he got in the last games.
“Of course, at 4-1, I am thinking about that. It is not just Madrid it’s Leeds as well. You have seen the schedule.
“That is why in that moment I am thinking the game is almost over and I give rest in the last minutes to the players who have played a lot of minutes.
“We don’t have lots of central defenders that is why Nathan played with a big problem in his ankle.”
Guardiola also revealed he does not know if Kyle Walker and John Stones will be fit to face Madrid.
An ankle injury kept Walker out for a third consecutive game against Watford, whilst Stones was unavailable after reporting muscle tightness against Brighton.
“We don’t have many options,” he added.
“We don’t have full-backs. I don’t know when Kyle will arrive. We will see. Joao is out [due to suspension] and John will be difficult to get through.”
Watch the full press conference in the video above.