De Bruyne has been in good form for City again this season, with 18 assists in 31 matches in all competitions.
Guardiola said Aymeric Laporte (28) would miss the game also with an unspecified illness and cast doubt on whether they would recover in time for Saturday's Premier League match at Bournemouth.
"Unfortunately, sometimes it happens. He (De Bruyne) didn't feel good right after the game with Forest... yesterday Aymer (Laporte) didn't feel good. Another player is going to play. It happens sometimes," Guardiola told reporters on Tuesday.
City will look to turn things around after being held to a 1-1 draw at Nottingham Forest on Saturday, falling two points behind Premier League leaders Arsenal.
Guardiola said he believes that his side is still in excellent shape.
"Last game against Nottingham was highest standards, I loved the way we play and we don't win because it's football. I do not have an answer on what happened in that situation," he said.
"Today we trained and it's there but that doesn't mean we'll win. But I have a good feeling."
He added that his side would face a challenge against Marco Rose's Leipzig, who are fifth in Bundesliga, trailing Bayern Munich by four points.
City also played Leipzig last season in the Champions League group stage, with Leipzig winning 2-1 at home and City thrashing them 6-3 at the Etihad Stadium.
"We know the quality of them for many years. A culture for young players, recruitment, physicality, clear patterns of play, go to the channels, a lot of play in the middle... in the transition they are unstoppable," Guardiola said.
"Huge respect, I know the quality and it will be tough."
