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Gundogan is close to a return from a hamstring strain and has been training with the team, while Argentinian defender Otamendi is struggling to shake off a knock.
Kevin De Bruyne is ruled out with ligament damage sustained in Thursday's Carabao Cup win over Fulham.
On De Bruyne Guardiola said: "Unfortunately he is injured but fortunately he will come back in four-six weeks," before adding: "He was so sad. But today less sad and tomorrow he will be stronger again. He can spend time with his family, then it's international break and then he will be back."
Boss Guardiola is expecting a difficult game against Southampton, with City requiring last-minute winners in both games against Saints last season, including the famous Centurions moment at St Mary's.
He said: "I'm impressed with the quality they have up front and especially in the middle.
"They have talented players. They play so deep and so physical.
"It was so hard to beat them and so complicated. We have to be sharp and move well in small spaces and concede few chances in set pieces as they are strong there too.
"They had one week to prepare for this game so it will be tough. We have to be ready to get the three points."
City remain unbeaten in the Premier League, with 26 points from 10 games so far. In the corresponding fixture last season Saints pushed us all the way, with Raheem Sterling coming up with the late winner.
City are into the last eight