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Manchester City boss Pep Guardiola must decide whether to recall Sergio Aguero, who has featured as a substitute in the last two games.
Bacary Sagna and Pablo Zabaleta are injured, while City will monitor Vincent Kompany, who was left out in midweek because he was not fully fit.
Shane Long misses out for Southampton after suffering a hamstring injury against Inter Milan on Thursday.
Matt Targett, Ryan Bertrand and Cedric Soares are doubts and will be assessed.
Club-record signing Sofiane Boufal came off the bench in midweek for his debut and could make his first Premier League appearance, although a lack of match fitness means he is unlikely to start.
Steve Bower: "Both clubs are back in action after defeat in glamour European away games this week, but it was Manchester City who returned with more unanswered questions.
"Pep Guardiola won’t anticipate many spells of four games without a win this season. One fact we do know is that the City manager won’t change his approach as he continues to learn about his new players and stamp his mark on the team.
"That is what Claude Puel is beginning to do with Southampton after a slow start, and luck wasn’t on his side in the San Siro in midweek.
“He’ll be fully aware that a sterner test lies in wait at the Etihad Stadium, where the Saints have lost on their last six visits. They have kept clean sheets in their last two away games, but it would raise some eyebrows if they continue that particular record.”
Man City manager Pep Guardiola on leaving out Sergio Aguero and Vincent Kompany against Barcelona: "They are the future for Manchester City. Vincent Kompany was not perfectly fit and that is why we took the decision.
"It was a tactical decision [with Aguero]. I wanted one more midfielder, I tried to keep the ball in the Camp Nou and when you have the ball, Lionel Messi, Neymar and Luis Suarez don’t.
"I spoke with Sergio and he was understanding, I thought in the last 30 minutes, with the Barcelona centre-halves tiring, he could help a lot from the bench.
“When Sergio decides to leave it will be his decision. Next time before you [the media] decide he is not in my plans you can call me.”
Southampton manager Claude Puel: "I managed against Pep early in his career and he has not changed his philosophy.
"It’s difficult to defend against them, because they like to have good possession.
“But for us it is important to play our football, and I think we can have a good game.”
Southampton look very solid at the back and do not seem to make too many mistakes. At the other end, Charlie Austin is going through the sort of spell where he cannot miss.
City’s defeat by Barcelona means they have now gone four games without a win in all competitions, but they were still top of the league going into the weekend.
Some people might be painting it as a crisis but it really isn’t.
SAM (Sports Analytics Machine) is a super-computer created by @ProfIanMcHale at the University of Salford that is used to predict the outcome of football matches.
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