The Sky Blues have received a series of worrying injury setbacks ahead of their tie against the Saints, with Oleksandr Zinchenko and Rodri ruled out of the match due to injury.
Guardiola confirmed in his pre-match press-conference that John Stones and Aymeric Laporte were both out of contention for the clash with muscle injuries.
After claiming four wins on the spin across all competitions, City are without a series of key men for their league meeting with Ralph Hasenhüttl's side at the Etihad Stadium.
Speaking to Sky Sports prior to the 15:00 (UK) kick-off in the east side of Manchester, Guardiola justified his team selection against the Saints, who will be looking to claim their first league win of the season.
The Catalan boss said: "After the Champions league, it's always so demanding. We never select a team that we don't believe cannot win. You always select a team that you believe can do a good game."
Nathan Aké, whose father passed away this week, is set to start for the second time in the space of four days alongside Rúben Dias in central defence, with Stones and Laporte unavailable.
Guardiola added: "He (Aké) did well in the last game, and has another today with the situation that we have; two central defenders (Stones and Laporte) injured, Rodri injured, Zinchenko injured. We are not in a good condition at the back. But Nathan (Aké) is an exceptional person and has our trust."
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Rodri appeared to have suffered a minor knock towards the closing stages of City's mid-week win over Leipzig, whilst Zinchenko played the full 90 minutes against the German side.
Fernandinho has slotted into the middle of the park for Rodri, while Kyle Walker's return to the right side of defence means that João Cancelo, who starred against Leipzig, will operate as left-back against Ralph Hasenhüttl's side.
Guardiola has also handed a start to England forward Raheem Sterling, who makes the starting XI for the first time since City's 1-0 defeat away at Tottenham on the opening day of the Premier League campaign in August.
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