Fin Smith comes into the starting line-up at fly-half and is joined by Ben Spencer, with George Ford and Alex Mitchell (injured) dropping out of the squad altogether.
Maro Itoje will captain an England side which features nine personnel changes from the starting team that lost to Ireland in round three of the 2026 Six Nations.
The new faces coming into Borthwick's XV include Jamie George, Alex Coles, Guy Pepper, Spencer, Smith, Cadan Murley, Seb Atkinson, Tom Roebuck and Elliot Daly, while Tommy Freeman moves from the wing to centre for this weekend's fixture.
Other players joining Ford and Mitchell in missing out entirely after the recent defeat to Ireland are Freddie Steward, Ollie Lawrence (injury), Fraser Dingwall and Henry Arundell, with the backline clearly coming under fire from Borthwick and co.
There will be a milestone in the England side on Saturday as number eight Ben Earl is set to win his 50th cap, having made his debut against Scotland back in 2020.
"We're expecting a big test in Rome and it's one the players are really looking forward to," said Borthwick when looking ahead to the fixture.
"We know the challenge Italy will bring at the Stadio Olimpico, and we've selected a team we believe will deliver the level of performance we're striving for."
On Earl's milestone, Borthwick added: "To reach 50 caps for England speaks volumes about Ben's professionalism and the consistency of his performances.
"He's an important leader within this group, someone who drives standards and brings energy every day. It's a wonderful achievement and one he should be very proud of."
England - 15 Elliot Daly, 14 Tom Roebuck, 13 Tommy Freeman, 12 Seb Atkinson, 11 Cadan Murley, 10 Fin Smith, 9 Ben Spencer, 8 Ben Earl, 7 Tom Curry, 6 Guy Pepper, 5 Alex Coles, 4 Maro Itoje (c), 3 Joe Heyes, 2 Jamie George, 1 Ellis Genge.
Replacements: 16 Luke Cowan-Dickie, 17 Bevan Rodd, 18 Trevor Davison, 19 Ollie Chessum, 20 Sam Underhill, 21 Henry Pollock, 22 Jack van Poortvliet, 23 Marcus Smith.
Everton manager David Moyes has said Kiernan Dewsbury‑Hall is closer than many think to forcing his way into the England squad if he keeps producing strong performances for the Blues.
The original Six Nations trophy has been severely damaged in an accident, resulting in the organisers rolling out a new trophy for the 2027 edition.
Ireland are awaiting further assessments on star winger James Lowe, who is recovering from a groin injury sustained during their recent win over England.
England's Six Nations title hopes were effectively ended after a record 42-21 defeat to Ireland at Allianz Stadium, Twickenham, with Ellis Genge apologising to supporters and admitting the squad had "believed the hype" after their opening-round win.
