There are nine changes in personnel and a further three positional switches following the 42-21 rout by Ireland that removed England from title contention with two rounds remaining. It is the most changes ever made by England in the Six Nations era.
Smith will direct operations in his first start since the autumn at the expense of George Ford, who has been jettisoned from the matchday 23 entirely after underperforming against Andy Farrell's men.
British and Irish Lions playmaker Smith marshals a back line that includes only one survivor from the Ireland mauling in Tommy Freeman, and even he has been relocated from wing to outside centre.
Seb Atkinson and Freeman form the centre partnership and there is an entirely new back three in wings Cadan Murley, Tom Roebuck and full-back Elliot Daly. Ben Spencer starts at halfback
Borthwick's hand is partly forced by injuries to Alex Mitchell and Ollie Lawrence, but by ripping up the remainder of his backline England's head coach has rolled the dice for Saturday's Stadio Olimpico showdown.
None of the units behind the scrum have previously played together.
There are three changes to the pack with hooker Jamie George, second row Alex Coles and flanker Guy Pepper promoted to the starting XV having filled the bench against Ireland.
England have won all 32 previous encounters with Italy but Gonzalo Quesada's men are the strongest team fielded by the Azzurri since they joined the Six Nations in 2000.
Back-to-back heavy defeats by Scotland and Ireland have heaped pressure on Borthwick, with a trip to Paris to face Grand Slam chasing France concluding another disappointing Six Nations.
"We're expecting a big test in Rome and it's one the players are really looking forward to," Borthwick said.
"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."
ENGLAND (v ITALY)
Daly; Roebuck, Freeman, Atkinson, Murley; F Smith, Spencer; Genge, George, Heyes, Itoje (capt), Coles, Pepper, Curry, Earl.
Replacements: Cowan-Dickie, Rodd, Davison, Chessum, Underhill, Pollock, Van Poortvliet, M Smith.
