Instant Replay: A first under Harbaugh -- 49ers lose two in a row
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SAN FRANCISCO – Now, the 49ers have plenty of on-field issues, too.

The 49ers came back from their humbling loss to the Seattle Seahawks with a sluggish performance against the Indianapolis Colts on Sunday at Candlestick Park.

Quarterback Andrew Luck made enough plays -- and 49ers penalties provided him with extra chances -- and the Colts defense thoroughly handled the 49ers in a 27-7 upset to send the 49ers to their first back-to-back losses under coach Jim Harbaugh.

The 49ers, who were 7-0 after losses in Harbaugh’s first two seasons as coach, fall to 1-2 on the season. They are two games behind the Seattle Seahawks in the NFC West. The 49ers were 29-3 losers at Seattle last week.

All-Pro outside linebacker Aldon Smith, who was arrested on suspicion of driving under the influence and possession of marijuana on Friday morning, was in the starting lineup and saw the same amount of playing time as usual.

But his status for the immediate future is uncertain amid growing concern within the organization for his personal life, sources indicated. The 49ers will encourage Smith to seek treatment, and it’s not known if Smith will remain with the team.

Also, All-Pro linebacker Patrick Willis sustained a groin injury late in the third quarter that sidelined him. With a quick turnaround on Thursday night, the 49ers are not likely to have Willis’ services for that game, either.

The 49ers played Sunday without tight end Vernon Davis, who sustained a left hamstring strain against the Seahawks. Without Davis on the field, the 49ers’ passing game was pedestrian, at best.

Wide receiver Anquan Boldin caught 5 passes for 67 yards, but the 49ers provided no other threats in the passing game.

Quarterback Colin Kaepernick completed just 13 of 27 pass attempts for 150 yards, lost a fumble inside the 49ers' own 10-yard line when he was sacked with less than 4 minutes left, and threw a pick on a deflected pass with less than a minute remaining.

Luck got the better of the 49ers in the head-to-head matchup against his former Stanford coach. Luck provided the clinching points with a 6-yard bootleg to give the Colts a 20-7 lead with 4:13 remaining in the fourth quarter.

Gore picks it up: Running back Frank Gore, who gained just 60 yards in the 49ers’ first two games, looked like the Gore of old on Sunday fron the outset.

Gore had 70 yards rushing on eight first-half carries alone. He had rushes of 22, 11 and 21 yards on a first-quarter drive that ended with Kendall Hunter’s 13-yard touchdown run to tie the game at 7-7.

He finished the game 82 yards on 11 carries.

Colts’ strong start: Luck wasted little time in setting the tone for the game on the first offensive possession with a seven-play, 80-yard drive that resulted in newcomer Trent Richardson’s 1-yard touchdown run on his first attempt.

Richardson was acquired in a midweek trade with the Cleveland Browns for a first-round pick in next year’s draft. Richardson, a second-year pro, was chosen with the No. 3 overall pick in 2012.

The drive began with back-to-back 49ers penalties that resulted in first downs. Safety Donte Whitner was called for unnecessary roughness for using the crown of his helmet to tackle running back Ahmad Bradshaw. Replays showed that Whitner led with his shoulder, not his helmet. On the next play, cornerback Tarell Brown was called for a 9-yard pass-interference penalty.

Injury concerns: Willis sustained a groin injury on a play in which Reggie Wayne caught a 25-yard pass from Luck in the third quarter. The team’s medical staff gathered around Willis, who was immediately ruled out of the game.

Special-teams ace Bubba Ventrone sustained a concussion in the first quarter and did not return to the game.

This ‘n’ that: Kendall Hunter replaced Perrish Cox as the deep man on kickoff returns. Cox lost a fumble last week against the Seattle Seahawks. . . . Fullback Owen Marecic, who was signed during the week, was among the 49ers’ 46 active players. Quarterback B.J. Daniels, running back LaMichael James, receivers Chris Harper and Jon Baldwin, tight end Davis, and guard Joe Looney were inactive.