Pope Francis issued a stark warning to the European Union
The Pontiff addressed EU leaders at the event which highlighted the 60th anniversary of the bloc’s foundation.
In his address, he warned Brussels faced a “vacuum of values” and was losing its “sense of direction”.
He said: “When a body loses its sense of direction and is no longer able to look ahead, it experiences a regression and, in the long run, risks dying.”
The Pope went on to condemn anti-immigrant populism and extremism, which he said posed a “mortal threat” to the union.
Prime ministers and presidents from 27 EU members states have gathered in Italy to mark the 1957 founding of the Treaty of Rome, receiving a Papal blessing on the eve of the anniversary.
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Pope Francis receives a parrot from a performer of the Golden Circus during his Wednesday general audience in Paul VI Hall at the Vatican
Celebrations around the milestone have been muted by unease within the bloc, mainly due to a number of prolonged economic crises and an unresolved migrant situation.
Prime Minister Theresa May did not attend the meeting of leaders at the Vatican.
The addition of Brexit has caused extra strain on relations, with Britain due to trigger Article 50 within days, marking the beginning of divorce proceedings with the EU.
The Pope greets Italian PM Paolo Gentiloni
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Just six nations signed the original treaty in 1957 – and on many levels the EU can be viewed as a success.
Over the last 60 years, it has grown to 28 countries and become the world’s largest trading bloc, with rising life expectancy and solid prosperity.
But with anti-European parties gaining support, the pope warned of a growing split between EU citizens and their institutions and said greater solidarity was the "most effective antidote to modern forms of populism".
German Chancellor Angela Merkel attended the audience with the Pope
The Argentinian-born pontiff told the leaders they needed to promote Europe's "patrimony of ideals and spiritual values" with greater passion and vigour.
"For it is the best antidote against the vacuum of values of our time, which provides a fertile terrain for every form of extremism," he said, mentioning the attack in London this week by a British-born convert to Islam, who killed four people.
The pope has repeatedly criticised Europe over the past five years for its perceived lack of vision, drawing the ire of German Chancellor Angela Merkel in 2014 when he described the EU as an elderly woman who was "no longer fertile and vibrant".
French President Francois Hollande awaits the start of the audience with the Pope
Despite adopting a less hostile tone, but urged the continent not to close in on itself and resurrect walls – a message aimed at US President Donald Trump as well as EU leaders struggling to deal with mass immigration.
Some 1.6 million refugees and migrants reached the European Union between 2014 and 2016 and how to handle them has been a major point of contention between member states.
He said: "It is not enough to handle the grave crisis of immigration of recent years as if it were a mere numerical or economic problem, or a question of security."