When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88–116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43–56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36–52 kya, after the Out of Africa migrations around 60 kya.
We previously showed that the population history of H. pylori may be used as a marker for human migrations, including the demonstration that humans carried H. pylori out of Africa 60,000 years ago during their recent global expansions. But how long were humans infected by H. pylori prior to the out-of-Africa event? Here we showed that chimpanzees in Central-East Africa do not possess Helicobacter-like bacteria, as would have been expected for pathogen-host co-evolution over millions of years. Using H. pylori gene sequences isolated from San, a group of click-speaking hunter-gatherers, and numerous other sources, we calculated that humans have been infected with H. pylori for at least 88,000–116,000 years. Phylogenetic comparisons showed similar evolutionary histories for human and H. pylori lineages and suggest that this association stemmed from a single host jump. We showed that hpAfrica2, the most divergent H. pylori population, arose in the San and that their progenitors were the source of H. acinonychis which was acquired by large felines approximately 50,000 years ago. Furthermore, our data provided clear evidence for a recent second exodus Out of Africa in the last 52,000 years which was essential for the formation of the hybrid population that currently infects Europeans.