Transmission of H. pylori occurs predominantly within families, mostly from mother to infants. In the long run, the quasi-vertical transmission leads to colonization by genetically distinct H. pylori subpopulations in different human populations. In terms of CagA polymorphism, the vast majority of H. pylori isolates in East Asian countries bear East Asian CagA. In contrast, most if not all H. pylori cagA-positive strains isolated in non-East Asian countries carry Western CagA (Fig. 5). A clear exception is Southeast Asia, where H. pylori strains carrying East Asian CagA and Western CagA co-exist with various ratios in different areas/countries.(58–61) Notably, the incidence of H. pylori infection is extremely low in Java and Malaysia compared to the incidence in the rest of the world.(62,63) Based on this finding, Graham et al.(64) postulated that ancestral Javanese and Malaysian passed through a population bottleneck in which H. pylori infection/transmission was effectively prevented or a significant percentage of individuals infected with H. pylori were negatively selected. After the bottleneck, East Asian CagA-carrying H. pylori and Western CagA-carrying H. pylori may have been introduced into Southeast Asian people through migrations of ethnic Chinese and ethnic Indian people, respectively. Another interesting observation is that a substantial fraction of H. pylori strains isolated in Okinawa, the southmost prefecture of Japan consisting of more than 100 small islands, carry Western CagA with the EPIYA-C segment.(65,66) Geographically, Southeast Asia is much closer to Okinawa than other areas of Japan. Also, Okinawa was under administration by the USA for 27 years after the end of World War II until 1972, and there are still large US military bases in Okinawa. This raises the idea that Western H. pylori strains circulating in Okinawa originated from Southeast Asia or were introduced by recent Western influence. However, the Western CagA isolates in Okinawa are phylogenetically separable from the major Western CagA cluster.(66) As all of the Western CagA proteins isolated in Southeast Asian countries such as Vietnam, Thailand, and the Philippines belong to the major Western CagA cluster, the CagA variant termed “J-Western CagA” appears to be peculiar to Okinawa.(59,61) This finding argues against the idea that Western CagA in Okinawa was derived from Southeast Asia or Western countries. Drawing an analogy with the model proposed by Ishida and Hinuma(67) that explains the distribution of human T lymphotropic virus type 1 (HTLV-1) carriers in Japan, it is tempting to hypothesize that H. pylori strains carrying J-Western CagA had been accompanied by Japanese aboriginal people, known as Jomon people, who were the earliest inhabitants of the islands of Japan more than 10 000 years ago. Approximately 2500–1500 years ago, Yayoi people, who were the ancestors for most of the present Japanese population, moved from northern Asia through the Korean Peninsula to the central part of Japan (Fig. 6a). This movement pushed Jomon people away to the northern or southern periphery of Japan such as Hokkaido and Okinawa. As Yayoi people, who originated from northern Asia, were most likely to have carried H. pylori with East Asian CagA, the prehistoric racial movement could explain the enigmatic distribution of two distinct CagA species, East Asian CagA and J-Western CagA, in Japan. Notably, the incidence of gastric carcinoma is significantly lower in HTLV-1 carriers than in HTLV-1 non-carriers in Japan.(68) It would be interesting to know if H. pylori carrying J-Western CagA is also found in Ainu people, northern descendents of the Jomon people inhabiting Hokkaido, who share several physical and genetic traits in common with ethnic Okinawa people.
Figure 6. Prehistoric human migration from a Helicobacter pylori CagA perspective. (a) Post-Neolithic migration of Japanese ancestral people occurred 2500–1500 years ago. The unique migration pattern raises the idea that Jomon people, the ancestors of ethnic Okinawa people and ethnic Hokkaido people (Ainu), were infected with H. pylori strains carrying a unique J-Western CagA. (b) A model of human migration to the American continent. The model hypothesizes inhabitation of Northeast Asian people who carried H. pylori with Western CagA in the prehistoric era, which is supported by the isolation of H. pylori having a unique Western CagA subtype (J-Western CagA) in Okinawa, Japan. The model assumes that those ancient Northeast Asian people migrated to North America through the Bering Strait and then to South America (black arrow line) before or after dispersion of another dominant ancient Asian people who carried East Asian CagA to the American continent (red arrow line). Possibly because of its merit in agricultural society, H. pylori strains carrying East Asian CagA had already been expelled from the stomach of the prehistoric Asian immigrants in the American continent (indigenous Americans) by those carrying Western CagA before massive immigration of European people, who carried H. pylori with Western CagA, after the 15th century (yellow arrow lines). Consequently, H. pylori strains having East Asian CagA are now lost from all but a few indigenous Americans.
Download figure to PowerPoint
It is thought that H. pylori accompanied humans when they crossed the Bering Strait from Asia to the New World.(69) Consistent with this hypothesis, several H. pylori isolates from indigenous Colombian people carry East Asian-type CagA.(70) Curiously, however, the vast majority of H. pylori isolated from indigenous Americans carry Western CagA, even though they were living in areas where the influence of modern Western culture was almost negligible.(70,71) The seemingly controversial observation is currently explained by rapid extinction of H. pylori carrying East Asian CagA as a result of expansion of those carrying Western CagA that came with European and African immigrants after the 15th century. However, the possibility that a fraction of the ancient East Asian aboriginal peoples (such as Jomon people) carried H. pylori strains with Western CagA raises an alternative model (Fig. 6b). In this model, prehistoric Asian peoples carrying H. pylori with Western CagA and those carrying H. pylori with East Asian CagA migrated to North America and then to South America by turns. Subsequent founder effects, geographic separation, and differential efficiency of colonization in the human stomach may have resulted in predominant inhabitance of H. pylori with Western CagA in North America and South America, long before the settlement of European and African people carrying H. pylori with Western CagA, after the 15th century.