Human and Helicobacter pylori coevolution shapes the risk of gastric disease

Abstract

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.

Keywords: Latin America; admixture; histopathology; inflammation.

Fig. 1.

Human and H. pylori ancestry. (A) Human ancestry distributions of Colombian study participants from the coastal region of Tumaco (n = 122) and the mountain region of Tuquerres (n = 120). Black lines indicate median ancestry proportions; dotted lines indicate means. Box limits mark the 25th and 75th percentiles. (B) H. pylori ancestry distributions from the coastal region of Tumaco (n = 156) and the mountain region of Tuquerres (n = 132). Mean estimates were 0.47 ± 0.23 AA1, 0.34 ± 0.14 AE2, 0.14 ± 0.12 AE1, and 0.05 ± 0.04 AEA on the coast and 0.20 ± 0.12 AA1, 0.50 ± 0.11 AE2, 0.22 ± 0.09 AE1, and 0.08 ± 0.07 AEA in the mountain region. Black lines indicate median ancestry proportions; dotted lines indicate means. In the H. pylori ancestries: AEA, Ancestral East Asia; AA1, Ancestral Africa1; AE1, Ancestral Europe1; and AE2, Ancestral Europe2. Box limits mark the 25th and 75th percentiles. (C–F) Admixture proportions of human (C and D) and H. pylori (E and F) ancestry (n = 233). Each human host and his or her corresponding H. pylori isolate are represented by a vertical bar spanning both panels, with admixture proportions denoted by color. (C) Humans from the coastal region. (D) Humans from the mountain region. (E) H. pylori from the coastal region. (F) H. pylori from the mountain region. For the human admixture, blue = African, green = European, and Amerindian = yellow. For the H. pylori admixture, blue = AA1, green = AE2, gray = AE1, and lime green = AEA.

Fig. 2.

Relationship between H. pylori ancestry and human Amerindian ancestry. The proportion of European H. pylori ancestry (AE2) correlates positively and African H. pylori ancestry (AA1) correlates negatively with host Amerindian ancestry. The 90% density ellipses are demarcated by the shaded area in each plot. The wider minor axis of the lower ellipse indicates that AA1 is dispersed more broadly than AE2 in Amerinds. n = 233.

Fig. 3.

All subjects with low proportions of host African ancestry (<17.6%, the lowest decile on the coast) and carrying an H. pylori strain with >19.8% AA1 ancestry (dotted line) had advanced lesions (histopathology scores >2), regardless of place of residence, indicating the importance of the interaction of host Amerindian ancestry and H. pylori AA1. Closed circles represent coastal residents; open circles represent mountain residents. n = 56.