Genomic variation and ancestry of Helicobacter pylori in the admixed population of Cabo Verde reveal host adaptation, limited host–pathogen ancestry concordance, and signatures of trans-Atlantic slave trade migrations

Reviewer #1 (Public review):

Summary:

The authors are trying to characterize the sources of H. pylori in an island system. They find that, like the humans, the bacteria are admixed, but there is no correlation within the island between human ancestry and bacterial ancestry.

Strengths:

The study has taken particular care to characterize the humans from which isolates were obtained. Thus, it is a particularly convincing demonstration of a bacterial "melting pot".

Weaknesses:

The GWAS is highly confounded by population structure. In particular, there is a large group of strains that lack the cag pathogenicity island, and also differ in frequencies of other genes. So it's not clear that these differences are other than in cag status.

Figure 1 seems very inconclusive.

Reviewer #2 (Public review):

Summary:

This study investigates the population structure and ancestry of Helicobacter pylori in Cabo Verde, where the human population has mixed West African and European ancestry. The authors combine a population survey, serum markers, bacterial genome analysis, and paired human-bacterial ancestry data. They report high H. pylori seropositivity, several distinct bacterial groups, and limited correlation between human ancestry and bacterial ancestry. They also identify one European-derived bacterial group that appears to have undergone a recent expansion and carries fewer well-known virulence-related genes.

The study is interesting, and the dataset is valuable, especially because population-based H. pylori genomic data from Cabo Verde and West Africa are limited. The results provide useful information on bacterial diversity, historical migration, and host-bacterial ancestry. However, some of the main conclusions are stronger than the evidence currently supports, particularly the claims of host adaptation, increased transmission, and reduced virulence.

Strengths:

(1) A major strength is the study population. Participants were recruited from the general population and not only from patients with gastrointestinal disease. This gives a broader view of H. pylori diversity in Cabo Verde than studies based only on hospital patients.

(2) The number of participants tested for H. pylori antibodies is substantial, and the authors also obtained a relatively large number of bacterial genomes. The combination of human and bacterial genomic information is another important strength. This allows the authors to directly examine whether human ancestry is related to the ancestry of the colonising bacteria.

(3) The population genetic analyses are extensive. The authors use several different approaches, and these generally support the existence of African-derived and European-derived bacterial groups in Cabo Verde. The identification of two low-diversity European-derived groups is also interesting and suggests a relatively recent expansion.

(4) The addition of new strains from Ghana and Portugal improves the reference dataset. The results may help future studies of H. pylori population structure in Africa, Europe, Cabo Verde, and populations affected by historical Atlantic migration.

(5) The finding that human ancestry and bacterial ancestry are only weakly related in this population is potentially important. It suggests that the long-term relationship between human and bacterial ancestry may be less stable in recently admixed populations.

Weaknesses:

The main weakness is that several biological conclusions are based on indirect evidence. The genomic results support recent expansion of one bacterial group, but they do not directly show that this expansion was caused by adaptation to local hosts or by increased transmission. Founder effects, population history, geographic clustering, household transmission, or random expansion may also explain the pattern. The wording should therefore be more cautious.

The conclusion of reduced virulence is also not fully supported. The expanded lineage often lacks the cag pathogenicity island and carries less virulent forms of vacA, which suggests lower virulence potential. However, this does not prove that the strains cause less gastric damage or lower disease risk. There are no endoscopic or histological data, and serum pepsinogen values are only indirect markers.

The description of the study population as having limited gastric inflammation is too strong. Serum pepsinogen measurements are useful for estimating gastric atrophy, but they do not directly measure the degree of histological gastritis. In addition, participants were recruited independently of symptoms, but this does not mean that they were all asymptomatic.

The epidemiological estimate is based on antibody testing. This measures seropositivity and cannot clearly distinguish current from previous infection. Therefore, terms such as active infection or colonisation should be used carefully.

The proposed new West-Central African bacterial group is based on a small number of reference strains from Ghana and Nigeria. The result is interesting, but broader sampling from African countries is needed before this group can be considered firmly established.

The interpretation related to the trans-Atlantic slave trade is plausible, but the data mainly show patterns consistent with known historical migration. They do not directly demonstrate when or how the bacterial lineages moved.

The gastric cancer comparison may also be affected by bacterial population structure. Differences between the Cabo Verdean lineage and gastric cancer strains may reflect ancestry or lineage differences rather than disease association alone.

Overall, the study achieves its main aim of describing H. pylori diversity and ancestry in Cabo Verde. The evidence is strong for the population structure and ancestry findings, but less strong for the proposed mechanisms of adaptation, transmission, and reduced disease-causing potential. The work will be useful to the field, but the main conclusions should be stated more carefully.