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, 10 (1), 2273

Within-host Evolution of Helicobacter Pylori Shaped by Niche-Specific Adaptation, Intragastric Migrations and Selective Sweeps

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Within-host Evolution of Helicobacter Pylori Shaped by Niche-Specific Adaptation, Intragastric Migrations and Selective Sweeps

Florent Ailloud et al. Nat Commun.

Abstract

The human pathogen Helicobacter pylori displays extensive genetic diversity. While H. pylori is known to evolve during infection, population dynamics inside the gastric environment have not been extensively investigated. Here we obtained gastric biopsies from multiple stomach regions of 16 H. pylori-infected adults, and analyze the genomes of 10 H. pylori isolates from each biopsy. Phylogenetic analyses suggest location-specific evolution and bacterial migration between gastric regions. Migration is significantly more frequent between the corpus and the fundus than with the antrum, suggesting that physiological differences between antral and oxyntic mucosa contribute to spatial partitioning of H. pylori populations. Associations between H. pylori gene polymorphisms and stomach niches suggest that chemotaxis, regulatory functions and outer membrane proteins contribute to specific adaptation to the antral and oxyntic mucosa. Moreover, we show that antibiotics can induce severe population bottlenecks and likely play a role in shaping the population structure of H. pylori.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Genetic diversity within H. pylori populations from 16 human individuals. a Global phylogeny including 440 H. pylori isolates from 16 human individuals. Isolates from the same patient are clustering together tightly indicating that no mixed infection was sampled. The scale bar represents the number of substitutions per site. Source data are provided as a Source Data file. b Every circle represents the H. pylori population from one individual patient. Each population consists of 20–30 clones (see text for details). Circles are ordered by decreasing genetic within-host diversity from outer to inner circle. From the outer to inner ring: patient 476, 479, 25, 19, 169, 24, 21, 13, 5, 381, 23, 26, 20, 478, 173, 280. Genetic coordinates were synchronized across all populations by mapping onto the reference strain 26695. Spontaneous mutation and recombination events are represented by red and blue lines, respectively. Regions present in 26695 but not fully covered in a population are indicated by black lines (the 23S region indicated here corresponds to the second copy, which is not always properly assembled in draft genomes, resulting in uncovered regions)
Fig. 2
Fig. 2
Clustering structure of the H. pylori population varies between individual patients. Representative phylogenetic trees of within-host H. pylori populations displaying different degrees of clustering. Trees were generated as described in the methods (source data are provided as a Source Data file). The time since the most recent common ancestor (TMRCA), expressed in years, is represented by the X axis. Pie charts correspond to the posterior probability distribution of ancestral characters (i.e., likelihood that ancestral lineages originated from antrum: blue, corpus: orange or fundus: green). a Phylogenetic tree of patient 381 isolates showing a well-defined cluster structure. b Phylogenetic tree of patient 24 isolates showing a poorly defined cluster structure
Fig. 3
Fig. 3
H. pylori preferentially migrates between the corpus and fundus regions of the stomach. a Estimation of symmetric migration rates by marginal state reconstruction based on a global structure constructed by concatenating individual time-scaled trees (A: antrum, C: corpus, F: fundus; *: p < 0.05). Error bars represent 95% confidence intervals of the maximum likelihood estimates. b Schematic representation of the migration events distribution predicted by stochastic character mapping in relation to the stomach anatomy (blue: antrum, orange: corpus, green: fundus). Source data are provided as a Source Data file. Panel 3b is a derivative of “Stomach 4” by Servier Medical Art, used under CC BY 3.0 [https://creativecommons.org/licenses/by/3.0/]
Fig. 4
Fig. 4
Evidence of natural selection in niche-specific genotypes from enriched functional categories. For each H. pylori population, black and gray squares represent polymorphic genes with and without association to gastric regions, respectively; white squares indicate genes without non-synonymous mutations. Locus tags from H. pylori strain 26695 are given as reference. MK indicates the Fisher’s exact FDR adjusted p value from a McDonald–Kreitman test (bolded values indicate significance at p < 0.05). N.I.: Neutrality Index
Fig. 5
Fig. 5
Major population bottleneck in a H. pylori population. Two sets of gastric biopsies were obtained two years apart in a 34 years old treatment-naive patient with chronic gastritis (patient 476). A time-scaled tree was created using the isolates obtained at both time points (blue: antrum, orange: corpus, green: fundus). The population observed at the first time point had an estimated TMRCA of 7 years. The directly related population observed at the second time point had a TMRCA < 1 year and displayed a phylogenetic structure suggesting a fast clonal expansion subsequent to a bottleneck. Source data are provided as a Source Data file

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