6 research outputs found
A Changing Gastric Environment Leads to Adaptation of Lipopolysaccharide Variants in Helicobacter pylori Populations during Colonization
The human gastric pathogen Helicobacter pylori colonizes the stomachs of half of the human population, and causes development of peptic ulcer disease and gastric adenocarcinoma. H. pylori-associated chronic atrophic gastritis (ChAG) with loss of the acid-producing parietal cells, is correlated with an increased risk for development of gastric adenocarinoma. The majority of H. pylori isolates produce lipopolysaccharides (LPS) decorated with human-related Lewis epitopes, which have been shown to phase-vary in response to different environmental conditions. We have characterized the adaptations of H. pylori LPS and Lewis antigen expression to varying gastric conditions; in H. pylori isolates from mice with low or high gastric pH, respectively; in 482 clinical isolates from healthy individuals and from individuals with ChAG obtained at two time points with a four-year interval between endoscopies; and finally in isolates grown at different pH in vitro. Here we show that the gastric environment can contribute to a switch in Lewis phenotype in the two experimental mouse models. The clinical isolates from different human individuals showed that intra-individual isolates varied in Lewis antigen expression although the LPS diversity was relatively stable within each individual over time. Moreover, the isolates demonstrated considerable diversity in the levels of glycosylation and in the sizes of fucosylated O-antigen chains both within and between individuals. Thus our data suggest that different LPS variants exist in the colonizing H. pylori population, which can adapt to changes in the gastric environment and provide a means to regulate the inflammatory response of the host during disease progression
Genetic adaptations of Helicobacter pylori during gastric disease progression
Helicobacter pylori colonizes the stomachs of approximately half of all
humans. In the absence of treatment, H. pylori can persist throughout the
life of the host. Although most infected individuals are asymptomatic, a
significant proportion develops peptic ulcer disease, chronic atrophic
gastritis (ChAG) or gastric adenocarcinoma. ChAG is considered to be a
precursor to gastric cancer and is characterized by loss of acidproducing
parietal cells and pepsinogen-secreting zymogenic cells, and an
accompanying amplification of gastric stem cells in the gastric mucosa.
The precise mechanisms by which H. pylori causes gastric cancer are
unknown.
This thesis aimed to identify genetic adaptations of H. pylori to the
atrophic gastric environment of hosts with ChAG during disease
progression, and to examine the impact of H. pylori isolates on gastric
stem cell biology. To obtain information concerning the long-term
adaptation of H. pylori to an acid-free gastric environment, we examined
genomic and transcriptional adaptations of the ChAG-associated strain
HPAG1, which was isolated from a Swedish patient with ChAG. We found that
the 1,596,366 bp HPAG1 genome is smaller than the two previously
sequenced H. pylori genomes 26695 and J99 due to deletions of
strain-specific plasticity zone-associated genes. Interestingly, a number
of the missing genes have been shown to be acidregulated. The loss of
these genes might illustrate a genomic adaptation and a streamlining of
the genome size to an acid-free gastric environment where these genes are
no longer needed. Whole-genome genotyping of additional ChAG-associated
strains revealed that outer membrane proteins (OMPs) and genes involved
in metal utilization were over-represented among ChAG-associated genes.
The enrichment of these genes indicates that they play important roles in
the adhesive adjustments and nutrient adaptations of H. pylori in the
setting of ChAG. Further, we assessed the diversity and structural
adjustments of the surface-exposed LPS-molecule and of Lewis antigens to
varying gastric conditions in individuals during disease progression and
in two mouse models. We observed extensive diversity in H. pylori Lewis
antigen expression both within and between individuals, however the
proportions of presented Lewis epitopes appeared relatively stable over a
time-period of four years. Interestingly, we noted that Lewis antigen
expression differed between H. pylori isolates obtained after an
experimental infection of two types of mice with distinct gastric pH.
Thus, the LPS diversity within the bacterial population provides a means
for H. pylori to adapt to changes in the gastric environment and enables
modulation of the inflammatory response. A genome-wide comparison of deep
draft assemblies of 24 H. pylori genomes collected from six patients at
two time points with a four-year interval was performed. We found that
genomic variations clustered by host rather than disease state, and that
intra-individual strains exhibited remarkable stability over the four
years. Functional genomic studies of both host and microbial responses to
H. pylori infection of a mouse gastric epithelial progenitor (mGEP) cell
line, disclosed host transcriptional responses enriched in genes related
to cell proliferation and gastric carcinogenesis, as well as bacterial
genes encoding OMPs and genes involved in metal ion binding. Our findings
have provided new insights on H. pylori´s genetic and functional
adaptations to ChAG. Varying expression and composition of surfaceexposed
structures as well as regulating genes involved in metal ion utilization,
are associated with this disease state. The intimate association with GEP
cells may be important for survival in a gastric ecosystem that lacks
parietal cells. However, this dangerous liaison may also increase the
risk of tumorigenesis