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Helicobacter pylori colonization critically depends on postprandial gastric conditions.

ABSTRACT: The risk of Helicobacter pylori infection is highest in childhood, but the colonization process of the stomach mucosa is poorly understood. We used anesthetized Mongolian gerbils to study the initial stages of H. pylori colonization. Prandial and postprandial gastric conditions characteristic of humans of different ages were simulated. The fraction of bacteria that reached the deep mucus layer varied strongly with the modelled postprandial conditions. Colonization success was weak with fast gastric reacidification typical of adults. The efficiency of deep mucus entry was also low with a slow pH decrease as seen in pH profiles simulating the situation in babies. Initial colonization was most efficient under conditions simulating the postprandial reacidification and pepsin activation profiles in young children. In conclusion, initial H. pylori colonization depends on age-related gastric physiology, providing evidence from an in vivo infection model that suggests an explanation why the bacterium is predominantly acquired in early childhood.

SUBMITTER: Bucker R

PROVIDER: S-EPMC3524519 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Helicobacter pylori colonization critically depends on postprandial gastric conditions.

Bücker Roland R Azevedo-Vethacke Marina M Groll Claudia C Garten Désirée D Josenhans Christine C Suerbaum Sebastian S Schreiber Sören S

Scientific reports 20121218

The risk of Helicobacter pylori infection is highest in childhood, but the colonization process of the stomach mucosa is poorly understood. We used anesthetized Mongolian gerbils to study the initial stages of H. pylori colonization. Prandial and postprandial gastric conditions characteristic of humans of different ages were simulated. The fraction of bacteria that reached the deep mucus layer varied strongly with the modelled postprandial conditions. Colonization success was weak with fast gast ...[more]

PMID: 23251780

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Project description:Helicobacter pylori (H. pylori) is a pathogen contributing to peptic inflammation, ulceration, and cancer. A crucial step in the pathogenic sequence is when the bacterium first interacts with gastric tissue, an event that is poorly understood in vivo. We have shown that the luminal space adjacent to gastric epithelial damage is a microenvironment, and we hypothesized that this microenvironment might enhance H. pylori colonization. Inoculation with 106 H. pylori (wild-type Sydney Strain 1, SS1) significantly delayed healing of acetic-acid induced ulcers at Day 1, 7 and 30 post-inoculation, and wild-type SS1 preferentially colonized the ulcerated area compared to uninjured gastric tissue in the same animal at all time points. Gastric resident Lactobacillus spp. did not preferentially colonize ulcerated tissue. To determine whether bacterial motility and chemotaxis are important to ulcer healing and colonization, we analyzed isogenic H. pylori mutants defective in motility (?motB) or chemotaxis (?cheY). ?motB (10(6)) failed to colonize ulcerated or healthy stomach tissue. ?cheY (10(6)) colonized both tissues, but without preferential colonization of ulcerated tissue. However, ?cheY did modestly delay ulcer healing, suggesting that chemotaxis is not required for this process. We used two-photon microscopy to induce microscopic epithelial lesions in vivo, and evaluated accumulation of fluorescently labeled H. pylori at gastric damage sites in the time frame of minutes instead of days. By 5 min after inducing damage, H. pylori SS1 preferentially accumulated at the site of damage and inhibited gastric epithelial restitution. H. pylori ?cheY modestly accumulated at the gastric surface and inhibited restitution, but did not preferentially accumulate at the injury site. H. pylori ?motB neither accumulated at the surface nor inhibited restitution. We conclude that bacterial chemosensing and motility rapidly promote H. pylori colonization of injury sites, and thereby biases the injured tissue towards sustained gastric damage.

Project description:Cyclopropane fatty acids (CFAs) are synthetized by the addition of a methylene group from S-adenosyl-l-methionine across the carbon-carbon double bonds of unsaturated fatty acid chains of membrane phospholipids. This fatty acid cyclopropanation, catalyzed by the CFA synthase (CfaS) enzyme, occurs in many bacteria, including the human pathogen Helicobacter pylori Although the cyclopropane modification was reported to play a key role in the adaptation in response to environmental stress, its role in H. pylori remains unknown. In this study, we showed that H. pylori HP0416 encodes a functional CfaS. The enzyme was demonstrated to be required for acid resistance, antibiotic resistance, intracellular survival and mouse gastric colonization, and cell membrane integrity. Moreover, the tool compound dioctylamine, which acts as a substrate mimic, directly inhibits the CfaS function of H. pylori, resulting into sensitivity to acid stress, increased antibiotic susceptibility, and attenuated abilities to avoid macrophage killing and to colonize mouse stomachs. These results validate CfaS as a promising antibiotic target and provide new potentials for this recognized target in future anti-H. pylori drug discovery efforts.IMPORTANCE The increasing prevalence of multidrug-resistant Helicobacter pylori strains has created an urgent need for alternative therapeutic regimens that complement the current antibiotic treatment strategies for H. pylori eradication; however, this is greatly hampered due to a lack of "druggable" targets. Although the CFAs are present in H. pylori cytoplasmic membranes at high levels, their physiological role has not been established. In this report, deletion of the CFA synthase CfaS was shown to attenuate acid and drug resistance, immune escape, and gastric colonization of H. pylori These findings were validated by inhibition of the CfaS activity with the tool compound dioctylamine. These studies identify this enzyme as an attractive target for further drug discovery efforts against H. pylori.

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Helicobacter pylori colonization critically depends on postprandial gastric conditions.

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Helicobacter pylori colonization critically depends on postprandial gastric conditions.

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