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Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.

ABSTRACT: Since Helicobacter pylori was first cultivated from human gastric biopsy specimens in 1982, it has become apparent that many related species can often be found colonizing the mucosal surfaces of humans and other animals. These other Helicobacter species can be broadly grouped according to whether they colonize the gastric or enterohepatic niche. Gastric Helicobacter species are widely distributed in mammalian hosts and are often nearly universally prevalent. In many cases they cause an inflammatory response resembling that seen with H. pylori in humans. Although usually not pathogenic in their natural host, these organisms serve as models of human disease. Enterohepatic Helicobacter species are an equally diverse group of organisms that have been identified in the intestinal tract and the liver of humans, other mammals, and birds. In many cases they have been linked with inflammation or malignant transformation in immunocompetent hosts and with more severe clinical disease in immunocompromised humans and animals. The purpose of this review is to describe these other Helicobacter species, characterize their role in the pathogenesis of gastrointestinal and enterohepatic disease, and discuss their implications for our understanding of H. pylori infection in humans.

SUBMITTER: Solnick JV

PROVIDER: S-EPMC88962 | biostudies-literature | 2001 Jan

REPOSITORIES: biostudies-literature

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Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.

Solnick J V JV Schauer D B DB

Clinical microbiology reviews 20010101 1

Since Helicobacter pylori was first cultivated from human gastric biopsy specimens in 1982, it has become apparent that many related species can often be found colonizing the mucosal surfaces of humans and other animals. These other Helicobacter species can be broadly grouped according to whether they colonize the gastric or enterohepatic niche. Gastric Helicobacter species are widely distributed in mammalian hosts and are often nearly universally prevalent. In many cases they cause an inflammat ...[more]

PMID: 11148003

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Project description:BACKGROUND:The genus Helicobacter are gram-negative, microaerobic, flagellated, mucus-inhabiting bacteria associated with gastrointestinal inflammation and classified as gastric or enterohepatic Helicobacter species (EHS) according to host species and colonization niche. While there are over 30 official species, little is known about the physiology and pathogenic mechanisms of EHS, which account for most in the genus, as well as what genetic factors differentiate gastric versus EHS, given they inhabit different hosts and colonization niches. The objective of this study was to perform a whole-genus comparative analysis of over 100 gastric versus EHS genomes in order to identify genetic determinants that distinguish these Helicobacter species and provide insights about their evolution/adaptation to different hosts, colonization niches, and mechanisms of virulence. RESULTS:Whole-genome phylogeny organized Helicobacter species according to their presumed gastric or EHS classification. Analysis of orthologs revealed substantial heterogeneity in physiological and virulence-related genes between gastric and EHS genomes. Metabolic reconstruction predicted that unlike gastric species, EHS appear asaccharolytic and dependent on amino/organic acids to fuel metabolism. Additionally, gastric species lack de novo biosynthetic pathways for several amino acids and purines found in EHS and instead rely on environmental uptake/salvage pathways. Comparison of virulence factor genes between gastric and EHS genomes identified overlapping yet distinct profiles and included canonical cytotoxins, outer membrane proteins, secretion systems, and survival factors. CONCLUSIONS:The major differences in predicted metabolic function suggest gastric species and EHS may have evolved for survival in the nutrient-rich stomach versus the nutrient-devoid environments, respectively. Contrasting virulence factor gene profiles indicate gastric species and EHS may utilize different pathogenic mechanisms to chronically infect hosts and cause inflammation and tissue damage. The findings from this study provide new insights into the genetic differences underlying gastric versus EHS and support the need for future experimental studies to characterize these pathogens.

Project description:BACKGROUND:Helicobacter saguini is a novel enterohepatic Helicobacter species isolated from captive cotton top tamarins with chronic colitis and colon cancer. Monoassociated H. saguini infection in gnotobiotic IL-10-/- mice causes typhlocolitis and dysplasia; however, the virulent mechanisms of this species are unknown. Gamma-glutamyltranspeptidase (GGT) is an enzymatic virulence factor expressed by pathogenic Helicobacter and Campylobacter species that inhibits host cellular proliferation and promotes inflammatory-mediated gastrointestinal pathology. The aim of this study was to determine if H. saguini expresses an enzymatically active GGT homologue with virulence properties. EXPERIMENTAL PROCEDURES:Two putative GGT paralogs (HSGGT1 and HSGGT2) identified in the H. saguini genome were bioinformatically analysed to predict enzymatic functionality and virulence potential. An isogenic knockout mutant strain and purified recombinant protein of HSGGT1 were created to study enzymatic activity and virulence properties by in vitro biochemical and cell culture experiments. RESULTS:Bioinformatic analysis predicted that HSGGT1 has enzymatic functionality and is most similar to the virulent homologue expressed by Helicobacter bilis, whereas HSGGT2 contains putatively inactivating mutations. An isogenic knockout mutant strain and recombinant HSGGT1 protein were successfully created and demonstrated that H. saguini has GGT enzymatic activity. Recombinant HSGGT1 protein and sonicate from wild-type but not mutant H. saguini inhibited gastrointestinal epithelial and lymphocyte cell proliferation without evidence of cell death. The antiproliferative effect by H. saguini sonicate or recombinant HSGGT1 protein could be significantly prevented with glutamine supplementation or the GGT-selective inhibitor acivicin. Recombinant HSGGT1 protein also induced proinflammatory gene expression in colon epithelial cells. CONCLUSIONS:This study shows that H. saguini may express GGT as a potential virulence factor and supports further in vitro and in vitro studies into how GGT expression by enterohepatic Helicobacter species influences the pathogenesis of gastrointestinal inflammatory diseases.

Project description:BackgroundChanges in bacterial populations termed "dysbiosis" are thought central to ulcerative colitis (UC) pathogenesis. In particular, the possibility that novel Helicobacter organisms play a role in human UC has been debated but not comprehensively investigated. The aim of this study was to develop a molecular approach to investigate the presence of Helicobacter organisms in adults with and without UC.Methodology/principal findingsA dual molecular approach to detect Helicobacter was developed. Oligonucleotide probes against the genus Helicobacter were designed and optimised alongside a validation of published H. pylori probes. A comprehensive evaluation of Helicobacter genus and H. pylori PCR primers was also undertaken. The combined approach was then assessed in a range of gastrointestinal samples prior to assessment of a UC cohort. Archival colonic samples were available from 106 individuals for FISH analysis (57 with UC and 49 non-IBD controls). A further 118 individuals were collected prospectively for dual FISH and PCR analysis (86 UC and 32 non-IBD controls). An additional 27 non-IBD controls were available for PCR analysis. All Helicobacter PCR-positive samples were sequenced. The association between Helicobacter and each study group was statistically analysed using the Pearson Chi Squared 2 tailed test. Helicobacter genus PCR positivity was significantly higher in UC than controls (32 of 77 versus 11 of 59, p?=?0.004). Sequence analysis indicated enterohepatic Helicobacter species prevalence was significantly higher in the UC group compared to the control group (30 of 77 versus 2 of 59, p<0.0001). PCR and FISH results were concordant in 74 (67.9%) of subjects. The majority of discordant results were attributable to a higher positivity rate with FISH than PCR.Conclusions/significanceHelicobacter organisms warrant consideration as potential pathogenic entities in UC. Isolation of these organisms from colonic tissue is needed to enable interrogation of pathogenicity against established criteria.

Project description:The discovery of Helicobacter hepaticus and its role in hepatitis, hepatocellular carcinoma, typhlocolitis, and lower-bowel carcinoma in murine colonies was followed by the isolation and characterization of other Helicobacter spp. involved in enterohepatic disease. Colonization of mouse colonies with members of the family Helicobacteriaceae has become an increasing concern for the research community. From 2001 to 2005, shipments of selected gift mice from other institutions and mice received from specified commercial vendors were screened for Helicobacter spp. by culture of cecal tissue. The identities of the isolates were confirmed by genus-specific PCR, followed by species-specific PCR and restriction fragment length polymorphism analysis. Sequencing of the 16S rRNA gene was performed if the species identity was not apparent. The survey included 79 mice from 34 sources: 2 commercial sources and 16 research sources from the United States and 1 commercial source and 15 research sources from Canada, Europe, or Asia. Helicobacter spp. were cultured from the ceca of 62 of 79 mice. No Helicobacter spp. were found in mice from advertised Helicobacter-free production areas from two U.S. vendors. Multiple Helicobacter spp. were found in mice from one vendor's acknowledged Helicobacter-infected production area. The European commercial vendor had mice infected with novel Helicobacter sp. strain MIT 96-1001. Of the U.S. academic institutions, 6 of 16 (37%) had mice infected with Helicobacter hepaticus; but monoinfection with H. bilis, H. mastomyrinus, H. rodentium, and MIT 96-1001 was also encountered, as were mice infected simultaneously with two Helicobacter spp. Non-U.S. academic institutions had mice that were either monoinfected with H. hepaticus, monoinfected with seven other Helicobacter spp., or infected with a combination of Helicobacter spp. This survey indicates that 30 of 34 (88%) commercial and academic institutions in Canada, Europe, Asia, Australia, and the United States have mouse colonies infected with Helicobacter spp. Mice from 20 of the 34 institutions (59%) were most commonly colonized with H. hepaticus alone or in combination with other Helicobacter spp. These results indicate that a broad range of Helicobacter spp. infect mouse research colonies. The potential impact of these organisms on in vivo experiments continues to be an important issue for mice being used for biomedical research.

Dataset Information

Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.

Publications

Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.

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