Helicobacter pylori and gastric cancer: Koch's postulates fulfilled?
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Animals↗
Biomedical subjects
J G Fox
Publications and source records attributed to J G Fox.
Mice lacking secretory phospholipase A2 show altered apoptosis and differentiation with Helicobacter felis infection.
BACKGROUND & AIMS: Infection with Helicobacter pylori uniformly leads to a chronic superficial gastritis that may progress to atrophic gastritis, a premalignant process. A mouse model of Helicobacter felis infection was used to study possible genetic determinants of the response to infection. METHODS: Three inbred mouse strains with known secretory phospholipase A2 (sPLA2) genotypes [BALB/c (+/+), C3H/HeJ (+/+), and C57BL/6 (-/-)] were orally infected with H. felis and examined longitudinally using routine histology, immunocytochemistry, electron microscopy, proliferating cell nuclear antigen, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, and Northern and Western blot studies. RESULTS: Only the C57BL/6 strain showed increased gastric fundic proliferation and apoptosis in response to infection. In addition, the C57BL/6 mouse showed a marked loss of parietal and chief cells, along with a marked expansion of an aberrant gastric mucous cell lineage that stained positive for spasmolytic polypeptide. In contrast, no significant change in these cell types was observed in BALB/c and C3H/HeJ strains. Increased expression of sPLA2 was observed in BALB/c and C3H/HeJ after H. felis infection, whereas sPLA2 expression was absent in C57BL/6 mice. CONCLUSIONS: H. felis infection leads to increased apoptosis and altered cellular differentiation in the C57BL/6 mouse, a strain that lacks gastric sPLA2 expression. Because sPLA2 has been identified recently as the MOM1 (modifier of MIN) locus that influences polyp formation in the colon, these studies suggest that sPLA2 may also influence the gastric epithelial response to Helicobacter infection.
Animals↗
Hepatic Helicobacter species identified in bile and gallbladder tissue from Chileans with chronic cholecystitis.
BACKGROUND & AIMS: Cancer of the gallbladder is the number one cause of cancer mortality in Chilean women. Incidence rates for this tumor vary widely on a worldwide basis, being approximately 30 times higher in high-risk than in low-risk populations, suggesting that environmental factors such as infectious microorganisms, carcinogens, and nutrition play a role in its pathogenesis. Because several Helicobacter sp. colonize the livers of animals and induce hepatitis, the aim of this study was to determine whether Helicobacter infection was associated with cholecystitis in humans. METHODS: Bile or resected gallbladder tissue from 46 Chileans with chronic cholecystitis undergoing cholecystectomy were cultured for Helicobacter sp. and subjected to polymerase chain reaction (PCR) analysis using Helicobacter-specific 16S ribosomal RNA primers. RESULTS: Recovery of Helicobacter sp. from frozen specimens was unsuccessful. However, by PCR analysis, 13 of 23 bile samples and 9 of 23 gallbladder tissues were positive for Helicobacter. Eight of the Helicobacter-specific PCR amplicons were sequenced and subjected to phylogenetic analysis. Five sequences represented strains of H. bilis, two strains of "Flexispira rappini" (ATCC 49317), and one strain of H. pullorum. CONCLUSIONS: These data support an association of bile-resistant Helicobacter sp. with gallbladder disease. Further studies are needed to ascertain whether similar Helicobacter sp. play a causative role in the development of gallbladder cancer.
Adult↗
Antibiotic properties of bovine lactoferrin on Helicobacter pylori.
To investigate a potential new treatment for gastric Helicobacter pylori infection, we have examined the use of the natural antibiotic lactoferrin, found in bovine milk, for activity against Helicobacter species both in vitro and in vivo. Lactoferrin was bacteriostatic to H. pylori when cultured at concentrations > or =0.5 mg/ml. Growth of H. pylori was not inhibited by another milk constituent, lysozyme, or by a metabolite of lactoferrin, lactoferricin B, but growth was inhibited by the iron chelator deferoxamine mesylate. Lactoferrin inhibition of growth could be reversed by addition of excess iron to the medium. Lactoferrin in retail dairy milk was found to be more stable intragastrically than unbuffered, purified lactoferrin. Treatment of H. felis-infected mice with lactoferrin partially reversed mucosal disease manifestations. It is concluded that bovine lactoferrin has significant antimicrobial activity against Helicobacter species in vitro and in vivo. Bovine lactoferrin should be further investigated for possible use in H. pylori infections in man.
Animals↗
Spontaneous inflammatory bowel disease in multiple mutant mouse lines: association with colonization by Helicobacter hepaticus.
BACKGROUND: Both genetic and microbial factors are thought to play a role in the development of inflammatory bowel disease (IBD): however, no causative microbial agent has been clearly defined for humans or animals. Normal flora or previously unrecognized intestinal pathogens may contribute to the development of disease in susceptible hosts. A newly recognized murine Helicobacter, H. hepaticus, causes hepatitis in mice and in one strain of mice is linked to liver cancer. This study investigates the association between colonization of the lower intestinal tract of multiple genetically altered lines of mice with H. hepaticus, and the occurrence of IBD. MATERIALS AND METHODS: Rectal prolapse noted clinically in multiple genetically altered mouse lines was evaluated for the presence of H. hepaticus and histologic evidence of IBD. Fifty-five mice representing 11 different genetic alterations were evaluated. RESULTS: H. hepaticus was detected in 85% of mutant mice with rectal prolapse. Histologic evidence of proliferative typhlitis, colitis or proctitis was present in 65% of the animals examined, 89% of which were positive for H. hepaticus as detected by species specific PCR. CONCLUSION: The presence of H. hepaticus in association with IBD in multiple lines of genetically altered mice suggests further studies are needed to test experimentally the role H. hepaticus plays in the development of IBD in susceptible mice. Additionally, specific mutant mouse lines infected with H. hepaticus in this study may provide additional models for elucidation of microbial and genetic factors in the pathogenesis of IBD.
Animals↗
Experimental infection in cats with a cagA+ human isolate of Helicobacter pylori.
BACKGROUND: Helicobacter pylori has been cultured from the inflamed gastric mucosa of naturally and experimentally-infected cats. The lesions in the H. pylori-infected cat stomach mimic many of the features seen in human stomachs infected with H. pylori. This study sought to determine whether H. pylori-negative, specific pathogen-free cats with normal gastric mucosa were susceptible to colonization with a human cagA+ strain of H. pylori, and whether gastritis developed after infections. METHODS: Four H. pylori-negative cats treated with cimetidine were orally dosed 3 times at 2-day intervals with 3 ml (1.5 x 108 CFU/ml) of H. pylori. RESULTS: All experimentally-infected cats became persistently colonized as determined by H. pylori isolation from gastric tissue by culture at 12 weeks, and all 4 cats were found positive by PCR during serial gastric biopsies and necropsy at 15 weeks postinoculation. The 2 control cats did not have H. pylori isolated, nor was gastric tissue positive by PCR. The H. pylori isolated from the 4 experimentally-infected cats had RFLP patterns specific for the flaA gene identical to those of the inoculating strain. All 4 H. pylori-infected cats had multifocal gastritis, consisting of lymphoid aggregates plus multiple large lymphoid nodules. In the control cats, one cat had a few focal lymphocytic aggregates in the body submucosa, whereas the second cat had normal gastric mucosa. CONCLUSION: Human cagA+ H. pylori readily colonized the cat stomach and produced a persistent gastritis. The findings demonstrate the utility of the cat to study H. pylori induced pathogenesis.
Animals↗
An artificial neural network can select patients at high risk of developing progressive IgA nephropathy more accurately than experienced nephrologists.
BACKGROUND: The object of the study was to develop an artificial neural network (ANN) to identify patients with IgA nephropathy (IgAN) with a poor prognosis and to compare the predictions of the ANN with the predictions of six experienced nephrologists. METHODS: The following data from the time of renal biopsy were retrieved from the records of 54 patients with IgAN: age, sex, systolic and diastolic blood pressure, number of prescribed antihypertensive drugs, 24-h urine protein excretion, and serum creatinine. Patients aged less than 14 years, or who had serum creatinine > 350 mumol/l at presentation, liver disease or concomitant kidney disease were excluded. Outcome was assigned as 'stable' if serum creatinine was < 150 mumol/l after 7 years and 'non-stable' if serum creatinine was > or = 150 mumol/l. The ANN was trained and tested using a 'jack-knife' sampling technique and performance evaluated in terms of number of correct predictions, sensitivity and specificity. The six nephrologists were asked to predict outcome at 7 years for each patient using the same data as the ANN and their performance was assessed in the same manner. RESULTS: The ANN assigned the correct outcome to 47/54 (87.0%) patients: sensitivity 19/22 (86.4%), specificity 28/32 (87.5%). The mean score for nephrologists was 37.5/54 (69.4%, range 35-40), mean sensitivity 72% and mean specificity 66%. CONCLUSIONS: An ANN trained using routine clinical information obtained at the time of diagnosis can potentially predict 7-year outcome for renal function in IgAN more accurately than experienced nephrologists, and can therefore identify a group of high-risk patients requiring close follow-up.
Adolescent↗
CAPD as fluid replacement in a patient with short-bowel syndrome.
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Adult↗
Aortic regurgitation caused by complex outflow calcification in a patient with chronic renal failure.
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Adult↗
Has the prognosis for patients with pauci-immune necrotizing glomerulonephritis improved?
BACKGROUND: Over the past 14 years, important advances have been made in diagnosis and treatment of patients with pauci-immune necrotizing glomerulonephritis (PINGN). The present study set out to evaluate the impact of these advances on prognosis by comparing patient survival during the period 1985-1995 with previously reported results for such patients between 1975 and 1982. METHOD: A retrospective analysis was carried out at two affiliated inner-city renal units on all patients considered to have PINGN during the period 1985 1995. Details of renal and extra-renal disease at presentation and during follow-up, along with treatment regimes, were noted. Figures for renal and patient survival were compared with those previously reported from one of these units. RESULTS: A total of 47 patients were diagnosed over the period 1985 1995, with a median age of 57 years. The overall patient survival (+/- standard error) at 1 and 5 years was 72.3 (+/- 0.06) and 51.2% (+/- 0.12) respectively, with corresponding renal survival (alive and independent of renal replacement therapy) at these times of 61.7 (+/- 0.07) and 49.9% (+/- 0.09) respectively. We identified increased age at presentation and advanced renal failure (requiring dialysis or serum creatinine > 300 micromol/l) as predictors of reduced patient and renal survival. When comparing our results with those previously reported (1975-1982), we found no improvement in prognosis for patients with PINGN during the latter period. CONCLUSIONS: These results suggest that the prognosis for patients with PINGN has not improved despite diagnostic and therapeutic advances. Delay in diagnosis and treatment may compromise the therapeutic potential in PINGN.
Age Factors↗
Review article: Helicobacter species and in vivo models of gastrointestinal cancer.
Although gastric cancer is an uncommon spontaneous neoplasm of laboratory animal species, rodents, and to a lesser extent other animals, have been used in chemically induced gastric carcinogenesis studies for decades. The role of diet in preventing or promoting gastric cancer has also been addressed in animal models. With the discovery of Helicobacter pylori and its causative role in gastric disease in humans, several animal models have been described for Helicobacter spp.-induced gastric disease, and in selected models, development of gastric and hepatic cancer. This review has attempted to highlight salient features of Helicobacter models and how these observations may be interpreted in light of data obtained from chemical carcinogenesis and nutritional studies. Further insight into mechanisms of Helicobacter-induced cancer should evolve by combining and comparing relevant features of these in vivo models.
Adenocarcinoma↗
SCID/NCr mice naturally infected with Helicobacter hepaticus develop progressive hepatitis, proliferative typhlitis, and colitis.
Hepatitis, proliferative typhlitis, and colitis were characterized in young adult and older SCID/NCr mice naturally infected with Helicobacter hepaticus. Liver lesions consisted of Kupffer, Ito, and oval cell hyperplasia along with multifocal to coalescing coagulative hepatocyte necrosis. Numerous Warthin-Starry-positive bacteria were observed in the parenchyma, and there were minimal to mild accumulations of monocytic cells and neutrophils. Proliferative typhlitis was characterized by moderate to marked mucosal epithelial cell hyperplasia with mild monocytic and neutrophilic infiltration. Minimal to mild colitis with mucosal epithelial cell hyperplasia of the colon was most marked in older mice. Comparable gastrointestinal lesions were not observed in uninfected control SCID/NCr mice. H. hepaticus was cultured from fetal viscera of 2 of 11 pups sampled late in gestation from infected SCID/NCr females, suggesting transplacental infection of H. hepaticus. As expected, most of the naturally infected SCID/NCr mice had no serum immunoglobulin G response against H. hepaticus. These findings contrast with those in infected immunocompetent A/JCr mice, which develop a significant immune response to H. hepaticus associated with prominent multifocal mononuclear cell infiltrates in the liver, with only rare bacteria observable at the periphery of inflammatory foci or in the biliary canaliculi. The results demonstrate that chronic inflammatory and proliferative lesions simultaneously affecting the liver, cecum, and colon are associated with natural infection of SCID/NCr mice with H. hepaticus and that lesions are progressive with age. Concurrent infection with H. hepaticus may confound studies that have been attributed to similar lesions due to other experimental manipulations of SCID/NCr mice.
Animals↗
Experimental Helicobacter pylori infection induces antral gastritis and gastric mucosa-associated lymphoid tissue in guinea pigs.
Humans infected with Helicobacter pylori have abnormally low levels of the antioxidant vitamin C, which protects against the formation of carcinogenic nitrosamines, in gastric juice. Guinea pigs, like humans and nonhuman primates, have a dietary requirement for vitamin C. As such, these species have gastrointestinal vitamin C transport systems not found in other animals. We have developed and characterized a guinea pig model of chronic gastric H. pylori infection with the rodent-adapted Sydney strain of H. pylori. At 4 weeks postinfection, five of six animals of the infected group and zero of two animals of the control group were positive for H. pylori as determined by culture or PCR. At 15 weeks, six of six animals of the infected group and zero of two animals of the control group were positive. H. pylori-specific seroconversion was observed among infected animals. There were no histologic abnormalities in the gastric antra or fundi of control guinea pigs. In contrast, there was multifocal, mild to moderate lymphohistiocytic antral gastritis and formation of antral lymphoid follicles in H. pylori-infected animals. The lesion distribution in the gastric antra paralleled that observed in H. pylori-infected humans. The H. pylori-infected guinea pig should prove useful in modeling the interaction of helicobacter and vitamin C in gastric carcinogenesis.
Animals↗
Chronic active hepatitis induced by Helicobacter hepaticus in the A/JCr mouse is associated with a Th1 cell-mediated immune response.
Helicobacter hepaticus infection in A/JCr mice results in chronic active hepatitis characterized by perivascular, periportal, and parenchymal infiltrates of mononuclear and polymorphonuclear cells. This study examined the development of hepatitis and the immune response of A/JCr mice to H. hepaticus infection. The humoral and cell-mediated T helper immune response was profiled by measuring the postinfection (p.i.) antibody response in serum, feces, and bile and by the production of cytokines and proliferative responses by splenic mononuclear cells to H. hepaticus antigens. Secretory immunoglobulin A (IgA) and systemic IgG2a antibody developed by 4 weeks p.i. and persisted through 12 months. Splenocytes from infected mice proliferated and produced more gamma interferon (IFN-gamma) than interleukin-4 (IL-4) or IL-5 when cultured with H. hepaticus outer membrane proteins. The predominantly IgG2a antibody response in serum and the in vitro production of IFN-gamma in excess of IL-4 or IL-5 are consistent with a Th1 immune response reported in humans and mice infected with Helicobacter pylori and Helicobacter felis, respectively. Mice infected with H. hepaticus developed progressively severe perivascular, periportal, and hepatic parenchymal lesions consisting of lymphohistiocytic and plasmacytic cellular infiltrates. In addition, transmural typhlitis was observed at 12 months p.i. The characterization of a cell-mediated Th1 immune response to H. hepaticus infection in the A/JCr mouse should prove valuable as a model for experimental regimens which manipulate the host response to Helicobacter.
Animals↗
Comparison of methods of identifying Helicobacter hepaticus in B6C3F1 mice used in a carcinogenesis bioassay.
In a long-term rodent bioassay evaluating the carcinogenicity of triethanolamine, there was equivocal evidence of carcinogenic activity in male B6C3F1 mice, based on a marginal increase in the number of hepatocellular adenomas and hepatoblastomas. Interpretation was complicated by the presence of Helicobacter hepaticus in selected silver-stained liver sections which also had histological evidence of karyomegaly and oval cell hyperplasia. An increase in numbers of liver tumors, as evidence of carcinogenic activity, was also noted in female mice. However, H. hepaticus was not considered a complicating factor, because the livers of the female mice did not have histological features compatible with H. hepaticus infection. A retrospective analysis of 51 liver tissue samples from the original carcinogenicity study was conducted to determine the incidence of H. hepaticus infection and to evaluate different diagnostic approaches for assessing the presence of H. hepaticus in livers lacking characteristic lesions. In an initial evaluation of seven mice with liver tumors, argyrophilic bacteria resembling H. hepaticus were observed in liver sections, associated with characteristic liver lesions of hepatocytic karyomegaly and oval cell hyperplasia. Frozen liver tissue was available from four of these mice; all were confirmed to be infected with H. hepaticus by culture and PCR. In a larger subsequent analysis using frozen liver tissues from 44 mice without characteristic hepatic lesions, H. hepaticus-specific DNA was amplified from the livers of 21 of 44 of the mice (47%), compared to 14 of 44 of the mice (32%) having H. hepaticus cultured from their frozen liver tumors. The results of H. hepaticus culture and H. hepaticus-specific PCR concurred (i.e., both positive and negative results) in 84% of the cases. Microscopic detection of immunofluorescence-labeled or silver-stained bacteria in liver sections was relatively insensitive compared to either culture or PCR detection. This study confirms the widespread prevalence of H. hepaticus in mice, its potential to confound experimental results, and the need to include diagnostic testing for H. hepaticus in a murine health monitoring program.
Animals↗
Proliferative enterocolitis associated with dual infection with enteropathogenic Escherichia coli and Lawsonia intracellularis in rabbits.
Both enteropathogenic Escherichia coli (EPEC) and an obligate intracellular bacterium, previously referred to as an intracellular Campylobacter-like organism and now designated Lawsonia intracellularis, have been reported as causes of enterocolitis in rabbits. An outbreak of enterocolitis in a group of rabbits, characterized by an unusually high rate of mortality, was found to be associated with dual infection with EPEC and L. intracellularis. The EPEC strain was found to have eaeA gene homology but was negative for afrA homology. The absence of the afrA gene, which encodes the structural subunit for the AF/R1 pilus, indicates that this rabbit EPEC strain is distinct from the prototypic RDEC-1 strain. This finding suggests that rabbit EPEC strains widely reported in Western Europe, which lack AF/R1 pili, are also present in rabbits in the United States. Dual infection with these two pathogens in rabbits has not been previously reported and may have contributed to the unusually high mortality observed in this outbreak.
Adhesins, Bacterial↗
Development of a PCR-restriction fragment length polymorphism assay using the nucleotide sequence of the Helicobacter hepaticus urease structural genes ureAB.
Infection with Helicobacter hepaticus causes chronic active hepatitis in certain strains of mice and is associated with hepatocellular carcinoma in A/JCr mice. Like the gastric helicobacters, H. pylori and H. mustelae, H. hepaticus possesses a high level of urease activity. However, the H. hepaticus urease structural gene sequences have not been previously determined, and the role of the urease enzyme in colonization and in pathogenesis is not known. PCR was used to amplify a portion of the urease structural genes from H. hepaticus genomic DNA. Amplified DNA fragments were cloned, and the nucleotide sequence was determined. The deduced amino acid sequence of the partial H. hepaticus ureA gene product was found to exhibit 60% identity and 75% similarity to the predicted H. pylori UreA. The deduced amino acid sequence of a partial H. hepaticus ureB gene product exhibited 75% identity and 87% similarity to the predicted H. pylori UreB. Diversity among H. hepaticus isolates was evaluated by means of a restriction fragment length polymorphism (RFLP) assay. The 1.6-kb fragments within the ureAB open reading frames, amplified from 11 independent isolates, were digested with the restriction endonuclease HhaI. Three distinct RFLP patterns were observed. Identical RFLP profiles were noted in sequential isolates of one strain of H. hepaticus during an 18 month in vivo colonization study, suggesting that the urease genes of H. hepaticus are stable. The urease genes among H. hepaticus strains were also well conserved, showing 98.8 to 99% nucleotide sequence identity among three isolates analyzed. These findings indicate that H. hepaticus has urease structural genes which are homologous to those of the gastric Helicobacter species and that these gene sequences can be used in a PCR and RFLP assay for diagnosis of this important murine pathogen.
Amino Acid Sequence↗
Inflammatory large bowel disease in immunodeficient rats naturally and experimentally infected with Helicobacter bilis.
Proliferative and ulcerative typhlitis, colitis, and proctitis were found incidentally in a breeding colony of male athymic nude (Cr:NIH-rnu) rats. Within the crypts of the large intestine, modified Steiner's silver stain revealed spiral organisms that were identified by culture, polymerase chain reaction, and sequencing to be Helicobacter bilis. The large bowel disease was reproduced in H. bilis-free male athymic nude rats that were injected intraperitoneally with a culture of H. bilis from the affected colony. The organism was isolated from the feces and cecum of the experimentally infected rats. H. bilis should be considered a potential pathogen in immunocompromised rats. The infection in immunocompromised rats may serve as an animal model for inflammatory large bowel disease.
Animals↗