Defining the temporal evolution of gut dysbiosis and inflammatory responses leading to hepatocellular carcinoma in Mdr2 -/- mouse model.

BACKGROUND: Emerging evidence implicates the gut microbiome in liver inflammation and hepatocellular carcinoma (HCC) development. We aimed to characterize the temporal evolution of gut dysbiosis, in relation to the phenotype of systemic and hepatic inflammatory responses leading to HCC development. In the present study, Mdr2 -/- mice were used as a model of inflammation-based HCC. Gut microbiome composition and function, in addition to serum LPS, serum cytokines/chemokines and intrahepatic inflammatory genes were measured throughout the course of liver injury until HCC development. RESULTS: Early stages of liver injury, inflammation and cirrhosis, were characterized by dysbiosis. Microbiome functional pathways pertaining to gut barrier dysfunction were enriched during the initial phase of liver inflammation and cirrhosis, whilst those supporting lipopolysaccharide (LPS) biosynthesis increased as cirrhosis and HCC ensued. In parallel, serum LPS progressively increased during the course of liver injury, corresponding to a shift towards a systemic Th1/Th17 proinflammatory phenotype. Alongside, the intrahepatic inflammatory gene profile transitioned from a proinflammatory phenotype in the initial phases of liver injury to an immunosuppressed one in HCC. In established HCC, a switch in microbiome function from carbohydrate to amino acid metabolism occurred. CONCLUSION: In Mdr2 -/- mice, dysbiosis precedes HCC development, with temporal evolution of microbiome function to support gut barrier dysfunction, LPS biosynthesis, and redirection of energy source utilization. A corresponding shift in systemic and intrahepatic inflammatory responses occurred supporting HCC development. These findings support the notion that gut based therapeutic interventions could be beneficial early in the course of liver disease to halt HCC development.

Endometriosis and the microbiome: a systematic review.

BACKGROUND: The aetiology and pathogenesis of endometriosis are still under investigation. There is evidence that there is a complex bidirectional interaction between endometriosis and the microbiome. OBJECTIVE: To systematically review the available literature on the endometriosis-microbiome interaction, with the aim of guiding future inquiries in this emerging area of endometriosis research. SEARCH STRATEGY: MEDLINE, Embase, Scopus and Web of Science were searched through May 2019. A manual search of reference lists of relevant studies was also performed. SELECTION CRITERIA: Published and unpublished literature in any language describing a comparison of the microbiome state in mammalian hosts with and without endometriosis. DATA COLLECTION AND ANALYSIS: Identified studies were screened and assessed independently by two authors. Data were extracted and compiled in a qualitative synthesis of the evidence. MAIN RESULTS: Endometriosis appears to be associated with an increased presence of Proteobacteria, Enterobacteriaceae, Streptococcus spp. and Escherichia coli across various microbiome sites. The phylum Firmicutes and the genus Gardnerella also appear to have an association; however, this remains unclear. CONCLUSIONS: The complex bidirectional relationship between the microbiome and endometriosis has begun to be characterised by the studies highlighted in this systematic review. Laboratory and clinical studies demonstrate that there are indeed differences in the microbiome composition of hosts with and without endometriosis. TWEETABLE ABSTRACT: Review findings show endometriosis associated with increased Proteobacteria, Enterobacteriaceae, Streptococcus and Escherichia coli across various microbiome sites.

Management of Helicobacter pylori infection-the Maastricht V/Florence Consensus Report.

Important progress has been made in the management of Helicobacter pylori infection and in this fifth edition of the Maastricht Consensus Report, key aspects related to the clinical role of H. pylori were re-evaluated in 2015. In the Maastricht V/Florence Consensus Conference, 43 experts from 24 countries examined new data related to H. pylori in five subdivided workshops: (1) Indications/Associations, (2) Diagnosis, (3) Treatment, (4) Prevention/Public Health, (5) H. pylori and the Gastric Microbiota. The results of the individual workshops were presented to a final consensus voting that included all participants. Recommendations are provided on the basis of the best available evidence and relevance to the management of H. pylori infection in the various clinical scenarios.

The stomach in health and disease.

The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.

The fungal microbiota of de-novo paediatric inflammatory bowel disease.

Inflammatory bowel disease (IBD) is characterised by an inappropriate chronic immune response against resident gut microbes. This may be on account of distinct changes in the gut microbiota termed as dysbiosis. The role of fungi in this altered luminal environment has been scarcely reported. We studied the fungal microbiome in de-novo paediatric IBD patients utilising next generation sequencing and compared with adult disease and normal controls. We report a distinct difference in fungal species with Ascomycota predominating in control subjects compared to Basidiomycota dominance in children with IBD, which could be as a result of altered tolerance in these patients.

Expression of neutrophil gelatinase-associated lipocalin in colorectal neoplastic progression: a marker of malignant potential?

BACKGROUND: Neutrophil gelatinase-associated lipocalin (NGAL) has a diverse functional repertoire, involved in the innate immune response as well as cell growth and differentiation. Expression has been linked to malignant disease development and progression. METHODS: Neutrophil gelatinase-associated lipocalin expression was assessed immunohistochemically in 98 colorectal neoplastic lesions (52 cancer polyps (CaPs) and 46 sporadic adenoma/adjacent normal mucosa paired specimens) to investigate association with adenoma progression and early colorectal carcinogenesis. RESULTS: Within CaPs, all adenomatous and carcinomatous epithelium expressed NGAL, with 92% (43 out of 47) and 58% (19 out of 33) epithelial positivity, respectively, as well as positive stromal cell expression. This was significantly increased compared with normal mucosal epithelium (P=0.0001). Neutrophil gelatinase-associated lipocalin positivity was also identified in sporadic low-grade adenomas, in both the epithelial and stromal compartments as compared with adjacent normal mucosa (P=0.0001 and 0.0002), and this increased along with adenoma size >1 cm (P=0.03). CONCLUSION: Neutrophil gelatinase-associated lipocalin is expressed by the majority of human neoplastic colorectal lesions. This phenotypic switch occurs at an early stage in neoplastic progression with clear differential expression between normal mucosa and adenomatous polyps, rather than further downstream in disease progression at the adenoma-carcinoma transformation. Thus, NGAL expression is not a useful biomarker for determining disease progression from adenomatous to malignant colorectal neoplasia.

Loss of sensory and noradrenergic innervation in benign colorectal adenomatous polyps--a putative role of semaphorins 3F and 3A.

BACKGROUND: Nerve fibers can exert trophic/anti-trophic effects on epithelial cells. Substance P (SP) is a pro-proliferative neuropeptide, whereas sympathetic noradrenaline is anti-proliferative at high concentrations. METHODS: Density of noradrenergic and sensory nerve fibers and presence of nerve repellent factors specific for noradrenergic (semaphorin 3F) and sensory nerve fibers (semaphorin 3A) were investigated in colorectal adenomas. KEY RESULTS: The pedunculus was innervated by noradrenergic fibers, whereas the mucosa was sparsely innervated. The control submucosa compared with control mucosa demonstrated increased density of noradrenergic fibers. Control tissue was much better innervated than the polyp. This was accompanied by strong expression of semaphorin 3F in epithelial cells. Density of sensory SP+ nerve fibers was higher in control colon mucosa compared with polyp mucosa, and SP+ cell clusters and semaphorin 3A-positive cells appeared in the intercrypt space in polyps, but not in control tissue. CONCLUSIONS & INFERENCES: This study demonstrated a marked loss of noradrenergic and sensory nerve fibers in polyp mucosa, which was associated with a strong increase of semaphorin 3F and 3A. Up-regulation of the sympathetic repellent semaphorin 3F in the polyps possibly triggers sympathetic repulsion and polyp growth due to the loss of anti-proliferative noradrenaline and presence of SP from local SP+ cells.

Interobserver reliability in the endoscopic diagnosis and grading of Barrett's esophagus: an Asian multinational study.

BACKGROUND AND STUDY AIM: The establishment of precise and valid diagnostic criteria is important for any disease. We determined the interobserver reliability in the endoscopic diagnosis and grading of Barrett's esophagus. PATIENTS AND METHODS: Video clips of endoscopy in 21 patients with/without Barrett's esophagus were used for training (n = 3) and for diagnosis/grading (n = 18) of Barrett's esophagus by endoscopists from seven hospitals in Asia. Barrett's esophagus was graded using the Prague C & M Criteria whereby the circumferential extent of the Barrett's segment (C value), maximum extent of Barrett's segment (M value), location of the gastroesophageal junction, and location of the diaphragmatic hiatus were scored. The intraclass correlation coefficients (ICC) were calculated as a measure of interobserver reliability. RESULTS: A total of 34 endoscopists participated. ICC values for the scores of the C value, M value, location of the gastroesophageal junction, and location of the diaphragmatic hiatus were: 0.92 (95 % confidence interval [CI] 0.88 - 0.97), 0.94 (95 %CI 0.90 - 0.98), 0.86 (95 %CI 0.78 - 0.94), and 0.81 (95 %CI 0.71 - 0.92), respectively, indicating excellent interobserver agreement. The differences in region/country, endoscopists' experience, case volume of participating centers, or primary practice type had no significant effect on the reliability. The ICC values for recognition of Barrett's esophagus of > or = 1 cm were 0.90 (95 %CI 0.80 - 1.00) and 0.92 (95 %CI 0.87 - 0.98) for the C and M values, respectively, whereas the corresponding ICC values for Barrett's segment of < 1 cm were 0.18 (95 %CI 0.03 - 0.32) and 0.21 (95 %CI 0.00 - 0.51), respectively. CONCLUSIONS: Despite the uncommon occurrence of Barrett's esophagus in Asia, our endoscopists exhibited excellent agreement in the endoscopic diagnosis and grading of Barrett's esophagus using the Prague C & M Criteria. However, in view of the low interobserver reliability in recognizing Barrett's segments of < 1 cm, future studies in Asia should take this into account when selecting the study population.

Role of endoscopic ultrasonography in predicting the response to cyclosporin A in ulcerative colitis refractory to steroids.

BACKGROUND AND AIMS: Although cyclosporin A has been reported to be effective in the treatment of severe ulcerative colitis, factors predicting its therapeutic efficacy remain unclear. Technical progress in endoscopic ultrasonography has improved visualisation of the structure of the colon wall. Here, to assess the value of endoscopic ultrasonography in predicting the response to cyclosporin A treatment, we evaluated the therapeutic effect of cyclosporin A by determining the pre- and post-cyclosporin A thickness of the mucosal layer in the rectum using endoscopic ultrasonography with an ultrasonic catheter probe. PATIENTS AND METHODS: Fifteen ulcerative colitis patients who did not respond to high-doses of corticosteroids were treated with cyclosporin A by continuous intravenous infusion at 4mg/kg/day for 20 days. Before and 20 days after cyclosporin A therapy, clinical disease activity was assessed using clinical activity index scores. Colonoscopy and endoscopic ultrasonography were undertaken before and 20 days after cyclosporin A therapy. RESULTS: Following treatment with cyclosporin A, nine patients showed a decrease in clinical activity index score by six points or more and were defined as responders, while the other six were defined as non-responders. Endoscopic ultrasonography measurement using an ultrasonic catheter probe showed that thickness of the rectal mucosal layer before cyclosporin A was significantly greater in responders than in non-responders (p<0.05). Further, thickness after cyclosporin A was statistically decreased (p<0.01) in the responders but not in the non-responders. CONCLUSIONS: The ultrasonic catheter probe may represent a useful means of predicting and evaluating the efficacy of cyclosporin A treatment in severely ill ulcerative colitis patients.

Helicobacter pylori infection and the pathogenesis of gastric cancer: a paradigm for host-bacterial interactions.

Helicobacter pylori infection is the most important acquired risk factor for gastric cancer. The infection initiates a chronic inflammatory process that eventually alters the physiology of the gastric environment and leads to achlorohydria. Gastric atrophy may be part of this process but cancer can arise without this precursor. The net effect of decades of inflammation is the establishment of a milieu awash with pro-inflammatory cytokines and characterized by the activation of signalling pathways that cross-talk between inflammation and carcinogenesis. Many of the factors involved in chronic inflammation play a dual role in the process-promoting neoplastic progression but also facilitating cancer prevention. H. pylori bacterial virulence factors as well as host genetic factors play a major role in orchestrating the increased risk of cancer. The study of such host-bacterial interaction is key to uncovering the molecular and cellular pathways involved and will ultimately lead to developing preventive and therapeutic strategies against this global killer.

COX-2 expression in sporadic colorectal adenomatous polyps is linked to adenoma characteristics.

AIMS: To assess cyclooxygenase-2 (COX-2) expression in sporadic colonic adenomas and to explore the association of COX-2 positivity with adenoma characteristics linked to increased risk of malignant transformation. METHODS AND RESULTS: COX-2 expression and localization were assessed in 64 colorectal adenomas and 35 paired adjacent normal colonic mucosal biopsy specimens. The number of adenoma specimens was then extended to include polyps exhibiting an increasing degree of epithelial dysplasia. Forty colonic hyperplastic polyps were also identified from the pathology diagnostic database and included in the analysis. Immunohistochemistry was performed with the Envision+ peroxidase-linked biotin-free system incorporating a signal amplification step. There was a statistically significant increase in COX-2 expression in colonic polyps compared with paired adjacent normal mucosa, chi(2) = 40.1, P = 0.001. The probability of COX-2 expression increased along with increasing adenoma size and increasing degree of epithelial dysplasia. Fifty-five per cent of the hyperplastic polyp specimens expressed COX-2. CONCLUSIONS: This study associates COX-2 epithelial expression with a number of adenoma characteristics that convey an increased risk of malignant transformation. This is in keeping with a positive role for COX-2 in early colorectal carcinogenesis.

OLGA staging for gastritis: a tutorial.

Atrophic gastritis (resulting mainly from long-standing Helicobacter pylori infection) is a major risk factor for (intestinal-type) gastric cancer development and the extent/topography of the atrophic changes significantly correlates with the degree of cancer risk. The current format for histology reporting in cases of gastritis fails to establish an immediate link between gastritis phenotype and risk of malignancy. The histology report consequently does not give clinical practitioners and gastroenterologists an explicit message of use in orienting an individual patient's clinical management. Building on current knowledge of the biology of gastritis and incorporating experience gained worldwide by applying the Sydney System for more than 15 years, an international group of pathologists (Operative Link for Gastritis Assessment) has proposed a system for reporting gastritis in terms of stage (the OLGA staging system). Gastritis staging arranges the histological phenotypes of gastritis along a scale of progressively increasing gastric cancer risk, from the lowest (stage 0) to the highest (stage IV). This tutorial aims to provide unequivocal information on how to consistently apply the OLGA staging system in routine diagnostic histology practice.

Polymorphisms in Toll-like receptor genes and risk of cancer.

Host genetic factors are emerging as key determinants of disease risk for many cancers. Identifying candidate genes is a major challenge that has to stem from a profound understanding of the pathophysiology of the disease. The Toll-like receptors are important members of the host's innate immune response and their genes have been found to be polymorphic. This genetic variation allows for a more intricate repertoire that enables the host to withstand microbial challenges. While this may be advantageous on a population level, there may be less favourable outcomes for individuals that harbour certain genotypes associated with excessive immune activation and inflammatory drive. The damage is often collateral and is manifest in organs where this chronic inflammation alters normal physiology. A classic example of this paradigm is the Helicobacter pylori-induced gastric cancer model. Another emerging model is prostate cancer where Toll-like receptor polymorphisms have also been found to play a role. In this review, we discuss polymorphisms in Toll-like receptors and give an insight into how they may influence risk of cancer.

The interaction of host genetic factors and Helicobacter pylori infection.

Helicobacter pylori plays an important role in the development of atrophic gastritis that represents the most recognized pathway in multistep gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of Helicobacter pylori infection. As to bacterial virulence factors, a high proportion of Japanese strains are cagA(+)vacAs1. The CagA protein is injected from attached Helicobacter pylori into gastric epithelial cells and the CagA-SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. Host cytokine gene polymorphisms and a frequent single nucleotide polymorphism in the PTPN11 gene that encodes SHP-2 may associate with gastric atrophy among Helicobacter pylori-infected subjects. Prevention of gastric cancer requires the development of better screening strategies for determining eradication candidates and further improvement of treatments of Helicobacter pylori infection.

Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report.

BACKGROUND: Guidelines on the management of Helicobacter pylori, which cover indications for management and treatment strategies, were produced in 2000. AIMS: To update the guidelines at the European Helicobacter Study Group (EHSG) Third Maastricht Consensus Conference, with emphasis on the potential of H pylori eradication for the prevention of gastric cancer. RESULTS: Eradication of H pylori infection is recommended in (a) patients with gastroduodenal diseases such as peptic ulcer disease and low grade gastric, mucosa associated lymphoid tissue (MALT) lymphoma; (b) patients with atrophic gastritis; (c) first degree relatives of patients with gastric cancer; (d) patients with unexplained iron deficiency anaemia; and (e) patients with chronic idiopathic thrombocytopenic purpura. Recurrent abdominal pain in children is not an indication for a "test and treat" strategy if other causes are excluded. Eradication of H pylori infection (a) does not cause gastro-oesophageal reflux disease (GORD) or exacerbate GORD, and (b) may prevent peptic ulcer in patients who are naïve users of non-steroidal anti-inflammatory drugs (NSAIDs). H pylori eradication is less effective than proton pump inhibitor (PPI) treatment in preventing ulcer recurrence in long term NSAID users. In primary care a test and treat strategy using a non-invasive test is recommended in adult patients with persistent dyspepsia under the age of 45. The urea breath test, stool antigen tests, and serological kits with a high accuracy are non-invasive tests which should be used for the diagnosis of H pylori infection. Triple therapy using a PPI with clarithromycin and amoxicillin or metronidazole given twice daily remains the recommended first choice treatment. Bismuth-containing quadruple therapy, if available, is also a first choice treatment option. Rescue treatment should be based on antimicrobial susceptibility. CONCLUSION: The global burden of gastric cancer is considerable but varies geographically. Eradication of H pylori infection has the potential to reduce the risk of gastric cancer development.

Polymorphisms in Th1-type cell-mediated response genes and risk of gastric cancer.

Helicobacter pylori infection, the dominant risk factor for gastric cancers, has been shown to elicit T helper type 1 (Th1) polarized immunological responses. We conducted a population-based study of 305 gastric cancer cases and 427 age- and gender-matched controls in Warsaw, Poland, to evaluate the association with several variants in genes responsible for Th1-cell-mediated response. Genotyping was performed on genomic DNA by TaqMan(TM) assays to determine TNFA (-308 G>A, -417 G>A, -555 G>A, -1036 C>T, -1042 C>A, -1210 T>C), IL1A (-889 C>T), IFNGR2 (Ex7-128 T>C, Ex2-34 C>G and Ex2-16 A>G) and IL12A (IVS2-798 T>A, IVS2-701 C>A and Ex7+277 G>A) polymorphisms. We used unconditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for sex, age, education and smoking status. Out of six single nucleotide polymorphisms (SNPs) tested in TNFA, gastric cancer risk was significantly associated with the TNFA (-308 G>A) polymorphism, with ORs of 1.4 (95% CI: 1.0-2.0) for the G/A and 2.5 (95% CI: 1.3-4.9) for the A/A genotype carriers, when compared with the more frequent genotype (G/G) (P-trend < 0.001). Among the three tested SNPs in the IFNGR2 gene, only the Ex7-128C>T polymorphism was associated with increased risk, with ORs of 1.5 (95% CI: 1.0-2.3) for T/C and 1.7 (95% CI: 1.1-2.7) for C/C carriers when compared with T/T carriers (P-trend = 0.01). Subjects carrying both IFNGR2 Ex7-128 C/C and TNFA -308 A/A genotypes had the highest risk (OR = 5.5, 95% CI: 1.5-19.4), although the interaction was not statistically significant. IL1A (-889 C>T) and the three examined IL12A variants were unrelated to gastric cancer risk. Our findings suggest that two Th1-related polymorphisms (TNFA -308 A>G and IFNGR2 Ex7-128 C>T) may increase the risk of gastric cancer.

Gastric histology, serological markers and age as predictors of gastric acid secretion in patients infected with Helicobacter pylori.

BACKGROUND: Acid secretion is intimately associated with most upper gastrointestinal diseases. Helicobacter pylori infection is a major environmental factor modifying acid secretion. AIM: To study the association between the pattern of H pylori gastritis and gastric secretory function in a large number of subjects without specific upper gastrointestinal disease. METHODS AND MATERIALS: Maximal acid output (MAO) was measured in 255 patients with dyspepsia showing normal endoscopy. Activity and severity of gastritis, atrophy and H pylori infection were assessed in body and antral biopsies. The correlations of histological parameters as well as age, sex, height, weight, smoking, serum gastrin, pepsinogen I and II, and their ratio with MAO were determined. Multiple linear regression was used to show the best possible predictors of MAO. RESULTS: Negative relationships: Body atrophy and body-combined (active and chronic) inflammatory scores showed a potent inverse correlation with MAO (correlation coefficients (CC) 0.59 and 0.50, respectively). Body:antral chronic gastritis ratio and body:antral combined inflammation ratio (both with CC = 0.49) and age (CC = 0.44) were also inversely correlated with MAO. Intestinal metaplasia at both antral and body sites had negative relationships with acid output with CC = 0.23 and 0.20, respectively. Positive relationships: Serum pepsinogen I, body H pylori density:combined inflammation ratio and pepsinogen I:II ratio with CC of 0.38, 0.38 and 0.30, respectively, correlated with MAO. The H pylori density: combined inflammation of both antrum and body positively correlated with MAO (CC = 0.29 and 0.38, respectively). Male sex and patient height also positively correlated with acid output. Modelling showed that body combined inflammatory score, body atrophy, age and serum pepsinogen I are independent predictors of acid output (R(2) = 0.62). CONCLUSION: Combination of body gastritis, body atrophy, age and serum pepsinogen I can be used as predictors of acid-secretory state in populations infected with H pylori.

Mechanisms of increased acid secretion after eradication of Helicobacter pylori infection.

Eradication of Helicobacter pylori infection leads to recovery of gastric acid secretion in some individuals but the mechanism is not fully understood. In the short term, there is an impressive increase in expression of H+/K+-ATPase pumps without an increase in the number of parietal cells. Longer follow up studies are needed to see if the parietal cell mass eventually recovers.

Interleukin 1B proinflammatory genotypes protect against gastro-oesophageal reflux disease through induction of corpus atrophy.

BACKGROUND AND AIMS: The relationship between Helicobacter pylori infection and gastro-oesophageal reflux disease (GORD) is controversial but it is accepted that GORD is associated with increased exposure to gastric acidity. The proinflammatory interleukin (IL)-1B polymorphisms increase the risk of hypochlorhydria and gastric atrophy. We examined the association between proinflammatory cytokine gene polymorphisms, presence of gastric atrophy, and risk of GORD in H pylori positive and negative subjects in Japan. METHODS: We studied 320 consecutive dyspeptic patients without peptic ulcers or cancers. GORD symptoms were scored using the Carlsson-Dent questionnaire and erosive oesophagitis was assessed endoscopically. H pylori infection was diagnosed by urea breath test, histological examination, and serology. Gastric atrophy was assessed histologically, and polymorphisms in the IL-1B, IL-10, and tumour necrosis factor alpha (TNF-A) genes were genotyped. RESULTS: Two hundred and eight patients were H pylori positive and 112 were negative. One hundred and eight (34%) were found to have erosive oesophagitis by endoscopic criteria (grade A: 78; grade B: 23; grade C: 6; grade D: 1). Erosive oesophagitis and GORD symptoms were significantly more common in H pylori negative compared with H pylori positive subjects (p<0.05). H pylori positive subjects were more likely to have corpus gastric atrophy than H pylori negative subjects (p<0.001). Among H pylori positive patients, those without erosive oesophagitis or GORD symptoms were significantly more likely to have corpus atrophy than subjects with erosive oesophagitis or GORD symptoms (p<0.05). Among H pylori positive patients, subjects homozygous for the proinflammatory allele IL-1B-511T had a significantly lower risk of erosive oesophagitis (odds ratio (OR) 0.06 (95% confidence interval (CI) 0.006-0.51); p=0.01) and GORD symptoms (OR 0.10 (95% CI 0.01-0.85); p=0.04) compared with those homozygous for the -511C allele, while none of the two other proinflammatory cytokine gene polymorphisms had significant correlations with erosive oesophagitis or GORD symptoms. CONCLUSIONS: A proinflammatory IL-1B genotype is associated with increased risk of atrophy and decreased risk of GORD in H pylori infected subjects in Japan. These data indicate that in some genetically predisposed subjects, H pylori infection may protect against GORD through induction of gastric atrophy.

DNA typing for Helicobacter pylori isolates from eradication-failed patients: comparison of the isolates before and after therapy.

BACKGROUND: Failure of Helicobacter pylori eradication occurs frequently despite use of multiple microbial agents. AIM: We aimed to study differences between H. pylori strains isolated before and after eradication failure. METHODS: We treated 87 patients with peptic ulcer using triple therapy consisting of omeprazole plus combinations of clarithromycin, amoxicillin, or metronidazole. We studied the status of cagA, vacA, and iceA by PCR, and examined the differences in H. pylori isolates by pulsed-field gel electrophoresis and arbitrary primer polymerase chain reaction. The minimum inhibitory concentration of clarithromycin, amoxicillin, or metronidazole was determined by an agar dilution method. RESULTS: Eradication therapy failed in 12 patients (14%); H. pylori isolates were obtained from all of these both before and after therapy. After eradication therapy, 10 patients were colonized with the same strain as before therapy, while the other two patients were colonized with different strains from those before therapy. In the former group, one isolate changed from metronidazole-sensitive to -resistant, one changed from clarithromycin- and metronidazole-sensitive to -resistant, and four were resistant to clarithromycin or metronidazole both before and after therapy. The other four isolates remained sensitive to clarithromycin and metronidazole after therapy. In the two patients who yielded apparently different isolates after therapy, they changed from clarithromycin- and metronidazole-sensitive to -resistant. CONCLUSION: Eradication of H. pylori by first-line therapy is an important goal in the treatment of H. pylori-positive peptic ulcer, and that appropriate antimicrobial sensitivity testing should be conducted in patients with eradication failure.