Prolonged Intake of Luvos Healing Earth does not alter the Composition of the Gut Microbiota in Patients with Diarrhea-predominant Irritable Bowel Syndrome and Healthy Controls.

BACKGROUND AND AIMS: The mineral compound Luvos Healing Earth (LHE) is a commercially available remedy empirically used for a variety of gastrointestinal disorders. The aim of this study was to investigate the possible effect of prolonged LHE therapy on gut microbiota in healthy individuals and in patients with diarrhea-predominant irritable bowel syndrome (IBS-D). METHODS: In this prospective exploratory study, a total of 20 participants, including 12 healthy controls and 8 patients with IBS-D, received treatment with LHE (Magenfein Granulat, 1 sachet bid) for 6 weeks. Fecal samples were collected for microbiota analysis in the morning fasting state at regular intervals at 6 different timepoints: 2 weeks before starting therapy (Screen), and every 2 weeks during LHE therapy (V0-V3). Additionally, a follow-up visit was scheduled 4 weeks after the end of treatment (V4). Microbiota analysis was performed using the GA-map® Dysbiosis Test Lx v2. Dysbiosis Index, bacterial diversity, as well as the balance or imbalance of functionally important bacteria were assessed. RESULTS: The microbiota analysis revealed an overlap in gut microbiota profiles between healthy controls and patients with IBS-D. Bacterial communities were consistently stable during the entire treatment period, and no significant variations in composition were observed 4 weeks after the end of the therapeutic intervention. There was a remarkable stability of microbiota profiles over time within each individual and a high inter-individual variation. The majority of fecal samples exhibited profiles, reflecting an eubiotic state, with no significant changes in dysbiosis index, functional bacteria profiles, or bacterial diversity. CONCLUSION: Our findings indicate intraindividual resilience of microbiota consortia during the entire study period. Prolonged intake of LHE does not cause significant alterations in fecal microbiota profiles in healthy controls and patients with IBS-D. Luvos Healing Earth does not affect the stability of gut microbial diversity and bacterial functions.

A multiserological line assay to potentially discriminate current from past Helicobacter pylori infection.

OBJECTIVES: Early diagnosis is important in controlling Helicobacter pylori-induced gastritis and progression to gastric malignancy. Serological testing is an efficient non-invasive diagnostic method, but currently does not allow differentiation between active and past infections. To fill this diagnostic gap we investigated the diagnostic value of a panel of ten H. pylori-specific antibodies in individuals with different H. pylori infection status within a German population. METHODS: We used the recomLine Helicobacter IgG 2.0 immunoblotting assay to analyse ten H. pylori-specific antibodies in serum samples collected from 1108 volunteers. From these, 788 samples were used to build exposure and infection status models and 320 samples for model validation. H. pylori infection status was verified by histological examination. We applied logistic regression to select antibodies correlated to infection status and developed, with independent validation, discriminating models and risk scores. Receiving operating characteristic analysis was performed to assess the accuracy of the discriminating models. RESULTS: Antibody reactivity against cytotoxin-associated gene A (CagA), H. pylori chaperone (GroEL), and hook-associated protein 2 homologue (FliD) was independently associated with the risk of H. pylori exposure with ORs and 95% CIs of 99.24 (46.50-211.80), 46.17 (17.45-122.17), and 22.16 (8.46-55.04), respectively. A risk score comprising these three selected antibodies differentiated currently H. pylori infected or eradicated participants from negatives with an area under the curve of 0.976 (95% CI: 0.965-0.987) (Model 1). Seropositivity for vacuolating cytotoxin A (VacA), GroEL, FliD, H. pylori adhesin A (HpaA), and γ-glutamyl transpeptidase (gGT) was associated with a current infection with an area under the curve of 0.870 (95% CI: 0.837-0.903), which may help discriminate currently infected patients from eradicated ones (Model 2). DISCUSSION: The recomLine assay is sensitive and specific in determining H. pylori infection and eradication status and thus represents a valuable tool in the management of H. pylori infection.

Intraprocedural gastric juice analysis as compared to rapid urease test for real-time detection of Helicobacter pylori.

BACKGROUND: Endofaster is an innovative technology that can be combined with upper gastrointestinal endoscopy (UGE) to perform gastric juice analysis and real-time detection of Helicobacter pylori (H. pylori). AIM: To assess the diagnostic performance of this technology and its impact on the management of H. pylori in the real-life clinical setting. METHODS: Patients undergoing routine UGE were prospectively recruited. Biopsies were taken to assess gastric histology according to the updated Sydney system and for rapid urease test (RUT). Gastric juice sampling and analysis was performed using the Endofaster, and the diagnosis of H. pylori was based on real-time ammonium measurements. Histological detection of H. pylori served as the diagnostic gold standard for comparing Endofaster-based H. pylori diagnosis with RUT-based H. pylori detection. RESULTS: A total of 198 patients were prospectively enrolled in an H. pylori diagnostic study by Endofaster-based gastric juice analysis (EGJA) during the UGE. Biopsies for RUT and histological assessment were performed on 161 patients (82 men and 79 women, mean age 54.8 ± 19.2 years). H. pylori infection was detected by histology in 47 (29.2%) patients. Overall, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value (NPV) for H. pylori diagnosis by EGJA were 91.5%, 93.0%, 92.6%, 84.3%, and 96.4%, respectively. In patients on treatment with proton pump inhibitors, diagnostic sensitivity was reduced by 27.3%, while specificity and NPV were unaffected. EGJA and RUT were comparable in diagnostic performance and highly concordant in H. pylori detection (κ-value = 0.85). CONCLUSION: Endofaster allows for rapid and highly accurate detection of H. pylori during gastroscopy. This may guide taking additional biopsies for antibiotic susceptibility testing during the same procedure and then selecting an individually tailored eradication regimen.

CagA-specific Gastric CD8+ Tissue-Resident T Cells Control Helicobacter pylori During the Early Infection Phase.

BACKGROUND & AIMS: Infection with Helicobacter pylori strongly affects global health by causing chronic gastritis, ulcer disease, and gastric cancer. Although extensive research into the strong immune response against this persistently colonizing bacterium exists, the specific role of CD8+ T cells remains elusive. METHODS: We comprehensively characterize gastric H pylori-specific CD8+ T-cell responses in mice and humans by flow cytometry, RNA-sequencing, immunohistochemistry, and ChipCytometry, applying functional analyses including T-cell depletion, H pylori eradication, and ex vivo restimulation. RESULTS: We define CD8+ T-cell populations bearing a tissue-resident memory (TRM) phenotype, which infiltrate the gastric mucosa shortly after infection and mediate pathogen control by executing antigen-specific effector properties. These induced CD8+ tissue-resident memory T cells (TRM cells) show a skewed T-cell receptor beta chain usage and are mostly specific for cytotoxin-associated gene A, the distinctive oncoprotein injected by H pylori into host cells. As the infection progresses, we observe a loss of the TRM phenotype and replacement of CD8+ by CD4+ T cells, indicating a shift in the immune response during the chronic infection phase. CONCLUSIONS: Our results point toward a hitherto unknown role of CD8+ T-cell response in this bacterial infection, which may have important clinical implications for treatment and vaccination strategies against H pylori.

The influence of gastric atrophy on Helicobacter pylori antibiotics resistance in therapy-naïve patients.

Background: Antibiotic susceptibility of Helicobacter pylori to antibiotics may vary among different niches of the stomach. The progression of chronic H. pylori gastritis to atrophy changes intragastric physiology that may influence selection of resistant strains. Aim: To study the antibiotic resistance of H. pylori taking the severity of atrophic gastritis in antrum and corpus into account. Methods: Helicobacter pylori-positive patients (n = 110, m = 32, mean age 52.6 ± 13.9 years) without prior H. pylori eradication undergoing upper gastrointestinal (GI) endoscopy for dyspeptic symptoms were included in a prospective study. Patients were stratified into three groups depending on the grade of atrophy: no atrophy (OLGA Stage 0), mild atrophy (OLGA Stage I-II) and moderate/severe atrophy (OLGA Stage III-IV). Two biopsies each from the antrum and the corpus and one from the angulus were taken and assessed according to the updated Sydney system. H. pylori strains were isolated from antrum and corpus biopsies and tested for antibiotic susceptibility (AST) for amoxicillin, clarithromycin, metronidazole, levofloxacin, tetracycline, and rifampicin by the agar dilution methods. A Chi-square test of independence with a 95% confidence interval was used to detect differences in the proportion of patients with susceptible and resistant H. pylori strains. Results: Among 110 patients, primary clarithromycin resistance (R) was 30.0%, both in the antrum and corpus; metronidazole resistance accounted for 36.4 and 34.5% in the antrum and corpus; and levofloxacin was 19.1 and 22.7% in the antrum and corpus, respectively. Resistance rates to amoxicillin, tetracycline, and rifampicin were below 5%. Dual antibiotic resistance rate was 21.8%, and triple resistance rate was 9.1%. There was a significant difference in the resistance rate distribution in antrum (p < 0.0001) and corpus (p < 0.0001). With increasing severity of atrophy according to OLGA stages, there was a significant increase in clarithromycin-R and metronidazole-R. Conclusion: In treatment-naïve patients, antibiotic resistance and heteroresistance were related to the severity of atrophy. The high clarithromycin resistance in atrophic gastritis suggests that H. pylori antibiotic susceptibility testing should always be performed in this condition before selecting the eradication regimen.

Impact of healthy aging on active bacterial assemblages throughout the gastrointestinal tract.

The adaption of gut microbiota (GM) throughout human life is a key factor in maintaining health. Interventions to restore a healthy GM composition may have the potential to improve health and disease outcomes in the elderly. We performed a comprehensive characterization of changes in the luminal and mucosa-associated microbiota composition in elderly compared with younger healthy individuals. Samples from saliva and feces, and biopsies from the upper and lower gastrointestinal tract (UGIT, LGIT), were collected from 59 asymptomatic individuals grouped by age: 40-55, 56-70, and 71-85 years). All underwent anthropometric, geriatric, and nutritional assessment. RNA was extracted and reverse-transcribed into complementary DNA; the V1-V2 regions of 16S ribosomal RNA genes were amplified and sequenced. Abundances of the taxa in all taxonomic ranks in each sample type were used to construct sample-similarity matrices by the Bray-Curtis algorithm. Significant differences between defined groups were assessed by analysis of similarity. The bacterial community showed strong interindividual variations and a clear distinction between samples from UGIT, LGIT, and feces. While in saliva some taxa were affected by aging, this number was considerably greater in UGIT and was subsequently higher in LGIT. Unexpectedly, aging scarcely influenced the bacterial community of feces over the age range of 40-85 years. The development of interventions to preserve and restore human health with increased age by establishing a healthy gut microbiome should not rely solely on data from fecal analysis, as the intestinal mucosa is affected by more significant changes, which differ from those observed in fecal analyses.

Gut microbiota profiles and the role of anti-CdtB and anti-vinculin antibodies in patients with functional gastrointestinal disorders (FGID).

BACKGROUND: Distinct faecal microbiota profiles are reported to be associated with various subtypes of IBS. Circulating antibodies to cytolethal distending toxin B (CdtB) and vinculin are proposed as biomarkers to identify post-infectious IBS. The aim of our study was to analyse serum levels of anti-CdtB and anti-vinculin antibodies in patients with different functional gastrointestinal disorders (FGID) and their correlation with the composition of faecal microbiome. METHODS: The study cohort comprised 65 prospectively recruited individuals: 15 with diarrhoea-type-IBS (IBS-D), 13 with constipation-type-IBS (IBS-C), 15 with functional dyspepsia (FD) and 22 healthy controls. FGID subgroups were defined according to Rome III criteria. Serum levels of anti-CdtB and anti-vinculin antibodies were measured by ELISA. Faecal microbiome composition analysis and assessment of dysbiosis were performed by GA-map® Dysbiosis Test. RESULTS: Positivity rate either for anti-CdtB or anti-vinculin antibodies was higher in the IBS-C group (76.9%) compared to IBS-D (40.0%), FD (60%) and healthy (63.6%) groups. Dysbiosis was more frequent in subjects positive for anti-CdtB antibodies and in IBS-C patients, who showed an increased amount of opportunistic/pro-inflammatory bacteria and reduced gut protective bacteria. IBS-C patients showed a high inter-individual variation of bacterial communities compared to other FGID subgroups and healthy individuals, whereas microbial profiles of patients with IBS-D and FD were overlapping with those of healthy controls. No bacteria markers showed significant differences between FGID subgroups and healthy controls. CONCLUSION: Neither anti-CdtB/anti-vinculin antibodies nor faecal microbial profiles allowed to discriminate between specific FGID subgroups. Dysbiosis was more frequent in patients presenting with anti-CdtB antibodies and in IBS-C patients.

Inflammatory microRNAs in gastric mucosa are modulated by Helicobacter pylori infection and proton-pump inhibitors but not by aspirin or NSAIDs.

Gastric carcinogenesis is associated with alterations of microRNAs (miRNAs) and reversal of these alterations may be a crucial element in cancer prevention. Here we evaluate the influence of H. pylori eradication, low-dose aspirin (LDA), non-steroidal anti-inflammatory drugs (NSAIDs) and proton-pump inhibitors (PPI) on modification of inflammatory mucosal miRNAs miR-155 and miR-223 in Helicobacter pylori-infected and non-infected subjects. The study was performed in two parts: 1) interventional study in 20 healthy subjects with and without H. pylori infection or following eradication (each n = 10) where LDA (100 mg) was given daily for 7 days; 2) prospective case-control observational study (n = 188). MiR-155 and miR-223 expression was strongly linked to H. pylori-infection and in short-term view showed a trend for reversal after eradication. Daily LDA as well as regular NSAIDs showed no influence on miRNAs expression both in healthy subjects and patients, while regular PPI intake was associated with lower miR-155 expression in antrum of patients with chronic gastritis independent of density of neutrophils and mononuclear infiltrate. In summary, PPI but not LDA or NSAIDs were associated with modification of inflammatory miRNAs miR-155 and miR-223 in an H. pylori dependent manner. The functional role of inflammatory miR-155 and miR-223 in understanding of H. pylori-related diseases needs further evaluation.

Analysis of Transcriptionally Active Bacteria Throughout the Gastrointestinal Tract of Healthy Individuals.

BACKGROUND & AIMS: The microbiome varies along the human gastrointestinal (GI) tract with exposure to luminal and mucosal factors. We analyzed active bacterial communities at 8 locations along the GI tract using high-throughput sequencing techniques. METHODS: We collected saliva, mucosal, and fecal samples from healthy adults (10 men and 11 women; mean age, 59 ± 12.3 years) who underwent upper and lower GI tract endoscopy in Germany from December 2015 through September 2016. Biopsies were taken from stomach, antrum, corpus, duodenum, terminal ileum, ascending colon, and descending colon. RNA was extracted from all samples and reverse transcribed into complementary DNA; V1-V2 regions of 16S ribosomal RNA genes were amplified and sequenced on an Illumina MiSeq platform. Abundances of the taxa in all taxonomic ranks in each sample type were used to construct sample-similarity matrices with the Bray-Curtis algorithm. Significant differences between a priori-defined groups were evaluated using analysis of similarity. RESULTS: After taxonomic annotation, 4045 phylotypes, belonging to 169 genera and 14 different phyla, were identified. Each subject had a different bacterial community. We identified distinct microbial consortia in saliva, upper GI tract, lower GI tract, and fecal samples. The predominant genera in the upper GI tract (Gemella, Veillonella, Neisseria, Fusobacterium, Streptococcus, Prevotella, Pseudomonas, and Actinomyces) were almost absent from the lower GI tract, where the microbial communities mainly comprised Faecalibacterium, Ruminococcus, and Bacteroides. The bacterial communities in the upper GI tract were characterized by greater richness and heterogeneity (measured by the Shannon index) than those in the lower GI tract. We detected Helicobacter pylori in only the upper GI tract. CONCLUSIONS: In an analysis of saliva, mucosal, and fecal samples from 21 healthy adults, we found each individual, and each GI region, to have a different bacterial community. The fecal microbiome is not representative of the mucosal microbiome. We propose a systematic method to analyze the bacterial communities of the GI tract.

Long-Term Effect of Rifaximin with and without Lactulose on the Active Bacterial Assemblages in the Proximal Small Bowel and Faeces in Patients with Minimal Hepatic Encephalopathy.

BACKGROUND: Gut microbiota play an essential role in the pathogenesis of hepatic encephalopathy (HE). Treatment strategies are directed to modulate intestinal microbiota profiles and their function by the administration of the non-absorbable disaccharide lactulose and the non-absorbable antibiotic rifaximin, which are required for long terms, but little is known on their long-term effect on gut microbiota composition and function. AIM: To characterize the active bacterial assemblages in duodenum and faeces in patients with minimal HE (MHE) before, during and after long-term therapy with rifaximin. METHODS: We analysed the microbiota composition in 5 patients with liver cirrhosis and MHE treated either with rifaximin 550 mg bid alone continuously for a period of 3 months or combined with lactulose 30-60 mL daily for 3 months. In addition to clinical assessments of HE, biopsies from duodenum and stool samples were analysed for their specific bacterial community applying NGS after RNA isolation before treatment, after 3 months of treatment and 3 months after the end of treatment. RESULTS: All 5 patients had a significant improvement of their MHE. Bacterial communities were different and distinct in duodenal samples and faeces. No statistically significant changes were found in the bacterial community profile at the different time points. CONCLUSION: Rifaximin therapy with and without lactulose over a period of 3 months does not affect the bacterial community composition. The improvement of HE with rifaximin is lasting also after the end of treatment and therefore a prolonged effect on microbiota metabolic function is suggested.

Gastric cancer: epidemiology, prevention, and therapy.

Gastric cancer (GC) is still the third leading cause of cancer death in both sexes worldwide. Helicobacter pylori infection is the most important risk factor for GC and, in spite of the consistent trend of a decreasing incidence, in 2015 approximately 4.4 billion individuals-more than half the world's population-were infected with H. pylori. The birth cohort pattern of decreased H. pylori infection reported in a systematic review contributes to explain the declining GC mortality in Japan. Current trends in estimated annual percentage change of GC incidence foreshadow expected reversals in both falling incidence and male predominance among US non-Hispanic whites. Combining serum pepsinogen 1 and H. pylori serology was shown to be useful for GC risk stratification in a Finnish population. Gastritis staging by operative link on gastritis assessment was confirmed to be reliable in predicting GC risk in a large prospective study. In a randomized trial from South Korea, H. pylori eradication therapy significantly reduced the rates of metachronous GC in patients who received curative endoscopic resection for early GC. A study based on a territory-wide health care database of the Hong Kong Hospital Authority showed that aspirin use is associated with a reduced GC risk. Another study based on the same database showed that proton pump inhibitors increase GC risk, but methodological biases have most likely acted as confounders. Confirmatory data on the role of endoscopic submucosal dissection in patients with early GC have been published. The phase III FLOT4 trial has shown that the FLOT triplet regimen (docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil) improves the outcome of patients with GC and locoregional disease as compared to the ECF triplet (epirubicin, cisplatin, and 5-fluorouracil). In the phase III ATTRACTION-2 trial, nivolumab was shown to be an effective treatment option with a relative safe profile for heavily pretreated patients with advanced GC.

Helicobacter pylori, gastric cancer and other gastrointestinal malignancies.

In a retrospective study performed in California, U.S.A., ca. 3% of patients with gastric intestinal metaplasia (GIM) developed gastric cancer (GC) within a median time period of 4.6 years after diagnosis of GIM. This observation stresses the importance of targeted surveillance even in regions with a low GC prevalence. Patients with alcoholic liver disease as well as survivors of colorectal and lobular breast cancer were found to be at increased risk of secondary GC. A population-based Chinese study confirmed "serologic biopsy" as a useful screening tool for stratifying the individual risk of developing GC. Concerning GC therapy, a post hoc analysis of the MAGIC trial reported that regression of lymph node metastases, but not the tumor regression itself, predicts overall survival. Furthermore, in patients with high microsatellite instable tumors, perioperative chemotherapy leads to an increased risk of mortality. Two studies confirmed that eradication therapy is worthwhile as an initial treatment for gastric mucosa-associated lymphoid tissue (MALT) lymphoma irrespective of the H. pylori infection status and stage. An increased risk of a second primary malignancy including GC was observed in these patients treated with immuno/chemotherapy but not in patients treated solely with an H. pylori eradication treatment. With respect to gastrointestinal malignancies other than GC, discrepant data have been published regarding the association of H. pylori with pancreatic cancer whereas no association has been reported with esophageal squamous cell carcinoma. The majority of published studies still support an association of H. pylori with colon neoplasms.

Helicobacter pylori and Gastric Cancer: Timing and Impact of Preventive Measures.

Helicobacter pylori (H. pylori) is a Gram negative spiraliform bacterium that is commonly found in the stomach. H. pylori infection is still one of the world's most frequent infections, present in the stomachs of approximately one-half of the world's people. H. pylori infection is etiologically linked to histologic chronic active gastritis, peptic ulcer disease, and primary B-cell gastric lymphoma (gastric MALT lymphoma) and represents the major risk factor for the development of sporadic non-cardia gastric cancer (GC) of both intestinal and diffuse type. Studies that have examined the impact of GC prevention through H. pylori eradication have shown mixed results, but recent data suggest that prevention is only efficacious in patients without intestinal metaplasia or dysplasia. This indicates that, like in Barrett's esophagus, we need better clinical risk markers to indicate which patients are at greatest risk of developing cancer to guide clinical strategies. Furthermore, recent epidemiological data have suggested a possible contribution of H. pylori in modifying the risk of developing other gastrointestinal malignancies (including esophageal, pancreatic, hepatocellular, and colorectal cancer), although mechanistically these associations remain unexplained. We review clinically relevant aspects of H. pylori infection in the context of GC development as well as studies that have examined the impact of eradication on GC development and, lastly, discuss these recent epidemiological studies connecting H. pylori infection to extragastric gastrointestinal malignancies.

Helicobacter pylori and non-malignant upper gastrointestinal diseases.

Peptic ulcer disease (PUD) has been further decreased over the last decades along with decreasing prevalence of Helicobacter pylori-associated PUD. A delayed H. pylori eradication has been associated with an increased risk of rehospitalization for complicated recurrent peptic ulcer and reemphasized the importance of eradication especially in patients with peptic ulcer bleeding (PUB). PUB associated with NSAID/aspirin intake and H. pylori revealed an additive interaction in gastric pathophysiology which favors the "test-and-treat" strategy for H. pylori in patients with specific risk factors. The H. pylori-negative and NSAID-negative "idiopathic PUD" have been increasingly observed and associated with slower healing tendency, higher risk of recurrence, and greater mortality. Helicobacter pylori-associated dyspepsia has been further investigated and finally defined by the Kyoto consensus. Helicobacter pylori eradication therapy is advised as first option in this group of patients. Only in the case of symptom persistence or recurrence after eradication therapy, dyspeptic patients should be classified as functional dyspepsia (FD). There were few new data in 2015 on the role of H. pylori infection in gastroesophageal reflux disease (GERD), and in particular Barrett's esophagus. A lower prevalence of gastric atrophy with less acid output in patients with erosive esophagitis confirmed previous findings. In patients with erosive esophagitis, no difference was observed in healing rates neither between H. pylori-positive and H. pylori-negative patients nor between patients that underwent eradication therapy compared to patients without eradication. These findings are in line with the current consensus guidelines concluding that H. pylori eradication has no effects on symptoms and does not aggravate preexisting GERD.

RiMINI - the influence of rifaximin on minimal hepatic encephalopathy (MHE) and on the intestinal microbiome in patients with liver cirrhosis: study protocol for a randomized controlled trial.

BACKGROUND: Hepatic encephalopathy (HE) is a clinically significant complication of liver cirrhosis impacting on the patients' quality of life. Minimal hepatic encephalopathy (MHE) is diagnosed by psychometric tests, found in up to 80 % of patients with liver cirrhosis and carries a high risk of progression to overt HE. Continuous therapy with rifaximin in combination with lactulose significantly reduces the risk of overt HE, recurrence of HE and HE-related hospitalizations in randomized, double-blind, placebo-controlled clinical trials. Rifaximin is approved for the therapy of overt HE in Germany. Treatment with lactulose has been shown to improve cognitive functions in patients with liver cirrhosis. Data from prospective clinical trials comparing the efficacy of rifaximin alone against a combination of rifaximin and lactulose in the treatment of MHE are scarce. Changes in the microbiome of the upper and lower gastrointestinal tract as a result of therapy with rifaximin have not yet been addressed in clinical studies. METHODS AND DESIGN: RiMINI is a monocentric exploratory pilot study on 60 patients with MHE as assessed by critical flicker frequency (CFF). Additionally, visual evoked potentials' (VEP) testing, electroencephalography (EEG) and psychometric testing (NCT-A) will be carried out. Patients will be randomized to treatment either with rifaximin alone (550 mg twice daily (bid) continuously for a period of 3 months) or with rifaximin (550 mg bid continuously) in combination with lactulose (30-60 ml daily) for 3 months. An esophagogastroduodenoscopy (EGD) will be performed at baseline, at the end of treatment and 6 and 12 weeks after the end of treatment to obtain gastric and duodenal biopsies and aspirates. The samples will be analyzed for their content of specific bacterial taxae by applying next generation sequencing (NGS) after rRNA isolation to identify the microbiome of the stomach and duodenum, and of the gut, in patients with liver cirrhosis and MHE before and after therapy. DISCUSSION: Differences of the effect of antibiotic therapy with rifaximin alone or in combination with lactulose on the clinical course of MHE are assessed. TRIAL REGISTRATION: The trial was registered as DRKS00006359 on March 17th 2015, with the universal trial number U1111-1163-9410 and with EudraCT2013-004414-18 .

Helicobacter pylori and Gastrointestinal Malignancies.

Helicobacter pylori infection is the principal trigger of gastric carcinogenesis and gastric cancer (GC) and remains the third leading cause of cancer-related death in both sexes worldwide. In a big Japanese study, the risk of developing GC in patients with peptic ulcer disease who received H. pylori eradication therapy and annual endoscopic surveillance for a mean of 9.9 years was significantly lower after successful eradication therapy compared to the group with persistent infection (0.21%/year and 0.45%/year, respectively, p = .049). According to a recent meta-analysis, H. pylori eradication is insufficient in GC risk reduction in subjects with advanced precancerous conditions (i.e., intestinal metaplasia and dysplasia). A microsimulation model suggested screening smokers over the age of 50 in the U.S. for serum pepsinogens. This would allow to detect advanced gastric atrophy with endoscopic follow-up of subjects testing positive as a cost-effective strategy to reduce GC mortality. In a Taiwanese study, the anti-H. pylori IgG-based test-and-treat program had lower incremental cost-effectiveness ratios than that with (13)C-urea breath test in both sexes to prevent GC whereas expected years of life lost for GC were higher and the incremental cost-effectiveness ratios of test-and-treat programs were more cost-effective in young adults (30-69 years old) than in elders (>70 years old). With respect to gastrointestinal malignancies other than GC, a meta-analysis confirmed the inverse association between H. pylori infection and esophageal adenocarcinoma. In a Finnish study, H. pylori seropositivity was associated with an increased risk of biliary tract cancers (multivariate adjusted OR 2.63; 95% CI: 1.08-6.37), another meta-analysis showed a slightly increased rate of pancreatic cancer in patients with CagA-negative strains (OR: 1.30; 95% CI: 1.02-1.65), whereas current data suggest that the association between H. pylori and colorectal neoplasms may be population dependent.