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Effects of long‐term PPI treatment on producing bowel symptoms and SIBO

Eur J Clin Invest 2011; 41 (4): 380–386

Efficacy of 5-Day Levofloxacin-Containing Concomitant Therapy in Eradication of Helicobacter pylori Infection

BACKGROUND & AIMS Helicobacter pylori have become resistant to antimicrobial agents, reducing eradication rates. A 10-day sequential regimen that contains levofloxacin was efficient, safe, and cost saving in eradicating H pylori infection in an area with high prevalence of clarithromycin resistance. We performed a noninferiority randomized trial to determine whether a 5-day levofloxacin-containing quadruple concomitant regimen was as safe and effective as the 10-day sequential regimen in eradicating H pylori in previously untreated patients. METHODS We randomly assigned patients with H pylori infection to groups that were given 5 days of concomitant therapy (esomeprazole 40 mg twice daily, amoxicillin 1 g twice daily, levofloxacin 500 mg twice daily, and tinidazole 500 mg twice daily; n = 90) or 10 days of sequential therapy (esomeprazole 40 mg twice daily, amoxicillin 1g twice daily for 5 days followed by esomeprazole 40 mg twice daily, levofloxacin 500 mg twice daily, and tinidazole 500 mg twice daily for 5 more days; n = 90). Antimicrobial resistance was assessed by the E-test. Efficacy, adverse events, and costs were determined. RESULTS Intention-to-treat analysis showed similar eradication rates for concomitant (92.2%; 95% confidence interval [CI], 84.0%-95.8%) and sequential therapies (93.3%; 95% CI, 86.9%-97.3%). Per-protocol eradication results were 96.5% (95% CI, 91%-99%) for concomitant therapy and 95.5% for sequential therapy (95% CI, 89.6%-98.5%). The differences between sequential and concomitant treatments were 1.1% in the intention-to-treat study (95% CI; -7.6% to 9.8%) and -1.0% in the per-protocol analysis (95% CI; -8.0% to 5.9%). The prevalence of antimicrobial resistance and incidence of adverse events were comparable between groups. Concomitant therapy cost

Protective effects of Lactobacillus paracasei F19 in a rat model of oxidative and metabolic hepatic injury

9 less than sequential therapy. CONCLUSIONS Five days of levofloxacin-containing quadruple concomitant therapy is as effective and safe, and less expensive, in eradicating H pylori infection than 10 days of levofloxacin-containing sequential therapy.

CD133 and CD44 Cell surface markers do not identify cancer stem cells in primary human gastric tumors

The liver is susceptible to such oxidative and metabolic stresses as ischemia-reperfusion (I/R) and fatty acid accumulation. Probiotics are viable microorganisms that restore the gut microbiota and exert a beneficial effect on the liver by inhibiting bacterial enzymes, stimulating immunity, and protecting intestinal permeability. We evaluated Lactobacillus paracasei F19 (LP-F19), for its potential protective effect, in an experimental model of I/R (30 min ischemia and 60 min reperfusion) in rats fed a standard diet or a steatogen [methionine/choline-deficient (MCD)] diet. Both groups consisted of 7 sham-operated rats, 10 rats that underwent I/R, and 10 that underwent I/R plus 8 wk of probiotic dietary supplementation. In rats fed a standard diet, I/R induced a decrease in sinusoid perfusion (P < 0.001), severe liver inflammation, and necrosis besides an increase of tissue levels of malondialdehyde (P < 0.001), tumor necrosis factor-alpha (P < 0.001), interleukin (IL)-1beta (P < 0.001), and IL-6 (P < 0.001) and of serum levels of transaminase (P < 0.001) and lipopolysaccharides (P < 0.001) vs. sham-operated rats. I/R also induced a decrease in Bacterioides, Bifidobacterium, and Lactobacillus spps (P < 0.01, P < 0.001, and P < 0.001, respectively) and an increase in Enterococcus and Enterobacteriaceae (P < 0.01 and P < 0.001, respectively) on intestinal mucosa. The severity of liver and gut microbiota alterations induced by I/R was even greater in rats with liver inflammation and steatosis, i.e., MCD-fed animals. LP-F19 supplementation significantly reduced the harmful effects of I/R on the liver and on gut microbiota in both groups of rats, although the effect was slightly less in MCD-fed animals. In conclusion, LP-F19 supplementation, by restoring gut microbiota, attenuated I/R-related liver injury, particularly in the absence of steatosis.

The human gastric microbiota: Is it time to rethink the pathogenesis of stomach diseases?

Emerging evidence suggests that tumors contain and are driven by a cellular component that displays stem cell properties, the so‐called cancer stem cells (CSCs). CSCs have been identified in several solid human cancers; however, there are no data about CSCs in primary human gastric cancer (GC). By using CD133 and CD44 cell surface markers we investigated whether primary human GCs contain a cell subset expressing stem‐like properties and whether this subpopulation has tumor‐initiating properties in xenograft transplantation experiments. We examined tissues from 44 patients who underwent gastrectomy for primary GC. The tumorigenicity of the cells separated by flow cytometry using CD133 and CD44 surface markers was tested by subcutaneous or intraperitoneum injection in NOD/SCID and nude mice. GCs included in the study were intestinal in 34 cases and diffuse in 10 cases. All samples contained surface marker‐positive cells: CD133+ mean percentage 10.6% and CD133+/CD44+ mean percentage 27.7%, irrespective of cancer phenotype or grade of differentiation. Purified CD133+ and CD133+/CD44+ cells, obtained in sufficient number only in 12 intestinal type GC cases, failed to reproduce cancer in two mice models. However, the unseparated cells produced glandular‐like structures in 70% of the mice inoculated. In conclusion, although CD133+ and CD133+/CD44+ were detectable in human primary GCs, they neither expressed stem‐like properties nor exhibited tumor‐initiating properties in xenograft transplantation experiments. J. Cell. Physiol. 227: 2686–2693, 2012.

Contribution of Gut Microbiota to Colonic and Extracolonic Cancer Development

Introduction Although long thought to be a sterile organ, due to its acid production, the human stomach holds a core microbiome. Aim To provide an update of findings related to gastric microbiota and its link with gastric diseases. Methods We conducted a systematic review of the literature. Results The development of culture-independent methods facilitated the identification of many bacteria. Five major phyla have been detected in the stomach: Firmicutes, Bacteroidites, Actinobacteria, Fusobacteria and Proteobacteria. At the genera level, the healthy human stomach is dominated by Prevotella, Streptococcus, Veillonella, Rothia and Haemophilus; however, the composition of the gastric microbiota is dynamic and affected by such factors as diet, drugs and diseases. The interaction between the pre-existing gastric microbiota and Helicobacter pylori infection might influence an individual’s risk of gastric disease, including gastric cancer. Conclusions The maintenance of bacterial homeostasis could be essential for the stomach’s health and highlights the chance for therapeutic interventions targeting the gastric microbiota, even if gastric pH, peristalsis and the mucus layer may prevent bacteria colonization; and the definition of gastric microbiota of the healthy stomach is still an ongoing challenging task.

Global DNA hypomethylation is an early event in Helicobacter pylori-related gastric carcinogenesis

It is estimated that 20% of malignancies worldwide can be attributed to infections, i.e. about 1.2 million cases per year. A typical example of the association between bacterial infection and gastrointestinal malignancies is Helicobacter pylori infection with both gastric cancer and mucosa-associated lymphoid tissue lymphoma. Bacteria are an important component of the human body. The human intestine contains >500 different types of microorganisms, the ‘gut microbiota’, that play important functions such as energetic metabolism, proliferation and survival of epithelial cells, and protection against pathogens. Chronic alteration of intestinal microbiota homeostasis, ‘dysbiosis’, could promote many diseases, including cancer. The mechanisms by which bacteria may induce carcinogenesis include chronic inflammation, immune evasion, and immune suppression. There are three effector pathways of T helper (Th) cell differentiation: Th1 responses promoted by procarcinogenic signal transducer and activator of transcription (Stat)1 and Stat4 signaling, Th2 responses promoted by Stat6 signaling, and Th17 responses promoted by Stat3 signaling. Interestingly, Th1 responses, driven by IL-12 and characterized by IFN-γ production, are typically anticarcinogenic, whereas Th17 responses are activated in various cancers. Furthermore, a T regulatory response, driven by IL-10 and TGF-β, counterbalances the proinflammatory effect of Th17 responses. Elevated numbers of T regulatory cells suppress the innate and adaptive immune responses, thereby contributing to tumor progression. The emerging relationship between gut microbiota and cancer has prompted new ways of thinking about cancer prevention and has led to the development of noninvasive diagnostic tests and innovative treatments, such as with probiotics. However, although in vitro and animal model studies suggest a protective anticancer effect of probiotics, the results of human epidemiological studies are controversial.

Helicobacter pylori and Epigenetic Mechanisms Underlying Gastric Carcinogenesis

Aim Cancer, particularly gastric cancer (GC), is prevalently an epigenetic phenomenon that is dependent on an altered DNA methylation pattern. In gastric carcinogenesis, many genes show aberrant methylation; however, none of them may be used as a biomarker of cancer risk and progression. The authors aimed to evaluate the global DNA methylation of gastric mucosa in Helicobacter pylori (Hp)-related chronic gastritis, in GC and in 10 patients with preneoplastic lesions (ie, atrophy and intestinal metaplasia) followed up for 10 years. Methods The authors analysed 93 dyspeptic patients who underwent upper endoscopy, 41 surgical GC samples and 10 patients with preneoplastic gastric lesions followed up for 10 years after successful Hp eradication therapy. Global DNA methylation status and surrogate markers of cell proliferation and apoptosis were evaluated by immunohistochemistry using the anti-5-methylcytosine (5-MC), anti-Ki-67 and anti-p53 (anti-apoptotic marker)-specific antibodies, respectively. Results Global DNA methylation of gastric mucosa gradually decreased from normal mucosa to Hp-positive gastritis, Hp-positive chronic atrophic gastritis, independent of Cag-A status and GC; however, the variation was significant (p<0.05) only between Hp-negative subjects and Hp-positive chronic gastritis. Interestingly, the 5-MC immunostaining was absent in areas of intestinal metaplasia. In the 10 patients with preneoplastic lesions, global DNA methylation decreased over time despite the eradication of Hp infection, but reached significance only at 10 years versus baseline. The 5-MC immunostaining negatively correlated with Ki-67 and p53 expression in all groups. Conclusion Global DNA hypomethylation is an early molecular event in Hp-related gastric carcinogenesis. Further studies with more cases and a longer follow-up are needed to establish the potential GC predictive role of DNA hypomethylation.

Cancer stem cell hypothesis and gastric carcinogenesis: Experimental evidence and unsolved questions.

Gastric carcinogenesis is a multistep process triggered by Helicobacter pylori and characterized by accumulation of molecular alterations. Two mechanisms are implicated in cancer-related molecular alterations: genetic and epigenetic. The former includes changes in the DNA sequence, the latter occurs without changes of DNA sequence. However, the most important difference between genetic and epigenetic alterations is that epigenetic changes are potentially reversible by eliminating toxic agents. DNA methylation is the major epigenetic phenomenon of eukaryotic genomes and involves the addition of a methyl group to the carbon 5 position of the cytosine ring within the CpG dinucleotide. DNA methylation is needed for the normal development of cells, whereas aberrant methylation of CpG islands confers a selective growth advantage that results in cancerous growth. The stomach is one of the organs frequently showing aberrant methylation of DNA epithelial cells because of its accessibility to exogenous toxic agents such as H. pylori infection. Aberrant methylation of CpG islands occurs early in gastric carcinogenesis, tends to increase as the process advances and is prevalently related to the infection. In conclusion, gastric cancer is mainly an epigenetic disease and H. pylori, acting through inflammatory mediators, may play a key role in the development of such molecular alterations.

MDR1-P-glycoprotein behaves as an oncofetal protein that promotes cell survival in gastric cancer cells

Traditionally, the clonal evolution model has been used to explain gastric cancer (GC) growth dynamics. According to this model, GC cells result from multiple mutations over time resulting in a population of continually diversifying cells. This heterogeneity enables the survival of different clones under particular conditions allowing growth at metastatic locations or resistance to chemotherapeutics. Cancer stem cell (CSC) theory completely overturns this traditional understanding of cancer suggesting that only CSCs can self-renew and promote tumor growth. CSCs are relatively refractory to conventional therapies, thus explaining why anti-cancer therapies are far from curative and why relapses of cancer are frequent. The identification of the CSC component of a tumor might, thus, open new therapeutic perspective based on the selective targeting of this small population of cells. In this review we examine the current scientific evidence supporting the existence of CSC in gastric tumors and analyze the main unsolved questions of this difficult field of cancer research.