Prevalence and Natural History of Segmental Colitis Associated With Diverticulosis.

INTRODUCTION: We assessed the prevalence and clinical outcomes of segmental colitis associated with diverticulosis (SCAD) in patients with newly diagnosed diverticulosis. METHODS: A 3-year international, multicenter, prospective cohort study was conducted involving 2,215 patients. RESULTS: SCAD diagnosis was posed in 44 patients (30 male patients; median age: 64.5 years; prevalence of 1.99%, 95% confidence interval, 1.45%-2.66%). Patients with SCAD types D and B showed worse symptoms, higher fecal calprotectin values, needed more steroids, and reached less likely complete remission. DISCUSSION: Although SCAD generally had a benign outcome, types B and D were associated with more severe symptoms and worse clinical course.

Probiotics in Gastrointestinal Diseases: All that Glitters Is Not Gold.

BACKGROUND: Multiple lines of evidence now support the notion that gut microbiota can contribute to digestive and extra-digestive diseases. The emergence of these observations enabled to postulate a bacteria-centric paradigm to rethink the treatment of many diseases. The goal of therapy should not be to eradicate the flora but to modify it in a way that leads to symptomatic improvement; thus, the interest in the use of probiotics to modulate microbiota composition has increased worldwide in both community and healthcare settings. SUMMARY: The results of published studies are conflicting for most probiotic strains and formulations, and clinicians and consumers need a better understanding of probiotic risks and benefits. Currently, clear guidelines on when to use probiotics and the most effective probiotic for different gastrointestinal conditions are still lacking. Here, we reviewed the studies on the use of probiotics in some diseases of relevant interest to gastroenterologists, such as Helicobacter pylori infection, irritable bowel syndrome, and inflammatory bowel disease. Key Message: Although the evidence is relevant and promising for probiotics in general, and for specific strains and combinations of strains, it is not yet sufficient to draw unequivocal conclusions and clear recommendations.

Bone Marrow of Contention: A Rare Case of Recurrent Acute Hepatitis.

Hepatitis-associated aplastic anemia is a well-recognized clinical syndrome in which marrow failure follows the development of hepatitis. Although aplastic anemia is intimately related to paroxysmal nocturnal hemoglobinuria, until now, no cases of PNH-associated hepatitis have been described. We report a case of recurrent acute hepatitis preceding the clinical onset of PNH. Treatment of PNH with the complement inhibitor eculizumab (Soliris®) prevented both recurrences of episodes of intravascular hemolysis and liver enzyme alteration. This is the first known published case of PNH-associated hepatitis.

Non-bismuth and bismuth quadruple therapies based on previous clarithromycin exposure are as effective and safe in an area of high clarithromycin resistance: A real-life study.

BACKGROUND: Bismuth quadruple (BQT) and non-bismuth quadruple (N-BQT) therapies are the recommended first-line treatments for Helicobacter (H.) pylori infection. OBJECTIVE: To compare the efficacy of BQT and N-BQT in clinical practice in an area with high clarithromycin resistance, choosing the regimen on the basis of previous exposure to clarithromycin. METHODS: A total of 404 consecutive H pylori-positive, naïve patients were enrolled. A total of 203 patients without previous exposure to clarithromycin received N-BQT, 100 patients for 10 days and 103 for 14 days, whereas 201 with previous exposure to clarithromycin received 10-day BQT. Efficacy and treatment-related adverse events were assessed. RESULTS AND CONCLUSIONS: Eradication rates by intention-to-treat analysis were 88.2% for N-BQT and 91.5% for BQT (P = .26); per-protocol analysis eradication rates were 91.2% and 95.8% for N-BQT and BQT, respectively (P = .07). Eradication rates were significantly higher with 14-day than 10-day CT (P < .003). Almost all patients had a good compliance with both N-BQT (95.6%) and BQT (95%). Adverse events occurred in 24.1% and 26.9% (P = .53) of patients in the N-BQT and BQT group, respectively. In conclusion, clarithromycin-containing non-bismuth or bismuth quadruple therapy, based on the knowledge of previous clarithromycin exposure, is effective and safe even in an area of high prevalence of clarithromycin-resistant H pylori strains.

Lactobacillus casei DG and its postbiotic reduce the inflammatory mucosal response: an ex-vivo organ culture model of post-infectious irritable bowel syndrome.

BACKGROUND: The evidence on the role of gut microbiota in post-infectious irritable bowel syndrome (PI-IBS) is convincing. Lactobacillus spp. positively affect IBS symptoms, although the mechanisms through which probiotics exert their beneficial effects are largely unknown. The aim of the study is to evaluate the role of Lactobacillus casei DG (LC-DG) and its postbiotic (PB) in modulating the inflammatory/immune-response in PI-IBS in an ex-vivo organ culture model. METHODS: Ex vivo cultures of ileal and colonic mucosa from 10 PI-IBS, diarrhea predominant subtype (D) patients, and 10 healthy controls (HC) were treated with LPS, LC-DG and PB. Interleukin (IL)-1α, IL-6, IL-8 and IL-10 mRNA levels were assessed by real-time PCR and Toll like receptor 4 (TLR-4) protein expression by Western blotting. RESULTS: At baseline, IL-1α, IL-6 and IL-8 mRNA levels as well as TLR-4 protein expression were significantly higher while IL-10 mRNA levels were lower in PI-IBS D than in HC in both ileum and colon. LC-DG and PB significantly reduced the mRNA levels of pro-inflammatory cytokines and TLR-4 while increased that of IL-10 after LPS stimulation. The protective effect was more pronounced for PB than LC-DG treatment. CONCLUSION: LC-DG and its PB attenuate the inflammatory mucosal response in an ex-vivo organ culture model of PI-IBS D.

The Gut Bacteria-Driven Obesity Development.

It is now well established that a healthy gut flora is largely responsible for the overall health of the host, while a perturbation in gut microbial communities can contribute to disease susceptibility. Obesity is a complex process involving genetic and environmental factors with an epidemiological burden that makes it a major public health issue. Studies of germ-free or gnotobiotic mice provided evidence that the diversity, as well as the presence and relative proportion of different microbes in the gut play active roles in energy homeostasis. Similarly, human studies showed that both the diversity of the microbiota and the Bacteroidetes/Firmicutes ratio are decreased in obese individuals. The 'obese microbiota' seems to be able to increase dietary energy harvest and favor weight gain and fat deposition. Although research in this field has just started and many of the available data are still conflicting, the results are providing exciting perspectives, and gut microbiota manipulation has already become a new target for both prevention and treatment of obesity.

The Metabolic Role of Gut Microbiota in the Development of Nonalcoholic Fatty Liver Disease and Cardiovascular Disease.

The prevalence of metabolic disorders, such as type 2 diabetes (T2D), obesity, and non-alcoholic fatty liver disease (NAFLD), which are common risk factors for cardiovascular disease (CVD), has dramatically increased worldwide over the last decades. Although dietary habit is the main etiologic factor, there is an imperfect correlation between dietary habits and the development of metabolic disease. Recently, research has focused on the role of the microbiome in the development of these disorders. Indeed, gut microbiota is implicated in many metabolic functions and an altered gut microbiota is reported in metabolic disorders. Here we provide evidence linking gut microbiota and metabolic diseases, focusing on the pathogenetic mechanisms underlying this association.

The psyche and gastric functions.

Although the idea that gastric problems are in some way related to mental activity dates back to the beginning of the last century, until now it has received scant attention by physiologists, general practitioners and gastroenterologists. The major breakthrough in understanding the interactions between the central nervous system and the gut was the discovery of the enteric nervous system (ENS) in the 19th century. ENS (also called 'little brain') plays a crucial role in the regulation of the physiological gut functions. Furthermore, the identification of corticotropin-releasing factor (CRF) and the development of specific CRF receptor antagonists have permitted to characterize the neurochemical basis of the stress response. The neurobiological response to stress in mammals involves three key mechanisms: (1) stress is perceived and processed by higher brain centers; (2) the brain mounts a neuroendocrine response by way of the hypothalamic-pituitary-adrenal axis (HPA) and the autonomic nervous system (ANS), and (3) the brain triggers feedback mechanisms by HPA and ANS stimulation to restore homeostasis. Various stressors such as anger, fear, painful stimuli, as well as life or social learning experiences affect both the individual's physiologic and gastric function, revealing a two-way interaction between brain and stomach. There is overwhelming experimental and clinical evidence that stress influences gastric function, thereby outlining the pathogenesis of gastric diseases such as functional dyspepsia, gastroesophageal reflux disease and peptic ulcer disease. A better understanding of the role of pathological stressors in the modulation of disease activity may have important pathogenetic and therapeutic implications.

Vitamin B12 supplementation improves rates of sustained viral response in patients chronically infected with hepatitis C virus.

BACKGROUND: In vitro, vitamin B12 acts as a natural inhibitor of hepatitis C virus (HCV) replication. OBJECTIVE: To assess the effect of vitamin B12 on virological response in patients with chronic HCV hepatitis naïve to antiviral therapy. METHODS: Ninety-four patients with chronic HCV hepatitis were randomly assigned to receive pegylated interferon α plus ribavirin (standard-of-care; SOC) or SOC plus vitamin B12 (SOC+B12). Viral response-namely, undetectable serum HCV-RNA, was evaluated 4 weeks after starting treatment (rapid viral response), 12 weeks after starting treatment (complete early viral response) and 24 or 48 weeks after starting treatment (end-of-treatment viral response) and 24 weeks after completing treatment (sustained viral response (SVR)). Genotyping for the interleukin (IL)-28B polymorphism was performed a posteriori in a subset (42/64) of HCV genotype 1 carriers. RESULTS: Overall, rapid viral response did not differ between the two groups, whereas the rates of complete early viral response (p=0.03), end-of-treatment viral response (p=0.03) and SVR (p=0.001) were significantly higher in SOC+B12 patients than in SOC patients. In SOC+B12 patients, the SVR rate was also significantly higher in carriers of a difficult-to-treat genotype (p=0.002) and in patients with a high baseline viral load (p=0.002). Distribution of genotype IL-28B did not differ between the two groups. At multivariate analysis, only easy-to-treat HCV genotypes (OR=9.00; 95% CI 2.5 to 37.5; p=0.001) and vitamin B12 supplementation (OR=6.9; 95% CI 2.0 to 23.6; p=0.002) were independently associated with SVR. CONCLUSION: Vitamin B12 supplementation significantly improves SVR rates in HCV-infected patients naïve to antiviral therapy.

Exploring the Link between Helicobacter pylori, Gastric Microbiota and Gastric Cancer.

Gastric cancer (GC) still represents one of the leading causes of cancer-related mortality and is a major public health issue worldwide. Understanding the etiopathogenetic mechanisms behind GC development holds immense potential to revolutionize patients' treatment and prognosis. Within the complex web of genetic predispositions and environmental factors, the connection between Helicobacter pylori (H. pylori) and gastric microbiota emerges as a focus of intense research investigation. According to the most recent hypotheses, H. pylori triggers inflammatory responses and molecular alterations in gastric mucosa, while non-Helicobacter microbiota modulates disease progression. In this review, we analyze the current state of the literature on the relationship between H. pylori and non-Helicobacter gastric microbiota in gastric carcinogenesis, highlighting the mechanisms by which microecological dysbiosis can contribute to the malignant transformation of the mucosa.

The professional background of a referring physician predicts the diagnostic yield of small bowel capsule endoscopy in suspected small bowel bleeding.

Background and study aims The diagnostic yield of small-bowel capsule endoscopy (SBCE) in suspected small bowel bleeding (SSBB) is highly variable. Different reimbursement systems and equipment costs also limit SBCE use in clinical practice. Thus, minimizing non-diagnostic procedures is advisable. This study aimed to assess the SBCE diagnostic yield and identify factors predicting diagnostic findings in a cohort of patients with SSBB. Patients and methods In this retrospective cohort study, we analyzed the medical records of patients who consecutively underwent SBCE for SSBB over 9 years. By logistic regression, we identified covariates predicting diagnostic findings at SBCE. Finally, we performed a post-hoc cost analysis based on previous gastroenterologist or endoscopist consultations versus direct SBCE ordering by other specialists. Results The final analysis included 584 patients. Most SBCEs were ordered by a gastroenterologist or endoscopist (74%). The number of SBCEs without any finding was significantly lower in the gastroenterologist/endoscopist group P <0.001). The SBCE diagnostic yield ordered by a gastroenterologist or endoscopist was significantly higher than that by other specialists (63% vs 52%, odds ratio [OR] 1.57; 95% confidence interval [CI] 1.07-2.26, P =0.019). At multivariate analysis, older age (OR 1.7, 95%CI 1.2-2.4, P =0.005), anemia (OR 4.9, 95%CI 1.9-12, P =0.001), small bowel transit time (OR 1, 95%CI 1-1.02, P =0.039), and referring physician (OR 1.8, 95%CI 1.1-2.7, P =0.003) independently predicted diagnostic findings. Implementing prior gastroenterologist or endoscopist referral vs direct SBCE ordering would reduce medical expenditures by 16%. Conclusions The professional background of referring physicians significantly improves the diagnostic yield of SBCE and contributes to controlling public health costs.

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 $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.

Autoimmune liver diseases and SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), causing coronavirus disease 2019 (COVID-19), can trigger autoimmunity in genetically predisposed individuals through hyperstimulation of immune response and molecular mimicry. Here we summarise the current knowledge about auto-immune liver diseases (AILDs) and SARS-CoV-2, focusing on: (1) The risk of SARS-CoV-2 infection and the course of COVID-19 in patients affected by AILDs; (2) the role of SARS-CoV-2 in inducing liver damage and triggering AILDs; and (3) the ability of vaccines against SARS-CoV-2 to induce autoimmune responses in the liver. Data derived from the literature suggest that patients with AILDs do not carry an increased risk of SARS-Cov-2 infection but may develop a more severe course of COVID-19 if on treatment with steroids or thiopurine. Although SARS-CoV-2 infection can lead to the development of several autoimmune diseases, few reports correlate it to the appearance of de novo manifestation of immune-mediated liver diseases such as autoimmune hepatitis (AIH), primary biliary cholangitis (PBC) or AIH/PBC overlap syndrome. Different case series of an AIH-like syndrome with a good prognosis after SARS-CoV-2 vaccination have been described. Although the causal link between SARS-CoV-2 vaccines and AIH cannot be definitively established, these reports suggest that this association could be more than coincidental.

Diverticular Inflammation and Complication Assessment classification, CODA score and fecal calprotectin in clinical assessment of patients with diverticular disease: A decision curve analysis.

BACKGROUND AND AIMS: The Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) were found to be effective in predicting the outcomes of Diverticular Disease (DD). We ascertain whether fecal calprotectin (FC) can further aid in improving risk stratification. METHODS: A three-year international, multicentre, prospective cohort study was conducted involving 43 Gastroenterology and Endoscopy centres. Survival methods for censored observations were used to estimate the risk of acute diverticulitis (AD) in newly diagnosed DD patients according to basal FC, DICA, and CODA. The net benefit of management strategies based on DICA, CODA and FC in addition to CODA was assessed with decision curve analysis, which incorporates the harms and benefits of using a prognostic model for clinical decisions. RESULTS: At the first diagnosis of diverticulosis/DD, 871 participants underwent FC measurement. FC was associated with the risk of AD at 3 years (HR per each base 10 logarithm increase: 3.29; 95% confidence interval, 2.13-5.10) and showed moderate discrimination (c-statistic: 0.685; 0.614-0.756). DICA and CODA were more accurate predictors of AD than FC. However, FC showed high discrimination capacity to predict AD at 3 months, which was not maintained at longer follow-up times. The decision curve analysis comparing the combination of FC and CODA with CODA alone did not clearly indicate a larger net benefit of one strategy over the other. CONCLUSIONS: FC measurement could be used as a complementary tool to assess the immediate risk of AD. In all other cases, treatment strategies based on the CODA score alone should be recommended.

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

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.

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

P-glycoprotein (P-gp), traditionally linked to cancer poor prognosis and multidrug resistance, is undetectable in normal gastric mucosa and overexpressed in gastric cancer (GC). We propose that P-gp may be involved in Helicobacter pylori (Hp)-related gastric carcinogenesis by inhibiting apoptosis. Aim of the study was to evaluate the expression of P-gp in fetal stomach and in Hp-related gastric carcinogenesis, the epigenetic control of the multi-drug resistance-1 (MDR1) gene, the localization and interaction between P-gp and Bcl-x(L) and the effect of the selective silencing of P-gp on cell survival. P-gp and Bcl-xl expression was evaluated by immunohistochemistry on 28 spontaneously abortive human fetuses, 66 Hp-negative subjects, 138 Hp-positive chronic gastritis (CG) of whom 28 with intestinal metaplasia (IM) and 45 intestinal type GCs. P-gp/Bcl-x(L) colocalization was investigated by confocal immunofluorescence microscopy and protein-protein interaction by co-immunoprecipitation, in basal conditions and after stress-induced apoptosis, in GC cell lines AGS and MKN-28 and hepatocellular carcinoma cell line Hep-G2. The role of P-gp in controlling apoptosis was evaluated by knocking down its expression with a specific small interfering RNAs in stressed AGS and MKN-28 cell lines. P-gp is expressed in the gastric mucosa of all human fetuses while, it is undetectable in adult normal mucosa and re-expressed in 30/110 Hp-positive non-IM-CG, 28/28 IM-CG and 40/45 GCs. P-gp expression directly correlates with that of Bcl-x(L) and with the promoter hypomethylation of the MDR1 gene. In GC cell lines, P-gp is localized on the plasma membrane and mitochondria where it colocalizes with Bcl-x(L). Co-immunoprecipitation confirms the physical interaction between P-gp and Bcl-x(L) in AGS, MKN-28 and Hep-G2, at both basal level and after stress-induced apoptosis. The selective silencing of P-gp sensitizes GC cells to stress-induced apoptosis. P-gp behaves as an oncofetal protein that, by cross-talking with Bcl-x(L), acts as an anti-apoptotic agent in Hp-related gastric carcinogenesis.

13C-aminopyrine breath test accurately predicts long-term outcome of chronic hepatitis C.

BACKGROUND & AIMS: Although numerous non-invasive tests are currently available to explore liver function and disease activity in patients with HCV-related chronic diseases, none of these indicate the likelihood of disease progression in the individual patient. We aimed at assessing the prognostic ability of (13)C(2)-aminopyrine breath test ((13)C-ABT) in the prediction of liver fibrosis progression in patients with HCV chronic hepatitis who prospectively entered a long-term follow-up. METHODS: Fifty patients with HCV-related chronic disease who underwent paired liver biopsy (at baseline and after a mean period of 86 months) were included in the study. (13)C-ABT was carried out at baseline and every 3 years. Histological progression was defined as increase of at least 2 fibrosis units according to Ishak score. RESULTS: Fourteen patients progressed of at least 2 fibrosis units during the follow-up. These patients were more frequently infected with a HCV-1b genotype and had, at baseline, a significantly older age, higher BMI, AST levels, and AST to platelet ratio index (APRI). (13)C-ABT was altered in 57% of cases at baseline and in 100% of the cases at 3-year follow-up. In the univariate analysis, age (p=0.005), BMI (p=0.006), platelet count (p=0.03), AST (p=0.012) and ALT (p=0.04) levels, APRI (p=0.03), and baseline (13)C-ABT results (p<0.0001) were all independently associated with progression of liver fibrosis. By Cox's multiple regression analysis, the (13)C-ABT was the only covariate that significantly predicted liver fibrosis progression (HR 6.7; 95% CI 2.3-20.1; p<0.001). CONCLUSIONS: (13)C-ABT accurately predicts the risk of disease progression in patients with HCV-related chronic hepatitis.

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

BACKGROUND: Gastroesophageal reflux disease (GERD), including erosive reflux disease and non-erosive reflux disease (NERD), is a chronic disease with a significant negative effect on quality of life. State-of-the-art treatment involves proton pump inhibitors (PPIs). However, relapse of symptoms occurs in the majority of the patients who require recurrent or continuous therapy. Although PPIs are well tolerated, little information is available about gastrointestinal side effects. AIM: To evaluate the effects of long-term PPI treatment on development of bowel symptoms and/or small intestinal bacterial overgrowth (SIBO). METHODS: Patients with NERD not complaining of bowel symptoms were selected by upper endoscopy, 24-h pH-metry and a structured questionnaire concerning severity and frequency of bloating, flatulence, abdominal pain, diarrhoea and constipation. Patients were treated with esomeprazole 20 mg bid for 6 months. Prior to and after 8 weeks and 6 months of therapy, patients received the structured questionnaire and underwent evaluation of SIBO by glucose hydrogen breath test (GHBT). RESULTS: Forty-two patients with NERD were selected out of 554 eligible patients. After 8 weeks of PPI treatment, patients complained of bloating, flatulence, abdominal pain and diarrhoea in 43%, 17%, 7% and 2%, respectively. After 6 months, the incidence of bowel symptoms further increased and GHBT was found positive in 11/42 (26%) patients. By a post hoc analysis, a significant (P < 0·05) percentage of patients (8/42) met Rome III criteria for irritable bowel syndrome. CONCLUSIONS: Prolonged PPI treatment may produce bowel symptoms and SIBO; therefore, the strategy of step-down or on-demand PPI therapy should be encouraged in GERD.

Contribution of gut microbiota to colonic and extracolonic cancer development.

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-ß, 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.