Molecular Pathways of Carcinogenesis in Familial Adenomatous Polyposis.

Familial adenomatous polyposis (FAP) is a genetic syndrome characterized by the presence of multiple polyps in the gastrointestinal tract and a wide range of systemic extra-intestinal manifestations. Patients affected will inevitably undergo abdominal surgery due to the malignant transformation of one or more adenomas. The pathogenesis of the disease is based on a loss of function mutation in adenomatous polyposis coli (APC), a tumor-suppressor gene, inherited following a Mendelian pattern. This gene is a key component of multiple cell functions that cooperate for homeostasis; when mutated, it contributes to the progression of colorectal adenoma into cancer. Recent studies have demonstrated that several additional mechanisms may influence this process, such as alterations in gut microbiota composition and mucosal barrier immunity, interaction with the immune microenvironment and inflammation, the hormone estrogen, and other signaling pathways. These factors represent promising targets of future therapies and chemoprevention, aiming to alter the progressive nature of the disease and improve the quality of life of families affected. Therefore, we performed a narrative review about the current knowledge of the aforementioned pathways involved in colorectal cancer pathogenesis in FAP, exploring the genetic and environmental factors that may contribute to the development of CRC in FAP.

The State of the Art of Molecular Fecal Investigations for Helicobacter pylori (H. pylori) Antibiotic Resistances.

A new paradigm shift for the treatment of Helicobacter pylori (H. pylori) infection would be timely due to a progressive increase in antibiotic resistance. Such a shift in the perspective of the H. pylori approach should include the preliminary assessment of antibiotic resistance. However, the availability of sensitivity tests is not widespread and the guidelines have always indicated empirical treatments without taking into account the need to make sensitivity tests accessible, i.e., the necessary starting point for improving results in different geographical areas. Currently, the traditional tools for this purpose (culture) are based on performing an invasive investigation (endoscopy) and often involve technical difficulties; thus, they were only confined to the settings where multiple attempts at eradication have failed. In contrast, genotypic resistance testing of fecal samples using molecular biology methods is much less invasive and more acceptable to patients. The purpose of this review is to update the state of the art of molecular fecal susceptibility testing for the management of this infection and to extensively discuss the potential benefits of their large-scale deployment, i.e., novel pharmacological opportunities.

Fibres and Colorectal Cancer: Clinical and Molecular Evidence.

Colorectal cancer (CRC) is one of the leading causes of mortality for cancer in industrialized countries. The link between diet and CRC is well-known, and presumably CRC is the type of cancer which is most influenced by dietary habits. In Western countries, an inadequate dietary intake of fibers is endemic, and this could be a driving factor in the increase of CRC incidence. Indeed, several epidemiologic studies have elucidated an inverse relationship between daily fiber intake and risk of CRC. Long-term prognosis in CRC survivors is also dependent on dietary fibers. Several pathogenetic mechanisms may be hypothesized. Fibers may interfere with the metabolism of bile acids, which may promote colon carcinogenesis. Further, fibers are often contained in vegetables which, in turn, contain large amounts of antioxidant agents like resveratrol, polyphenols, or phytoestrogens. Moreover, fibers can be digested by commensal flora, thus producing compounds such as butyrate, which exerts an antiproliferative effect. Finally, fibers may modulate gut microbiota, whose composition has shown to be associated with CRC onset. In this regard, dietary interventions based on high-fiber-containing diets are ongoing to prevent CRC development, especially in patients with high potential for this type of tumor. Despite the fact that outcomes are preliminary, encouraging results have been observed.

Serrated Colorectal Lesions: An Up-to-Date Review from Histological Pattern to Molecular Pathogenesis.

Until 2010, colorectal serrated lesions were generally considered as harmless lesions and reported as hyperplastic polyps (HPs) by pathologists and gastroenterologists. However, recent evidence showed that they may bear the potential to develop into colorectal carcinoma (CRC). Therefore, the World Health Organization (WHO) classification has identified four categories of serrated lesions: hyperplastic polyps (HPs), sessile serrated lesions (SSLs), traditional serrated adenoma (TSAs) and unclassified serrated adenomas. SSLs with dysplasia and TSAs are the most common precursors of CRC. CRCs arising from serrated lesions originate via two different molecular pathways, namely sporadic microsatellite instability (MSI) and the CpG island methylator phenotype (CIMP), the latter being considered as the major mechanism that drives the serrated pathway towards CRC. Unlike CRCs arising through the adenoma-carcinoma pathway, APC-inactivating mutations are rarely shown in the serrated neoplasia pathway.

Small Bowel Metastatic Melanoma: An Emblematic "Coal-Black" Appearance at Videocapsule Endoscopy.

A 80-year-old woman underwent vulvar melanoma resection and segmental lung resection for pulmonary metastasis. Immunotherapy with Nivolumab was performed. One year later, the patient was admitted for gastrointestinal (GI) recurrent bleeding and severe anemia. Esophagoastroduodenoscopy and colonoscopy did not show any abnormality, while videocapsule endoscopy (VCE) revealed an irregular and exophytic whitish area with a "coal-black" central depression. Small bowel resection was performed and histological examination revealed S100 protein strongly positive melanoma metastasis. The patient died six months later from disease progression. A "coal-black" appearance of intestinal metastatic melanoma has been described only twice before this report. In one case the patient had been treated by immunotherapy with interferon A and dendritic cell-based vaccination. In our patient, it is presumable that the picture we observed was a consequence of Nivolumab treatment inducing the disappearance of melanocytes in the area surrounding the metastasis with the onset of the central coal-black lesion encircled by whitish tissue. This picture should be emblematic of intestinal metastatic melanoma in subjects treated with immunotherapy showing occult/obscure bleeding.

May Antitransglutaminase Levels Predict Severity of Duodenal Lesions in Adults with Celiac Disease?

Background and Objective: Pediatric guidelines on celiac disease (CD) state that children with anti-transglutaminase antibodies (TGAs) >×10 upper limit of normal (ULN) may avoid endoscopy and biopsy. We aimed to evaluate whether these criteria may be suitable for villous atrophy diagnosis in CD adults. Materials and Methods: We retrospectively enrolled patients with CD aged >18 years. TGAs were expressed as xULN. Duodenal lesions were classified as atrophic or non-atrophic according to Marsh-Oberhuber. Fisher's exact and t-test were used for variables comparison. Receiver operating characteristics (ROC) curve analysis was performed with estimation of area under the curve (AUC), sensitivity, specificity, and positive and negative predictive value (PPV/NPV). Results: One hundred and twenty-one patients were recruited. Sixty patients (49.6%) had TGA >×10 ULN, and 93 (76.8%) had villous atrophy. The cut-off of >×10 ULN had sensitivity = 53.7%, specificity = 64.3%, PPV = 83.3%, and NPV = 29.5% to predict atrophy. Therefore, considering pediatric criteria, in 50 (41.3%) patients, biopsy could have been avoided. Patient subgroup with atrophy had higher TGA levels despite being not significant (37.2 ± 15.3 vs. 8.0 ± 1.3 ULN, p = 0.06). In adults, a slightly better diagnostic performance was obtained using a cut-off of TGA >×6.2 ULN (sensitivity = 57.1%, specificity = 65.6%, and AUC = 0.62). Conclusions: Despite our confirmation that villous atrophy is linked to high TGA levels, CD and atrophy diagnosis based only on serology is not reliable in adults.

The Influence of Small Intestinal Bacterial Overgrowth in Digestive and Extra-Intestinal Disorders.

Small intestinal bacterial overgrowth (SIBO) is a condition hallmarked by an increase in the concentration of colonic-type bacteria in the small bowel. Watery diarrhea, bloating, abdominal pain and distension are the most common clinical manifestations. Additionally, malnutrition and vitamin (B12, D, A, and E) as well as minerals (iron and calcium) deficiency may be present. SIBO may mask or worsen the history of some diseases (celiac disease, irritable bowel disease), may be more common in some extra-intestinal disorders (scleroderma, obesity), or could even represent a pathogenetic link with some diseases, in which a perturbation of intestinal microbiota may be involved. On these bases, we performed a review to explore the multiple links between SIBO and digestive and extra-intestinal diseases.

Curcumin and Colorectal Cancer: From Basic to Clinical Evidences.

Curcumin diffuses through cell membranes into the endoplasmic reticulum, mitochondria, and nucleus, where it exerts actions, as an antioxidant property. Therefore, its use has been advocated for chemopreventive, antimetastatic, and anti-angiogenic purposes. We conducted a literature review to summarize studies investigating the relationship between curcumin and colorectal cancer (CRC). In vitro studies, performed on human colon cancer cell lines, showed that curcumin inhibited cellular growth through cycle arrest at the G2/M and G1 phases, as well as stimulated apoptosis by interacting with multiple molecular targets. In vivo studies have been performed in inflammatory and genetic CRC animal models with a chemopreventive effect. To improve curcumin bioavailability, it has been associated with small particles that increase its absorption when orally administered with excellent results on both inflammation and carcinogenesis. Curcumin has been used, moreover, as a component of dietetic formulations for CRC chemoprevention. These combinations showed in vitro and in vivo anticarcinogenetic properties in inflammation-related and genetic CRC. A synergic effect was suggested using an individual constituent dosage, which was lower than that experimentally used "in vivo" for single components. In conclusion, curcumin falls within the category of plant origin substances able to prevent CRC in animals. This property offers promising expectations in humans.

Human Leukocyte Antigen (HLA) Haplotype Does Not Influence the Inflammatory Pattern of Duodenal Lymphocytosis Linked to Irritable Bowel Syndrome.

Background and objectives: Duodenal lymphocytosis (DL) is a condition characterized by enhanced infiltration of intraepithelial lymphocytes (IELs) in the duodenal mucosa, and it can be linked to both gluten- and non-gluten-related diseases, such as irritable bowel syndrome (IBS). Materials and methods: We retrospectively selected patients with DL linked to IBS. Formalin-embedded biopsy samples of the duodenum were collected. CD3 lymphocyte immunohistochemistry was used for IELs. The real-time polymerase chain reaction was used to quantify the amount of mRNA coding for tissue transglutaminase 2 (tTG2), interferon-gamma (IFNγ), toll-like receptor 2 (TLR2), and myeloid differentiation primary response 88 (MyD88). All subjects underwent DQ2-8 haplotype analysis. Controls were represented by subjects with IBS without DL. Results: Thirty-two patients with IBS-DL were retrospectively recruited. Fourteen subjects (43.8%) had a DQ2-8 haplotype. DQ2-8 positive subjects had similar levels compared to negative ones for tTG2, IFNγ, TLR2, and MyD88. Cigarette smoke did not influence molecular expression in our study. Smokers had a statistically higher IELs count than non-smokers (54.2 ± 7.7 vs. 36.0 ± 8.8, p < 0.001). A significant, direct correlation between IELs and duodenal expression of IFNγ was found (r = 0.36, p = 0.04). Conclusions: IBS with DL showed higher expression of inflammatory markers than controls, but DQ2-8 haplotype did not seem to affect their expression. Smoking might increase IELs infiltration.

The Spectrum of Small Intestinal Lesions in Patients with Unexplained Iron Deficiency Anemia Detected by Video Capsule Endoscopy.

Background and objectives: Video-capsule endoscopy (VCE) has shown a large range (38⁻83%) of diagnostic yield in unexplained iron deficiency anemia (IDA) and obscure-occult bleeding. Therefore, we retrospectively investigated the VCE-detected spectrum and the prevalence of small bowel injuries and associated risk factors in inpatients with both of the above reported conditions. Methods: We selected inpatients with IDA (hemoglobin <12 g/dL in women, <13 g/dL in men) and obscure-occult bleeding. We excluded VCE indications other than IDA. Complete medical histories and laboratory tests were collected. All subjects underwent PillCam SB2/SB3. The VCE feature Lewis score was calculated when appropriate. We used the t-test and Fisher's exact test for continuous and categorical variables, respectively, in univariate analysis. For multivariate analysis, we used binomial logistic regression. Results: We retrieved 109 patients (female:male ratio of 53:56; age 63.4 ± 18.9 years). Eighty patients (73.4%) showed ≥1 small bowel lesions. The Lewis score was calculated in 41 patients: 13 (31.7%) showed a mild (<135) and 28 (68.3%) a moderate-severe (135⁻790 and >790, respectively) score. In univariate analysis, the small bowel transit time (6.2 ± 2.9 versus 5.2 ± 2.1 h; p = 0.049) and non-steroidal anti-inflammatory drug use for at least two weeks (17.5% versus 0%; p = 0.01) were significantly higher in subjects with injuries. These associations were not confirmed at multivariate analysis. The severity of a lesion directly correlated with proton pump inhibitor (PPI) use and duration (not confirmed in multivariate analysis). VCE can reveal the source of obscure-occult bleeding in a high percentage of unexplained IDAs. A wide spectrum of endoscopic pictures may be found. Known as well as supposed risk factors for small bowel lesions may be detected.

Chemoprevention of inflammation-related colorectal cancer by silymarin-, acetyl-11-keto-beta-boswellic acid-, curcumin- and maltodextrin-enriched dietetic formulation in animal model.

On the basis of preliminary in vitro experience, we assessed whether an enriched nutritional formulation with estrogen receptor (ER)-beta agonist and anti-inflammatory properties may prevent inflammation-associated colorectal cancer (CRC) in an animal model. Study sample enclosed 110 C57BL/6J male mice. Forty underwent dietary supplement safety assessment (20 standard diet and 20 enriched formulation). Seventy were treated with azoxymethane (AOM)/dextran sulfate sodium and divided into two groups: 35 received standard diet and 35 enriched formulation (curcumin, boswellic acids, silymarin and maltodextrins). Miniature colonoscopy demonstrated colitis and solid lesion development in five mice/group 100 days after first AOM injection. Mice were killed after 10 days. In each group, four subgroups received intraperitoneal bromodeoxyuridine (BrdU) injection at 24th/48th/72nd/96th hour before killing. Anti-inflammatory effect and chemoprevention were evaluated by lesion number/size, histological inflammation/dysplasia/neoplasia assessment, pro-inflammatory cytokine messenger RNA (mRNA), ER-beta/ER-alpha/BrdU immunohistochemistry and TUNEL immunofluorescence. Standard formulation assumption was associated with colon shortening compared with enriched one (P = 0.04), which reduced solid lesion number and size (P < 0.001 for both), histological inflammation score (P = 0.04), pro-inflammatory cytokine mRNA expression (P < 0.001), number of low-grade dysplasia (LGD; P = 0.03) and high-grade dysplasia (P < 0.001) areas. CRC was observed in 69.6% in standard and 23.5% in enriched formulation assuming animals (P < 0.001). Enriched formulation induced lower ER-alpha expression in CRC (P < 0.001) and higher ER-beta expression in LGD (P < 0.001) being associated to higher epithelial turnover (BrdU; P<0.001) in normal mucosa and increased apoptosis in LGD and CRC (P < 0.001 for both). Our results are promising for a successful anti-inflammatory and chemopreventive effect of enriched formulation in CRC arising from inflamed tissue.

The "three-in-one" formulation of bismuth quadruple therapy for Helicobacter pylori eradication with or without probiotics supplementation: Efficacy and safety in daily clinical practice.

BACKGROUND: Clinical trials have shown a good efficacy of the "three-in-one" formulation of bismuth quadruple therapy (BQT) for Helicobacter (H.) pylori eradication. We aimed to assess the efficacy and safety of the three-in-one BQT in clinical practice, and investigate the effect of probiotic supplementation, in Italy. MATERIALS AND METHODS: A retrospective database, multicentre observational study was conducted in seven Italian Hospitals. Consecutive H. pylori-positive patients who received the three-in-one BQT for 10 days were included in the analysis. H. pylori eradication was assessed by histology, 13 C-urea breath test, or stool antigen test. Compliance and adverse events were evaluated by interview. RESULTS: A total of 376 patients were included in the intention-to-treat (ITT) and 352 in the per protocol (PP) analyses. One hundred and ninety-three subjects received probiotics supplementation. Overall, eradication rates were 90.2% (95% Confidence Interval (CI):86.7-93.0) in ITT and 94.6% (95% CI: 91.7-96.7) in PP analyses. The compliance was good (≥90% of treatment taken) in 94.9% of patients. The proportion of patients with a good compliance was not different with and without probiotics supplementation (94.8% vs 95.1%). Eradication rates were equally high for first-line (91.4%), second-line (87.5%), and third-line treatments (91.7%) in the ITT analysis (P = .48). Adverse events were reported by 32.4% of patients, but only 6.1% of patients discontinued treatment. CONCLUSIONS: The three-in-one BQT is highly effective and well tolerated for H. pylori eradication in daily clinical practice. Probiotics supplementation fails to improve compliance.

The Interaction Between Celiac Disease and Intestinal Microbiota.

Celiac disease (CD) is the most common autoimmune enteropathy, triggered by a deregulated immune response to gliadin. It has been hypothesized that human intestinal microbiota may interfere with the pathogenesis of the disease and in the clinical course of CD. In the present review, we analyzed the microbiota alterations observed in the course of CD, how they may influence the pathogenesis of CD, and the possible applications for a microbiota modulation in CD. In detail, most of the current literature underlined that the dysbiosis in CD is hallmarked by an increase in gram-negative and Bacteroidetes species, and by a decrease in Bifidobacteria and Lactobacilli. As the intestinal microbiota is able to modulate the cytokine environment, an unfavorable microbiota could amplify the immune response to gliadin in individuals with CD, whereas the administration of probiotic species could lead to a decrease in proinflammatory cytokine production. Therefore, dysbiosis could represent an important trigger in CD pathogenesis, along with genetic (HLA-haplotypes) and environmental factors (antibiotic administration, mode of delivery, and breastfeeding). Although data on the modulation of microbiota by GFD are conflicting, current evidence has demonstrated that probiotic administration could be useful to improve symptoms and to reduce molecular mucosal inflammation, by downregulating the cytokines involved in CD pathogenesis. However, studies analyzing this aspect are few in number, thus stimulating the exploration of this field, with the aim of achieving a solid pathophysiological basis for probiotic administration in CD.

Helicobacter pylori DNA isolation in the stool: an essential pre-requisite for bacterial noninvasive molecular analysis.

PURPOSE: Real-time polymerase chain reaction (RT-PCR) is a widely used technique for bacterial and viral infection diagnosis. Herein, we report our preliminary experience in retrieving H. pylori genetic sequences in stools and analyzing genotypic clarithromycin resistance by RT-PCR (noninvasive), with the aim of comparing this procedure with that performed on biopsy samples (invasive). MATERIALS AND METHODS: After 'in vitro' demonstration of H. pylori DNA detection from pure and stool-mixed bacteria, 52 consecutive patients at the first diagnosis of infection were investigated. DNA was extracted from biopsy tissue and stool samples (THD® Fecal Test, Italy). RT-PCR was performed to detect 23S rRNA encoding bacterial subunit gene and search A2143G, A2142C, A2142G point mutations for clarithromycin resistance assessment. RESULTS: RT-PCR showed H. pylori positive DNA in all infected patients with full concordance between tissue and stool detection (100%). We found A2143G mutation in 10 (19.2%), A2142G in 4 (7.7%) and A2142C in 5 (9.6%) patients; there was a full agreement between biopsy and fecal samples. A2143G was found in all the four A2142G positive cases and in three out of the five A2142C positive strains. Overall clarithromycin resistance rate in our series was 23%. CONCLUSIONS: Despite the need of confirmation on large sample, stool RT-PCR analysis could represent a feasible tool to detect H. pylori DNA sequences and antibiotic resistance point mutations. As compared to tissue molecular analysis, this technique is noninvasive, with potential advantages such as improvement of patient compliance, reduction of diagnostic procedure time/cost and improvement of therapeutic outcome.

Macronutrient intakes in obese subjects with or without small intestinal bacterial overgrowth: an alimentary survey.

OBJECTIVE: Obesity is a multifactorial disorder with a possible microbiota derangement in its pathogenesis. Moreover, in obese patients the likelihood of small intestinal bacterial overgrowth (SIBO) is greater than in controls, although few studies are currently available. This study investigates the prevalence of SIBO and the possible role of dietary macronutrients in obesity. MATERIALS AND METHODS: Sixty obese patients and normal lean controls were enrolled for SIBO detection. Diagnosis of SIBO was performed by a glucose breath test. A 24-hour recall questionnaire was administered to investigate macronutrient daily intake between the two obese patient subgroups (with/without SIBO). RESULTS: The presence of SIBO in obese and controls was respectively 23.3% and 6.6% (p = 0.02, OR = 4.26, 95% Confidence interval = 1.31-13.84). Obese patients with SIBO ingested more carbohydrates (252.75 ± 30.53 vs 201 ± 70.76 g/day, p = 0.01), more refined sugars (104.15 ± 28.69 vs 73.32 ± 44.93 g/day, p = 0.02) and less total and insoluble fibers (9.6 ± 1.97 vs 14.65 ± 8.80 g/day, p = 0.04 and 4.7 ± 1.11 vs 8.82 ± 5.80 g/day, p = 0.01, respectively). There were no significant differences in lipid and protein intake between the two groups. CONCLUSIONS: SIBO is widespread in obese subjects. Carbohydrates might promote the development of SIBO in obesity and fibers provide a protective function. Our results suggest a close relationship between diet and SIBO in obesity, thus supporting a possible role for intestinal microbiota.

Helicobacter pylori, liver cirrhosis, and portal hypertension: an updated appraisal.

OBJECTIVE: Helicobacter pylori (H. pylori) is the most common cause of gastritis and peptic ulcer. However, H. pylori is even involved in extragastric diseases, and it has been hypothesized that H. pylori could be a risk factor for several hepatic diseases. For instance, a direct involvement of H. pylori in the development of portal hypertension (PH) in cirrhotic patients has been postulated. METHODS: We performed a literature search in major databases to elucidate the relationship between H. pylori, portal hypertension, and liver cirrhosis. RESULTS: The effect of H. pylori on PH may be multifactorial. Endothelial dysfunction, alterations in the vasodilating dynamics, and neoangiogenesis are the most appealing theories about this issue, but the proofs come mainly from experimental studies, therefore a solid pathophysiological basis is still to be demonstrated. Congestive gastropathy (CG) and gastric antral vascular ectasia (GAVE) are two common endoscopic entities responsible for acute/chronic upper gastrointestinal bleeding, and a link with H. pylori has been hypothesized: the gastric mucosa, exposed to H. pylori, could develop both inflammatory microcirculatory alterations and thrombi, resembling the histologic pattern of GAVE. CONCLUSIONS: Despite clues for an association between H. pylori and PH have been shown, these evidences are mostly experimental, therefore, in the absence of a direct proof on human beings, the role of H. pylori in the development of PH is uncertain. However, since this germ may be a cause of peptic ulcer, it should be found and eradicated in cirrhotic patients to reduce the risk of blood loss anemia.

The sharp decline of beta estrogen receptors expression in long-lasting ulcerative-associated carcinoma.

OBJECTIVE: Colorectal carcinoma is an important cause of death in inflammatory bowel diseases, thus requiring surveillance for dysplasia in long-standing ulcerative colitis (UC). Females show a lower incidence probably related to hormonal factors; therefore, a role of estrogen receptors (ERs) has been supposed in carcinoma-associated colitis (CAC) development. Our aim was to identify ER beta/alpha expression in long-lasting pancolitis through each grade of dysplasia to carcinoma and, furthermore, to investigate the simultaneous epithelial apoptosis/proliferation. MATERIALS AND METHODS: Forty-eight patients affected by long-lasting pancolitis were retrospectively investigated. Samples were divided into four groups: UC, low-grade dysplasia/high-grade dysplasia (UC-HGD), and CAC. Normal colon samples were used as controls. ER-beta, ER-alpha, Ki-67, and TUNEL expression (labeling/H index) were evaluated by immunohistochemistry. RESULTS: ER-beta expression revealed an impressive reduction in CAC (10.4 ± 5.1; p < 0.001) compared to controls and UC (34.3 ± 3.1 and 26.8 ± 7.8, respectively), meanwhile ER-beta level in LGD (29.4 ± 3.7) was comparable to UC. As far ER-beta/ER-alpha mean value ratio revealed a progressive reduction. Ki67 demonstrated a progressive significant increase from UC until CAC (37.9 ± 6.4 < 45.7 ± 6.2 < 60.6 ± 5.2 < 71.1 ± 5.1; p < 0.001). Apoptotic index (TUNEL) revealed a strong fall in UC-HGD and CAC. CONCLUSIONS: ER-beta fall could be considered as a biomarker of UC-dysplasia progression. It occurs in HGD and overt neoplasia, while in LGD shows a normal expression. At the moment, we are unable to use this tool in the clinical practice to predict tumor progression, but it would be appropriate to encourage ER expression investigations in large samples for the interesting perspectives of application.

Why do we still have Helicobacter Pylori in our Stomachs.

The existence of any infectious agent in a highly acidic human stomach is contentious, but the chance finding of Helicobacter pylori is by no means an accident. Once H. pylori colonises the gastric mucosa, it can persist for a lifetime, and it is intriguing why our immune system is able to tolerate its existence. Some conditions favour the persistence of H. pylori in the stomach, but other conditions oppose the colonisation of this bacterium. Populations with high and extremely low prevalence of H. pylori provide useful insights on the clinical outcomes that are associated with this type of infection. Adverse clinical outcomes including peptic ulcer disease and gastric cancer depend on a delicate balance between a harmless inflammation and a more severe kind of inflammation. Is the only good H. pylori really a dead H. pylori? The jury is still out.