IntroductionFungal microbiota's involvement in the pathogenesis of Crohn's disease (CD) is incompletely understood. The terminal ileum is a predilection site both for primary involvement and recurrences of CD. We, therefore, assessed the mucosa-associated mycobiota in the inflamed and non-inflamed ileum in patients with CD. MethodsThe mucosa-associated mycobiota was assessed by ITS2 sequencing in a total of 168 biopsies sampled 5 and 15 cm proximal of the ileocecal valve or ileocolic anastomosis in 44 CD patients and 40 healthy controls (HC). CD patients with terminal ileitis, with endoscopic inflammation at 5 cm and normal mucosa at 15 cm and no history of upper CD involvement, were analyzed separately. The need for additional CD treatment the year following biopsy collection was recorded. ResultsCD patients had reduced mycobiota evenness, increased Basidiomycota/Ascomycota ratio, and reduced abundance of Chytridiomycota compared to HC. The mycobiota of CD patients were characterized by an expansion of Malassezia and a depletion of Saccharomyces, along with increased abundances of Candida albicans and Malassezia restricta. Malassezia was associated with the need for treatment escalation during follow-up. Current anti-TNF treatment was associated with lower abundances of Basidiomycota. The alpha diversity of the inflamed and proximal non-inflamed mucosa within the same patients was similar. However, the inflamed mucosa had a more dysbiotic composition with increased abundances of Candida sake and reduced abundances of Exophiala equina and Debaryomyces hansenii. ConclusionsThe ileal mucosa-associated mycobiota in CD patients is altered compared to HC. The mycobiota in the inflamed and proximal non-inflamed ileum within the same patients harbor structural differences which may play a role in the CD pathogenesis. Increased abundance of Malassezia was associated with an unfavorable disease course.

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Background: Oral 5-aminosalicylic acid (5-ASA) is the mainstay treatment of ulcerative colitis (UC) and therapy with oral 5-ASA is associated with beneficial outcomes. We have examined factors associated with the persistence of oral 5-ASA treatment in a national cohort of UC patients. Methods: Patients with newly diagnosed UC from 2010 to 2014 using oral 5-ASA monotherapy were identified by combining data from the Norwegian Patient Registry and the Norwegian Prescription Database. The median follow-up time was 1029 days. Drug persistence was defined as duration of oral 5-ASA preparation as monotherapy. Non-persistence of a oral 5-ASA preparation as monotherapy was defined as stopping oral 5-ASA, initiation of any further anti-inflammatory treatment including a course of glucocorticoids and a change to another oral 5-ASA preparation. Drug persistence was analyzed using the Kaplan–Meier method and influence of covariates on drug persistence was analyzed with the Cox proportional hazard model. Results: A total of 3421 patients were identified. The overall median 5-ASA drug persistence was 179 days. In univariate analyses, persistence was associated with preparation type and high-dose treatment, while oral glucocorticoid use or hospitalization around the start of oral 5-ASA were associated with shorter 5-ASA persistence. In multivariate analyses, oral glucocorticoids [HR 1.67 (1.54–1.80), p < 0.005] and hospitalization around start of 5-ASA [HR 1.23 (1.14–1.34), p < 0.005] were associated with non-persistence, whereas high dose (⩾3 g/day) 5-ASA was associated with longer persistence [HR 0.68 (0.65–0.71), p < 0.005]. Conclusion: High-dose treatment with oral 5-ASA was associated with longer persistence of oral 5-ASA monotherapy, whereas the presence of factors indicating more severe disease around initiation of 5-ASA monotherapy was associated with a shorter persistence.

BACKGROUND:Microbiota is most likely essential in the pathogenesis of Crohn's disease (CD). Fecal diversion after ileocecal resection (ICR) protects against CD recurrence, whereas infusion of fecal content triggers inflammation. After ICR, the majority of patients experience endoscopic recurrence in the neoterminal ileum, and the ileal microbiome is of particular interest. We have assessed the mucosa-associated microbiome in the inflamed and noninflamed ileum in patients with CD.METHODS:Mucosa-associated microbiome was assessed by 16S rRNA sequencing of biopsies sampled 5 and 15 cm orally of the ileocecal valve or ileocolic anastomosis.RESULTS:Fifty-one CD patients and forty healthy controls (HCs) were included in the study. Twenty CD patients had terminal ileitis, with endoscopic inflammation at 5 cm, normal mucosa at 15 cm, and no history of upper CD involvement. Crohn's disease patients (n = 51) had lower alpha diversity and separated clearly from HC on beta diversity plots. Twenty-three bacterial taxa were differentially represented in CD patients vs HC; among these, Tyzzerella 4 was profoundly overrepresented in CD. The microbiome in the inflamed and proximal noninflamed ileal mucosa did not differ according to alpha diversity or beta diversity. Additionally, no bacterial taxa were differentially represented.CONCLUSIONS:The microbiome is similar in the inflamed and proximal noninflamed ileal mucosa within the same patients. Our results support the concept of CD-specific microbiota alterations and demonstrate that neither ileal sublocation nor endoscopic inflammation influence the mucosa-associated microbiome.

Oral mesalazine is the mainstay treatment of ulcerative colitis (UC). Mesalazine exerts its anti-inflammatory effect locally in the colonic mucosa. The mucosal mesalazine concentration is inversely correlated with the degree of inflammation and previous studies have found that mucosal drug concentrations differ between various oral mesalazine preparations. In the current study we have examined the drug persistence of oral mesalazine preparations in a national cohort of UC patients. Patients with newly diagnosed UC from 2010 to 2014 using oral mesalazine as anti-inflammatory monotherapy 3 months after the time of diagnosis were identified by combining data from the Norwegian Patient Registry and the Norwegian Prescription Database. The patients were retrospectively followed through 2017, median follow-up time was 1029 days. Treatment failure was defined as start of topical mesalazine or glucocorticoid preparations, systemic glucocorticoids, immunomodulators and biologic treatment or a change to another oral mesalazine preparation. Drug persistence was defined as duration of oral mesalazine preparation in monotherapy. Disease was categorised as more severe in patients who had dispensed systemic glucocorticoids the first three months after diagnosis. Drug persistence at national and regional level was stratified by mesalazine preparation (Mezavant (MEZ), Asacol (ASA), Pentasa (PEN), Salofalk (SAL)) and disease severity. Consumption was estimated based on defined daily doses (DDD = 1.5 g) of mesalazine dispensed from pharmacies. A total of 3421 patients were identified. Overall median mesalazine drug persistence was 311 days. The persistence differed between the preparations in descending order: MEZ (398 days), SAL (374 days), PEN (273 days), ASA (266 days), and the order was similar in the four regions. Patients with more severe disease at diagnosis had shorter drug persistence (193 vs. 407 days). Systemic glucocorticoids were given to similar proportion of patients for ASA (0.60) and PEN (0.61), while this proportion of MEZ users was lower (0.52) and even lower for SAL users (0.43). The number of prescribed DDD the first year after diagnosis was slightly higher in MEZ users (MEZ 1.75, ASA 1.36, PEN 1.42, SAL 1.40). There were significant differences in drug persistence between oral preparations that were not explained by differences in prescription at regional level, but could partially be related to differences in disease severity. These differences could have clinical implications and bear further investigations.

Gastric juice is a unique combination of hydrochloric acid (HCl), lipase, and pepsin. Acidic gastric juice is found in all vertebrates, and its main function is to inactivate microorganisms. The phylogenetic preservation of this energy-consuming and, at times, hazardous function (acid-related diseases) reflects its biological importance. Proton pump inhibitors (PPIs) are one of the most widely used drugs in the world. Due to the reduced prevalence of Helicobacter pylori infection as well as the increased use of inhibitors of gastric acid secretion, the latter has become the most important cause of gastric hypoacidity. In the present manuscript, we review the microbiological consequences of removing gastric acidity. The resulting susceptibility to infections has not been studied extensively, and focus has mainly been restricted to bacterial and parasitic agents only. The strongest evidence concerning the relationship between hypochlorhydria and predisposition to infections relates to bacterial infections affecting the gastrointestinal tract. However, several other clinical settings with increased susceptibility to infections due to inhibited gastric acidity are discussed. We also discuss the impact of hypochlorhydria on the gut microbiome.

5-aminosalicylic acid (5-ASA) is the mainstay of ulcerative colitis (UC) treatment and acts locally in the colonic mucosa by a variety of purposed mechanisms. Recent in vitro studies suggest that 5-ASA may affect intestinal bacteria’s ability to adhere to and infiltrate to the intestinal mucosa, which may be important in the pathogenesis of UC. Mucosal 5-ASA concentration and bacterial microbiome in colon biopsies and faeces were analysed in patients with quiescent UC using mesalazine monotherapy 4.0–4.8 g/day. 5-ASA concentrations were measured in mucosal biopsies (sampled 10, 25 and 40 cm from the anal verge) by ultra-high-performance liquid chromatography. Bacterial microbiome was sequenced from one faecal sample and one biopsy sample (taken 25 cm from the anal verge) by 16S rRNA sequencing on Illumina MiSeq platform. Disease activity was assessed with Mayo score, Geboes histological score and faecal calprotectin. Regression analyses were performed to relate 5-ASA concentrations to bacterial abundances. Forty-two patients with UC were included. The disease activity was low with a median (IQR) total Mayo score of 1.0 (2.0), Geboes score of 1.1 (1.1) and a calprotectin concentration of 66 (211) mg/kg. Geometric mean (95% CI) 5-ASA mucosal concentration was 1.43 ng/mg (0.84–2.44). Mucosal 5-ASA concentration was positively associated with mucosal bacterial diversity (p = 0.0005), but not with faecal bacterial diversity (p = 0.66). The mucosal 5-ASA concentration was significantly associated with mucosal bacterial abundance on all taxonomic levels; high 5-ASA concentrations were associated with reduced abundance of Proteobacteria (p = 1.2·10–15) and increased abundance of Firmicutes (2.6·10–6) and Bacteroidetes (p = 3.1·10–4) on phylum-level. Furthermore, mucosal 5-ASA concentration was associated with abundances of 16 bacterial families and 19 bacterial genera; positive associations between mucosal 5-ASA concentration and Lachnospiraceae and Ruminococcaceae families, Faecalibacterium, Roseburia and Bifidobacterium genera and F. prausnitzii species were found. Mucosal 5-ASA concentration was negatively associated with the faecal abundance of Prevotella and Sutterella genera, for the former the association was also seen on family, order and class level. Mucosal 5-ASA concentration was not associated with disease activity. For the first time, we demonstrate that a high mucosal 5-ASA concentration is associated with high mucosal bacterial diversity and a mucosal bacterial composition which is perceived favourable in UC. 5-ASA may have beneficial effects on the mucosal microbiome, which in turn may affect disease course.

Background: Neuroendocrine tumours (NETs) in the ileum grow slowly but metastasise to the liver at an early stage. After resection of the primary tumour and mesenteric lymph nodes, selected patients with liver metastases have been operated with curative intention. Recurrence-free survival seems low, suggesting that micrometastases are present in the liver at the time of surgery. We have therefore examined whether NET metastases could be detected in perceived normal liver tissue at the time of liver resection. Material and methods: Liver tissue outside the macrometastases from patients (n = 10) operated by liver resection due to metastases from ileal NETs G1/2, were examined for NE cells by immunohistochemistry. Liver tissue from patients operated for metastatic colon cancer was used as control (n = 6). Groups of >= 3 NE cells >= 3 mm from macrometastases were considered micrometastases. Clinical course was recorded retrospectively. Results: Ten of 10 patients had micrometastases, consisting of multiple groups of NE cells. None of the control patients had NE cells in the liver tissue. After median follow-up time of 5.5 (0.8-18.7) years 6 of 10 patients had developed recurrent NET metastases detected by cross-sectional imaging. The follow-up time of the four patients without detectable metastases was 4.8 (0.8-7.5) years vs. with detectable metastases 7.9 (3.2-18.7) years. Conclusions: All patient had micrometastases outside macrometastases at the time of liver resection, suggesting that subsequently recurrent liver metastases develop from NET depositions in the liver already present at the time of surgery. The likelihood of curation by hepatic resection appears very low.

Proton pump inhibitors (PPIs) have been increasingly used over the last decades and there are concerns about overuse and the numerous reported side-effects. It is uncertain whether associations between PPI use and potential side effects are causal. However, important evidence from experimental and mechanistic studies that could support a causal relationship may have been underestimated by epidemiologists and meta-analysists. In the current manuscript we review the combined epidemiological and mechanistic evidence of the adverse effects of PPI use.

Summary Background 5‐aminosalicylic acid (5‐ASA) is the first‐line therapy for ulcerative colitis (UC). 5‐ASA acts locally in the colonic mucosa by numerous proposed mechanisms, and is metabolised by N‐acetyltransferase (NAT). Large variations in mucosal 5‐ASA concentrations have been reported, but the underlying mechanisms are not understood. Aim To study the relationship between 5‐ASA concentration, 5‐ASA formulation, NAT genotype and bacterial microbiome in patients with UC. Methods Patients with quiescent UC, using monotherapy of Mezavant (n = 18), Asacol (n = 14) or Pentasa (n = 10), 4.0‐4.8 g/day were included. 5‐ASA was measured in colonic mucosal biopsies and serum by ultra‐high performance liquid chromatography. NAT genotypes were determined by Sanger sequencing. Bacterial microbiome was sequenced from faeces and mucosa by 16S rRNA sequencing using Illumina Miseq. Results Mezavant provided the highest mucosal 5‐ASA levels (geometric mean 2.39 ng/mg), followed by Asacol (1.60 ng/mg, 33% lower, P = 0.50) and Pentasa (0.57 ng/mg, 76% lower, P = 0.033). Mucosal 5‐ASA concentration was not associated with NAT genotype, but serum 5‐ASA concentration and NAT1 genotype was associated ( P = 0.044). Mucosal 5‐ASA concentration was positively associated with mucosal bacterial diversity ( P = 0.0005) and bacterial composition. High mucosal 5‐ASA concentration was related to reduced abundance of pathogenic bacteria such as Proteobacteria, and increased abundance of several favourable bacteria such as Faecalibacterium. Conclusions Mucosal 5‐ASA concentration is positively associated with bacterial diversity and a mucosal bacterial composition that are perceived favourable in UC. Mezavant yielded higher mucosal 5‐ASA concentrations than Pentasa. 5‐ASA may have beneficial effects on the mucosal microbiome, and high concentrations possibly amend dysbiosis in UC.

Background: Mechanical obstruction of the appendiceal lumen is proposed as a possible factor in the pathogenesis of acute appendicitis. Hence, patients over the age of 40 are often referred to a follow-up colonoscopy after admission for acute appendicitis. The use of CT scans question whether routine colonoscopy still has a place in follow-up for these patients.Methods: All patients aged over 40 years with confirmed acute appendicitis admitted to St. Olav's Hospital in the period from 2010 to 2015 were included in this retrospective study. Findings and distribution of significant colorectal neoplasms (cancer and advanced adenomas) within three years after the admission were evaluated.Results: Fifty-four (7.4%) of the 731 patients were found to have colonic neoplasms; 9 patients (1.2%) were found to have colorectal cancer of which 7 were located on the right side, 22 patients (3.0%) were found to have advanced adenomas and 23 patients (3.1%) were found to have non-advanced adenomas. The sensitivity and specificity for CT to discover cancer was 0.25 and 0.97, respectively. A total of 316 patients (43.2%) had colonoscopy within three years after admission.Conclusion: There may be an increased risk of colorectal neoplasms in patients over the age of 40 admitted with acute appendicitis. There seems to be an increased proportion of right-sided cancer relatively to other colonic locations. The sensitivity for CT scans to discover colorectal cancer in this group is low. Further studies are needed to decide whether routine colonoscopy is indicated after acute appendicitis in patients over 40 years.

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Objective. The etiology of the inflammatory bowel diseases is unknown, although genetic factors play a role, and tobacco smoking has opposite effect on the two entities. Inflammation is central in the pathogenesis, and treatment is aiming to suppress it. The active part of salazopyrin, the oldest drug in use in the treatment of ulcerative colitis, is 5-aminosalicylic acid (5-ASA). In the present paper, we wanted to discuss the etiology and pathogenesis of ulcerative colitis in relation to the beneficial effects of 5-ASA and particularly whether this compound has a specific effect on ulcerative colitis. Methods/Results. 5-ASA seems to have a selective positive effect on ulcerative colitis in inducing remission, preventing relapse and possibly reducing the risk of cancer. In contrast to other agents used in the treatment of ulcerative colitis, 5-ASA does not have any known anti-inflammatory effect on other organs or other colonic inflammatory diseases like diverticulitis. Moreover, the effect on experimental colitis in rodents is not convincing. Conclusion. 5-ASA seems to have a specific effect on the inflammation in ulcerative colitis. Research on the mechanism of its action may give information on the etiology of ulcerative colitis. 5-ASA is a first-line treatment that should be given once daily in high doses and for long term to reduce the possibility of recurrence and risk of colonic cancer. Side effects with 5-ASA are rare, and every patient with ulcerative colitis who tolerate this drug, should be treated with 5-ASA.

BACKGROUND:Ulcerative colitis (UC) can be complicated by reactivation of cytomegalovirus (CMV). CMV reactivation may change the course of UC and may require antiviral treatment. Some risk factors of CMV reactivation have previously been identified, whereas the association between CMV reactivation and postoperative complications has not been examined systematically.METHODS:Patients with UC operated with colectomy due to active UC were studied (n = 77). Patient and disease characteristics, as well as postoperative complications were recorded and CMV was detected by immunohistochemical examination of multiple sections from the colectomy specimen.RESULTS:CMV was found in nine (11.7%) colectomy specimens. CMV-positive patients received significantly higher doses of corticosteroids at colectomy than CMV-negative patients (61.1 ± 23 vs 32.5 ± 32 mg/day, p = 0.01). CMV-positive patients were also older, had a higher risk of severe complications, higher American Society of Anesthesiologists (ASA) score, longer preoperative stay, and a higher rate of acute surgery. Complications occurred in 30 (39%) patients after surgery, 8(10.4%) of whom were serious. Two CMV-positive patients (2.6%) died in-hospital after the colectomy. High ASA score was associated with the occurrence of serious complications.CONCLUSION:A relatively small proportion of patients with UC operated by colectomy were CMV positive. CMV positivity was associated with old age, high dose of corticosteroids at operation, high ASA score, acute surgery, and severe postoperative complications. Patients with such characteristics may be at risk of CMV infection and may require special management.

Background: In inflammatory bowel disease (IBD), genetic susceptibility together with environmental factors disturbs gut homeostasis producing chronic inflammation. The two main IBD subtypes are Ulcerative colitis (UC) and Crohn's disease (CD). We present the to-date largest microarray gene expression study on IBD encompassing both inflamed and un-inflamed colonic tissue. A meta-analysis including all available, comparable data was used to explore important aspects of IBD inflammation, thereby validating consistent gene expression patterns.Methods: Colon pinch biopsies from IBD patients were analysed using Illumina whole genome gene expression technology. Differential expression (DE) was identified using LIMMA linear model in the R statistical computing environment. Results were enriched for gene ontology (GO) categories. Sets of genes encoding antimicrobial proteins (AMP) and proteins involved in T helper (Th) cell differentiation were used in the interpretation of the results. All available data sets were analysed using the same methods, and results were compared on a global and focused level as t-scores.Results: Gene expression in inflamed mucosa from UC and CD are remarkably similar. The meta-analysis confirmed this. The patterns of AMP and Th cell-related gene expression were also very similar, except for IL23A which was consistently higher expressed in UC than in CD. Un-inflamed tissue from patients demonstrated minimal differences from healthy controls.Conclusions: There is no difference in the Th subgroup involvement between UC and CD. Th1/Th17 related expression, with little Th2 differentiation, dominated both diseases. The different IL23A expression between UC and CD suggests an IBD subtype specific role. AMPs, previously little studied, are strongly overexpressed in IBD. The presented meta-analysis provides a sound background for further research on IBD pathobiology.

Background and aims: Patients with Crohn's disease (CD) may need anti-inflammatory drugs for decades. Anti-TNF-alpha agents have good efficacy and adverse events similar to placebo in randomized controlled trials (RCTs), but there are still questions about long-term safety and efficacy. In this respect, reports from clinical practice may be useful. We currently report on the clinical experience with infliximab and adalimumab in a single-center cohort of patients with CD. Material and Methods: Patients with CD treated with infliximab or adalimumab from 2000 to 2010 were reviewed. Patient and disease characteristics at start, reason for discontinuation, and adverse events were recorded retrospectively. Corticosteroid use, the need for hospitalization, and surgeries before and during anti-TNF-alpha therapy were recorded. Results: Eighty-three patients had received anti-TNF-alpha treatment against CD, median treatment duration was 11.4 months (0.2-99.5), and follow-up time 59 months (8-135). Eighteen of 43 patients using corticosteroids at treatment start discontinued corticosteroids during TNF-alpha therapy. Need for hospitalizations (6.13 vs. 3.28 days/year, p < 0.001) and surgeries (0.56 vs. 0.16 operations/year, p < 0.001) were lower during anti-TNF-alpha therapy than before treatment. Twenty-six percent discontinued therapy due to adverse events and 26% due to lack or loss of response. Two of four deaths observed during follow-up were believed to be related to anti-TNF-alpha treatment. Conclusions: Anti-TNF-alpha therapy was beneficial in many patients with CD, but the majority of patients discontinued treatment during follow-up. Reports from clinical experience with anti-TNF-alpha treatment may be valuable for clinicians treating patients with CD.

BackgroundSince the appearance of whole genome gene expression (WGGE) analysis, it has been used to analyse mucosal IBD samples. As ulcerative colitis (UC) and Crohn's disease (CD) are clinically distinct, many efforts have been made to differentiate these at a transcriptional level. Even though several studies have shown promise in discerning UC and CD, gene expression fingerprinting has not yet reached the clinic. However, using publicly available data sets from these previous analyses enable instant cross-platform, cross-laboratory validation of local analysis. This opens for powerful analysis comparing the two diseases on both a global and focused gene expression level. We present the to date largest WGGE analysis of colonic mucosal IBD samples including samples from inflamed and uninflamed tissue from both UC and CD, as well as normal controls. Focusing on subsets of genes representing areas of particular interest in IBD, T helper (Th) cell differentiation and antimicrobial peptide (AMP)-related expression, eases the interpretation of results. A meta-analysis including all available, comparable data was used to validate and strengthen observations.

Gastric juice is a unique combination of hydrochloric acid and the proteolytic enzyme pepsin. Its main function is to inactivate ingested microorganisms. Prions cause fatal transmissible degenerative encephalopathies in animals and man. These diseases have attracted attention due to the proposed link between bovine spongiform encephalopathy in cattle and the occurrence of a new variant Creutzfeldt-Jakob disease in humans where the most probable route of transmission is via contaminated food. The role of gastric juice in the protection against these agents is not settled. Objective. The aim of this study was to examine if drug-induced gastric hypoacidity increases the susceptibility of prion infection transmitted by the oral route. Material and methods. Forty-six mice (tg338) were given brain homogenates contaminated with scrapie by gastric intubation. Twenty-two of these animals were concomitantly dosed with omeprazole increasing the median gastric pH from 1.2 to 5.3. After 381 days, the animals were sacrificed and all the brains were examined for detection of pathogenic prion proteins by enzyme-linked immunosorbent assay and western blot. Results. Drug-induced decrease in gastric acidity more than doubled the rate (59% vs. 25%, p < 0.035) of brain infection compared to controls with normal gastric acidity at the time of inoculation. Conclusions. Our results demonstrate that the normal gastric juice constitutes a significant defense against prion disease in mice. Thus, gastric hypochlorhydria would be expected to enhance the susceptibility to prion infection by the oral route. This finding may have relevance to the pathogenesis of the new variant Creutzfeldt-Jakob disease and prion diseases in general.

We present a case of a gastric neuroendocrine carcinoma in a patient with a history of long-term proton pump inhibitor (PPI) use. A 49-year-old man using PPI for the last 15 years due to gastroesophageal reflux disease developed progressive dysphagia, dyspepsia and weight loss. Upper gastrointestinal endoscopy, endoscopic ultrasonography and abdominal CT diagnosed a malignant tumor localized to a hiatal hernia. Fasting serum chromogranin A and gastrin concentrations were elevated (32 nmol/l and 159 pmol/l, respectively). Helicobacter pylori PCR analysis of antral biopsies was negative. Biopsies from endoscopically normal oxyntic mucosa showed enterochromaffin-like (ECL) cell hyperplasia. Tumor biopsies revealed a poorly differentiated neuroendocrine carcinoma. Sevier-Munger staining, immunohistochemistry and electron microscopy indicated ECL cell as origin of the tumor cells. Concerns have previously been raised about the safety of long-term PPI use due to a possible increased risk of cancer. This case illustrates a patient with a poorly differentiated neuroendocrine carcinoma with ECL cell characteristics probably induced by hypergastrinemia secondary to long-term PPI use.

Patients with chronic hypergastrinemia due to chronic atrophic gastritis or gastrinomas have an increased risk of developing gastric malignancy, and it has been questioned whether also patients with hypergastrinemia caused by long-term use of acid inhibiting drugs are at risk. Gastric carcinogenesis in humans is affected by numerous factors and progresses slowly over years. When using animal models with the possibility of intervention, a complex process can be dissected by studying the role of hypergastrinemia in carcinogenesis within a relatively short period of time. We have reviewed findings from relevant models where gastric changes in animal models of long-term hypergastrinemia have been investigated. In all species where long-term hypergastrinemia has been induced, there is an increased risk of gastric malignancy. There is evidence that hypergastrinemia is a common causative factor in carcinogenesis in the oxyntic mucosa, while other cofactors may vary in the different models.