Benign serrated polyps are commonly found in the colorectum but have rarely been described in other parts of the gastrointestinal tract. We report a series of 9 serrated polyps arising in the duodenum with clinicopathologic features, immunohistochemical expression profile of mucins (MUC2, MUC5AC, MUC6), and molecular analysis for BRAF and KRAS. The polyps were diagnosed as incidental endoscopy findings in 9 different patients, comprising 3 male and 6 female patients, with a mean age of 52.2 years (range, 21-72 years). The second part of the duodenum was the most common site (n = 5), followed by the ampulla (n = 1) and the distal duodenum (n = 1), with the location of the 2 remaining polyps unspecified. Other upper gastrointestinal tract pathology features included Barrett esophagus for 5 patients, Helicobacter gastritis for 1 patient, and mild chronic gastritis for 1 patient. The histologic appearance of the polyps was similar to microvesicular hyperplastic polyp in the colorectum. Immunostaining for mucins showed MUC6 expression in the crypt bases of all polyps, MUC5AC expression in 8 cases (89%), and mucin 2 expression in 6 cases (67%). Molecular testing was successful in 6 polyps, showing BRAF mutation (V600E) in 2 polyps, KRAS mutation in 2 polyps, and no mutation for either gene in 2 polyps. Colonoscopy reports were available for 6 patients, of whom 4 were diagnosed with hyperplastic polyps or sessile serrated polyps in the colorectum. However, no patient met the criteria for serrated polyposis. Although probably rare and of uncertain malignant potential, hyperplastic polyp should be considered in the differential diagnosis of benign duodenal polyp.

Pyloric gland-type adenoma of the duodenum with documented malignant progression is rare. A case is presented of an 87-year-old man with bloating and nausea, who on investigation was found to have a polyp on the anteroinferior wall of the duodenal cap. Histologic examination of the polyp showed features of a pyloric gland adenoma (PGA) demonstrating the full spectrum of progression from low- to high-grade dysplasia and finally invasive adenocarcinoma. The carcinoma showed gastric-type differentiation highlighted by its mucin immunohistochemistry profile and was of advanced stage with lymph node metastasis. The literature on PGAs and the little documentations on progression to carcinoma in duodenal PGAs are reviewed.

Mucins are a family of heavily glycosylated proteins that are the major organic components of the mucus layer, the protective layer covering the epithelial cells in many human and animal organs, including the entire gastro-intestinal tract. Microbes that can associate with mucins benefit from this interaction since they can get available nutrients, experience physico-chemical protection and adhere, resulting in increased residence time. Mucin-degrading microorganisms, which often are found in consortia, have not been extensively characterized as mucins are high molecular weight glycoproteins that are hard to study because of their size, complexity and heterogeneity. The purpose of this review is to discuss how advances in mucus and mucin research, and insight in the microbial ecology promoted our understanding of mucin degradation. Recent insight is presented in mucin structure and organization, the microorganisms known to use mucin as growth substrate, with a specific attention on Akkermansia muciniphila, and the molecular basis of microbial mucin degradation owing to availability of genome sequences.

Whether the regression of gastric metaplasia in the duodenum can be achieved after eradication of Helicobacter pylori is not clear. The aim of the present study was to investigate the relationship between H. pylori infection and gastric metaplasia in patients with endoscopic diffuse nodular duodenitis. Eighty-six patients with endoscopically confirmed nodular duodenitis and 40 control patients with normal duodenal appearance were investigated. The H. pylori-positive patients with duodenitis received anti-H. pylori triple therapy (20 mg omeprazole plus 250 mg clarithromycin and 400 mg metronidazole, all twice daily) for one week. A control endoscopy was performed 6 months after H. pylori treatment. The H. pylori-negative patients with duodenitis received 20 mg omeprazole once daily for 6 months and a control endoscopy was performed 2 weeks after treatment. The prevalence of H. pylori infection was 58.1%, and the prevalence of gastric metaplasia was 57.0%. Seventy-six patients underwent endoscopy again. No influence on the endoscopic appearance of nodular duodenitis was found after eradication of H. pylori or acid suppression therapy. However, gastric metaplasia significantly decreased and complete regression was achieved in 15/28 patients (53.6%) 6 months after eradication of H. pylori, accompanied by significant improvement of other histological alterations. Only mild chronic inflammation, but not gastric metaplasia, was found in the control group, none with H. pylori infection in the duodenal bulb. Therefore, H. pylori infection is related to the extent of gastric metaplasia in the duodenum, but not to the presence of diffuse nodular duodenitis.

In cases of known aetiology, gastric duodenal metaplasia (GMD) is a reversible lesion. In cases of unknown aetiology, the fate of GMD remains elusive. GMD was recently found in a duodenal adenoma.

To audit the frequency of GMD occurring in a cohort of duodenal adenomas.

Filed H&E-stained sections from 306 consecutive duodenal adenomas were investigated for the presence of GMD.

68% of the adenomas (n = 208) were from patients with familial adenomatous polyposis (FAP), and the remaining 32% (n = 98) were sporadic. GMD was found in 31.7% (66/208) of the duodenal FAP adenomas and in 59.2% (58/98) of the duodenal sporadic adenomas (p<0.05). The causes for this difference are elusive.

As for other metaplasias of the gastrointestinal tract (intestinal metaplasia of the oesophagus and of the stomach, and metaplastic-hyperplastic polyposis of the colon, known to antedate neoplastic transformation), a subset of GMDs of unknown cause might be present in the duodenal mucosa before adenomatous changes ensue. That subset of GMD might have neoplastic proclivity similar to the metaplastic epithelium in other organs of the gastrointestinal tract. The known carcinogenic effect of high concentrations of bile acids and pancreatic juices bathing the duodenal mucosa carrying an irreversible subset of GDM might set aflame the adenomatous neoplastic transformation in these patients.

In cases of known aetiology, gastric duodenal metaplasia (GMD) is a reversible lesion. In cases of unknown aetiology, the fate of GMD remains elusive. GMD was recently found in a duodenal adenoma.

To audit the frequency of GMD occurring in a cohort of duodenal adenomas.

Filed H&E-stained sections from 306 consecutive duodenal adenomas were investigated for the presence of GMD.

68% of the adenomas (n = 208) were from patients with familial adenomatous polyposis (FAP), and the remaining 32% (n = 98) were sporadic. GMD was found in 31.7% (66/208) of the duodenal FAP adenomas and in 59.2% (58/98) of the duodenal sporadic adenomas (p<0.05). The causes for this difference are elusive.

As for other metaplasias of the gastrointestinal tract (intestinal metaplasia of the oesophagus and of the stomach, and metaplastic-hyperplastic polyposis of the colon, known to antedate neoplastic transformation), a subset of GMDs of unknown cause might be present in the duodenal mucosa before adenomatous changes ensue. That subset of GMD might have neoplastic proclivity similar to the metaplastic epithelium in other organs of the gastrointestinal tract. The known carcinogenic effect of high concentrations of bile acids and pancreatic juices bathing the duodenal mucosa carrying an irreversible subset of GDM might set aflame the adenomatous neoplastic transformation in these patients.

Vater's ampulla is of great clinical relevance with regard to the influx of chyme, ascending inflammation, intubation during diagnostic and therapeutic endoscopic maneuvers, therapeutic papillotomy and, especially, the formation of malignancies. Little is known about the distribution of trefoil factor family (TFF) peptides in the ampulla. We have therefore examined TFF peptide distribution in the normal ampulla of Vater and compared it with that in duodenal mucosa and Brunner's glands. Expression and synthesis of TFF peptides in Vater's ampulla and duodenum was investigated by reverse transcription-polymerase chain reaction, Western blot and immunohistochemistry. The samples studied originated from 30 autopsy cases with short postmortem intervals. TFF3 was expressed in the ampulla of Vater. mRNA expression of TFF1 was detected in only approximately 25% of the investigated samples. Western blot revealed the production of TFF3 and immunohistochemistry showed that TFF3 was the product of goblet cells. TFF peptide composition of Vater's ampulla varied in comparison with that in the duodenum regarding TFF2 expression. The ampulla of Vater thus has a unique profile of TFF peptide production, supporting the hypothesis that the ampulla is an autonomous organ. The observed differences in the TFF peptide distribution between the duodenum and Vater's ampulla favour the investigation of TFF peptides as prognostic markers in the classification of ampullary carcinomas.

Chronic gastritis with gastric mucosa atrophy, intestinal metaplasia and endocrine cell hyperplasia are alterations with an increased risk for the development of gastric neoplasias. Immunological studies in autoimmune gastritis, in atrophic Helicobacter pylori gastritis and in studies with transgenic mice point to a central role of the parietal cell in the development of gastric mucosa atrophy. Destruction of gastric epithelial cells alone might not be sufficient for the loss of complete gastric glands. Gastric atrophy, endocrine cell hyperplasia and intestinal and pancreatic metaplasia can be regarded as the result of altered morphogenesis within the gastric mucosa. Impaired expression of the gastric morphogenic factor Sonic Hedgehog by parietal cells and increased expression of the transcriptional activators of intestinal and pancreatic differentiation, namely CDX2 and PDX1, seem to be crucial for the development of gastric atrophy and for intestinal, endocrine and pancreatic transdifferentiation processes. Altered expression of these morphogenic factors is partly caused by changes in the gastric milieu. Further studies concerning the normal and pathological morphogenesis of the gastric mucosa and related tissues might give new insight into the pathogenesis of gastric atrophy and metaplasia.

Gastric metaplasia in the duodenum (GMD) is characterized by transdifferentiation of intestinal epithelial cells into gastric foveolar cells within the duodenal mucosa. GMD is often associated with duodenal ulceration. Higher duodenal acidity due to increased gastric acid output into the duodenum has been implicated in the development of GMD. Intestinal development and homeostasis are controlled by the homeobox transcription factor Cdx2, which is considered to be the master regulator of intestinal differentiation. Using immunohistochemistry, the present study shows that GMD is associated with loss of expression of Cdx2 and its target gene product sucrase-isomaltase. Quantitative RT-PCR experiments using the intestinal cell line Caco2 revealed that Cdx2 and sucrase-isomaltase were down-regulated and gastric mucins MUC5AC and MUC6 were up-regulated under acidic culture conditions. Thus, it is suggested that increased acid exposure leads to GMD by impairing the transcription of Cdx2 and subsequently that of its intestine-specific target genes.

TFF peptides are involved in mucosal maintenance and repair through motogenic and antiapoptotic activities. These peptides are overexpressed during inflammatory processes and cancer progression. They also function as scatter factors, proinvasive and angiogenic agents. Such a divergence is related to the pathophysiological state of tissues submitted to persistent aggressive situations during digestive processes in the normal gastrointestinal tract, inflammatory and neoplastic diseases. In agreement with this model, TFF peptides are connected with multiple oncogenic pathways. As a consequence, the TFF signaling pathways may serve as potential targets in the control of chronic inflammation and progression of human solid tumors.

The nucleotide sequence of the pMS1 clone was submitted to the GenBank Nucleotide Sequence Database under accession number AF288076. Changes in the expression of mucin genes in gastrointestinal cancers is thought to contribute to the development of the disease. In our laboratory we have shown previously that MUC5AC is aberrantly expressed in rectosigmoid villous adenomas. However, the regulatory mechanisms underlying that altered profile of expression is unknown. In order to study its regulation at the transcriptional level, we have isolated and characterized 5.5 kb of the 5'-flanking region of the mouse Muc5ac mucin gene. The promoter is flanked by a TATA box and a transcriptional start site is located 22 bp downstream of the TATA box. Analysis of the sequence showed a high density of binding sites for Smad4, an essential factor in the signalling cascade activated by TGF-beta (transforming growth factor-beta), and Sp1, an important factor in the regulation of MUC5AC. This led us to study Muc5ac regulation by TGF-beta. We show that exogenous addition of TGF-beta to the cells induces Muc5ac endogenous expression, promoter activity and Smad4 binding to the promoter. By co-transfection studies we show that Smad4 is essential for Muc5ac promoter activation and that it does not synergize with Smad2 or Smad3. By gel-retardation and co-transfection assays, we identified Sp1 and Sp3 as important regulators of Muc5ac expression and showed that Smad4 and Sp1 act in a co-operative manner to transactivate Muc5ac promoter activity. Altogether these results bring new insights into the molecular mechanisms of TGF-beta-mediated up-regulation of Muc5ac and enhance our understanding as to how Muc5ac is regulated in certain pathologies of the gastrointestinal tract.

Helicobacter pylori shows a characteristic tropism for the mucus-producing gastric epithelium. In infected patients, H. pylori colocalizes in situ with the gastric secretory mucin MUC5AC. The carbohydrate blood-group antigen Lewis B (LeB) was deemed responsible for the adherence of H. pylori to the gastric surface epithelium. We sought to determine if MUC5AC is the carrier of LeB, and thus if MUC5AC is the underlying gene product functioning as the main receptor for H. pylori in the stomach.

We studied three types of human tissue producing MUC5AC: Barrett's esophagus (BE), normal gastric tissue, and gastric metaplasia of the duodenum (GMD). Tissue sections were immuno-fluorescently stained for MUC5AC or LeB, and subsequently incubated with one of three strains of Texas red-labeled H. pylori, one of which was unable to bind to LeB. We determined the colocalization of MUC5AC or LeB with adherent H. pylori.

The binding patterns for the two LeB-binding strains to all tissues were similar, whereas the strain unable to bind to LeB did not bind to any of the tissues. In normal gastric tissue, the LeB-binding strains always bound to MUC5AC- and LeB-positive epithelial cells. In four nonsecretor patients, colocalization of the LeB-binding strains was found to MUC5AC-positive gastric epithelial cells. In BE, the LeB-binding H. pylori strains colocalized very specifically to MUC5AC-positive cells. MUC5AC-producing cells in GMD contained LeB. Yet, LeB-binding H. pylori not only colocalized to MUC5AC or LeB present in GMD, but also bound to the LeB-positive brush border of normal duodenal epithelium.

Mucin MUC5AC is the most important carrier of the LeB carbohydrate structure in normal gastric tissue and forms the major receptor for H. pylori.