Gastric Oxyntic Mucosa Research Articles

Origins of the Glandular Mucosae in the Gastro-Esophageal Junction—A Study in a South Asian Population With Low Incidence of Esophageal Adenocarcinoma

Introduction: Gastro-esophageal junction (GEJ) is subjected to controversy due to limited knowledge of its anatomy and histology. We conducted a study to determine the origins of the glandular mucosa at GEJ. Methods: Three groups were used, groups A and B, with grossly normal GEJs and Group C with endoscopic evidence of reflux damage. Group A comprised 23 esophago-gastrectomies, group B, 112 dyspeptic patients with normal GEJ and group C, 46 dyspeptic patients with reflux damaged GEJs. Origins of cardiac mucosa (CM), intestinal metaplasia (IM), and oxyntocardiac mucosa (OCM) were determined by studying their associations with esophageal markers (EM): esophageal glands and ducts, multilayered epithelium and squamous islands highlighted with immunohistochemistry. The histological gap between esophageal squamous and gastric oxyntic mucosa containing CM/IM/OCM was considered as squamo-oxyntic (SO) gap. Results: In Group A and B, a microscopic SO gap was detected in 58.1% and the prevalence of CM was 43% and IM 4.4% and CM 89.7%; 100% IM were associated with EM. Prevalence of CM and IM, in group C was 56.5% and 15.2% respectively and EM were present in 85.7% IM and 88.5% CM. When only OCM is present, 41.2% were proven to be metaplastic. Conclusions: Even when GEJ is grossly normal, microscopic columnar lined esophagus was common at the GEJ and with increased sampling and using several EM almost all CM and IM at the GEJ could be proven to be metaplastic in origin.

Update on Serum Biomarkers in Autoimmune Atrophic Gastritis.

Autoimmune atrophic gastritis (AAG) is a persistent, corpus-restricted immune-mediated destruction of the gastric corpus oxyntic mucosa with reduced gastric acid and intrinsic factor secretion, leading to iron deficiency and pernicious anemia as a consequence of iron and cobalamin malabsorption. Positivity toward parietal cell (PCA) and intrinsic factor (IFA) autoantibodies is very common. AAG may remain asymptomatic for many years, thus making its diagnosis complex and often delayed. Due to the increased risk of gastric neoplasms, a timely diagnosis of AAG is clinically important. The gold standard for AAG diagnosis is histopathological assessment of gastric biopsies obtained during gastroscopy, but noninvasive, preendoscopic serological screening may be useful in some clinical scenarios. Serum biomarkers for AAG may be divided into 2 groups: gastric autoimmunity-related biomarkers, such as PCA and IFA, and gastric corpus atrophy/reduced gastric acid secretion-related biomarkers, such as serum gastrin and pepsinogens. The present review focuses on the clinical significance and pitfalls of serum biomarkers related to gastric autoimmunity and gastric corpus atrophy, including some discussion of analytical methods. Serum assays for PCA, IFA, gastrin, and pepsinogen I show good diagnostic accuracy for noninvasive diagnostic work-up of AAG. Diagnostic performance may increase by combining >1 of these tests, overcoming the problem of seronegative AAG. However, appropriately designed, comparative studies with well-characterized patient cohorts are needed to better define the reliability of these biomarkers in the diagnosis of patients with AAG. Currently, positive serum tests should always be followed by the state-of-art diagnostic test, that is, histopathological assessment of gastric biopsies obtained during gastroscopy to definitively confirm or rule out AAG and eventually neoplastic complications.

S2001 Chronic Norovirus Infection in a Double Solid Organ Transplant Patient

Introduction: Infectious diarrhea is a common complication in the postoperative course of a solid organ transplant (SOT) recipient. While self-limiting in immunocompetent patients, transplant patients on long-term immunosuppression can have severe, prolonged disease with significant morbidity. We present a case of chronic diarrhea due to recurrent norovirus infection in a double SOT patient to encourage early recognition. Case Description/Methods: A 61-year-old male presented with 35-pound weight loss despite a good appetite and large-volume watery diarrhea intermittently for 2 years. He had a liver-kidney transplant 14 years prior secondary to cryptogenic cirrhosis and renal cell carcinoma. Immunosuppression consisted of prednisone, tacrolimus, and mycophenolate mofetil (MMF). Stool PCR was positive for norovirus and negative for other viruses, bacteria, and parasites. His MMF dose was reduced with no benefit. He was discharged with supportive care with initial improvement in the diarrhea but returned to the hospital 4 other times with worsening diarrhea and weight loss. Infectious workup was persistently positive for norovirus. Bi-directional endoscopy with biopsies revealed colonic mucosa with rare epithelial apoptosis, chronic duodenitis, and increased intraepithelial lymphocytosis in the duodenum and ileum consistent with chronic norovirus (Figure). The full diagnostic workup is detailed in Table 1. He was managed conservatively during each hospitalization with fluids and antimotility agents and recently discharged home with plans to start nitazoxanide outpatient. Discussion: Norovirus infection among SOT patients can lead to severe and symptomatic chronic infection. Patients can develop dehydration, transplant rejection, and malnutrition making them higher risk for hospitalizations and death. It is unclear why some immunocompromised patients recover spontaneously while others demonstrate a protracted course but supportive care is the mainstay of therapy. Limited case series have shown nitazoxanide to be effective in treating SOT patients with chronic norovirus infection. However, nitazoxanide needs to be continued until stool RNA studies become negative. This case highlights the importance of considering chronic norovirus when a SOT patient presents with chronic diarrhea and weight loss. Early initiation of supportive care and nutrition consultation are imperative in reducing morbidity in these patients. Nitazoxanide can be effective in patients that are refractory to supportive therapy.Figure 1.: Duodenal biopsy (A): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates. Terminal ileum biopsies (B,C): Focal intraepithelial lymphocytosis and lamina propria plasma cell infiltrates (B); popcorn-like epithelial apoptosis (C). Table 1. - Diagnostic Workup Test/Procedure Result Creatinine, serum 2.1 mg/dl (baseline 1 mg/dl) Stool PCR -Positive for norovirus-Negative for Clostridium difficile toxins, Salmonella, Shigella, Yersinia, and Campylobacter Osmolality, feces 420 mOsm/kg Fecal fat Abnormal Duodenal biopsy -Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in the lamina propria, and rare apoptotic bodies-Negative for CMV, EBV, HSV Stomach biopsy -Gastric antral and oxyntic gland mucosa with chronic inactive gastritis-Negative for H. pylori Right colon biopsy Rare epithelial apoptosis Left colon biopsy Rare epithelial apoptosis Terminal ileum biopsy Mucosa with intraepithelial lymphocytosis, dense plasma cell infiltrates in lamina propria, and rare apoptotic bodies

S3664 Russel Body Gastritis: When the Rare Meets the Odd

Introduction: The significance of chronic gastritis is underrated. Even though Helicobacter pylori (HP) has been the main contributing factor to this condition, if testing for it comes back negative, we should always rule out other underlying diseases, especially if the biopsy reveals Russell body (RB) gastritis. Case Description/Methods: A 67-year-old male with a past medical history of immune thrombocytopenic purpura (ITP) on prednisone and eltrombopag, hypertension, and choledocholithiasis status post cholecystectomy complicated by abscess formation and drain placement, presented with worsening nausea, vomiting, and abdominal pain for three days associated with early satiety and weight loss. His symptoms were not related to food or activity. Vital signs and physical exam were unremarkable except for right upper quadrant abdominal tenderness. Labs were remarkable for WBC 55 k/ul, HGB 11 g/dl, and PLT 90 k/ul. Full infectious workup was negative. CT scan showed massive splenomegaly with widespread lymphadenopathy and circumferential wall thickening of the gastric fundus and body. An upper endoscopy was performed and revealed diffuse gastric erythema in a mosaic pattern, most pronounced in the body of the stomach (Fig. 1a). Biopsies were obtained from the gastric antrum and body. Gastric body biopsies revealed gastric oxyntic mucosa with RB gastritis (Fig. 1b), and it was negative for HP, intestinal metaplasia, dysplasia, or malignancy. Kappa and lambda immunohistochemistry stain showed a polyclonal mixed population of plasma cells (Fig. 1c), indicating no underlying malignancy. HP stool antigen was checked twice, and it was negative. His WBC continued to rise, and bone marrow (BM) biopsy was performed. Findings were suspicious for myelodysplastic/myeloproliferative disorder; however, a reactive process could not be ruled out. Since the patient's condition significantly deteriorated, a repeat BM biopsy revealed morphological changes consistent with chronic myelomonocytic leukemia (CMML). After discussing goals of care with the patient, he opted for hospice care and expired after three days.Figure 1.: (a) An upper endoscopy showing diffuse punctuate gastric erythema with mucosal mosaic pattern. (b) A high power stomach biopsy with Hematoxylin and Eosin stain showing atypical plasma cells with Russell bodies (yellow arrow) which are eosinophilic homogeneous immunoglobulin-containing inclusions. (c) A high power stomach biopsy with kappa and lambda immunohistochemistry stain showing polyclonal mixed population of plasma cells (positive for both kappa and lambda). Discussion: RB gastritis is a reactive mucosal infiltration of plasma cells filled with cytoplasmic RB. There is a strong association with HP infection, but there is also an association with hematopoietic malignancies and gastric adenocarcinoma. Our case represents the vital importance of looking for underlying malignancies in HP negative RB gastritis patients.

Unique membranous gastrin receptor expression of parietal cells and its distribution pattern in the gastric oxyntic mucosa and fundic gland polyps

The aim of this study was to clarify the correlation between gastrin receptor (GR) expression in the gastric oxyntic mucosa and fundic gland polyps (FGPs) and the histological and immunohistochemical findings of the mucosa as well as the history of proton pump inhibitor (PPI) administration. The unique membranous linear positivity of GR in parietal cells was reproducibly observed by immunohistochemistry, which was also validated by immunofluorescence. Further histological and immunohistochemical examination of 34 oxyntic mucosae and 43 FGPs revealed the following: 1) parietal cells (PCs) with membranous linear GR expression (mGR) were observed to be limited to the isthmus-neck region in the normal state; 2) appearance of PCs with mGR in the deep oxyntic gland regions was significantly related to the PPI medication history; 3) PCs with mGR were more frequently observed in the deep oxyntic gland regions when the oxyntic mucosa showed derangement of mucosal component cell compartmentalization revealed by MUC5AC and MUC6 immunohistochemistry, which was also significantly related to the PPI use; and 4) PCs with intense membranous linear positivity of GR were observed to be diffusely distributed in all of the cases of FGPs. In conclusion, the distribution of unique GR membranous linear expression in PCs of the oxyntic mucosa under PPI medication and FGPs could reflect the pathologic mucosal state characterized by derangement of the compartmentalization of mucosal component cells, which could be another basis for evaluating physiologic and/or pathophysiologic conditions of the gastric mucosa.

Intestinal Metaplasia of the Cardia is Associated With Barrett Esophagus and Esophageal Adenocarcinoma

The cardia, defined as the area distal to the endoscopic gastro-esophageal junction (GEJ), is rarely subject to biopsy in patients with gastro-esophageal reflux disease (GERD). In this study we examine the clinical significance of intestinal metaplasia (IM) found in a biopsy of the cardia. The epithelia in biopsies taken 1 cm distal to the endoscopic GEJ in 963 patients undergoing esophago-gastroduodenoscopy were classified into cardiac mucosa (CM) with IM, CM without IM, oxyntocardiac mucosa (OCM) and gastric oxyntic mucosa. The associations of these mucosal types with visible columnar lined esophagus (CLE) without IM, CLE with IM, and esophageal neoplasia proximal and within 2 cm distal to the endoscopic GEJ were determined. Cardiac mucosa with IM in a biopsy 1 cm distal to the endoscopic GEJ was present in 18 (21%) of the 86 patients with all visible CLE ( P < .01), in 16 (22%) of the 74 patients with visible CLE with IM (Barrett esophagus) ( P < .01), and in 12 (22%) of the 55 patients with neoplasia proximal and within 2 cm distal to the endoscopic GEJ ( P = .01). All other epithelial types had no such associations. The significant association of CM with IM in the cardia with visible CLE, visible CLE with IM, and esophageal neoplasia proximal and within 2 cm distal to the endoscopic GEJ indicates that CM with IM 1 cm distal to the endoscopic GEJ is a likely precursor of these entities. Identification of precursor lesions of CLE and esophageal neoplasia has the potential to stimulate new methods aimed at preventing Barrett esophagus and esophageal adenocarcinoma.

Common Pitfalls in the Management of Patients with Micronutrient Deficiency: Keep in Mind the Stomach.

Micronutrient deficiencies are relatively common, in particular iron and cobalamin deficiency, and may potentially lead to life-threatening clinical consequences when not promptly recognized and treated, especially in elderly patients. The stomach plays an important role in the homeostasis of some important hematopoietic micronutrients like iron and cobalamin, and probably in others equally important such as ascorbic acid, calcium, and magnesium. A key role is played by the corpus oxyntic mucosa composed of parietal cells whose main function is gastric acid secretion and intrinsic factor production. Gastric acid secretion is necessary for the digestion and absorption of cobalamin and the absorption of iron, calcium, and probably magnesium, and is also essential for the absorption, secretion, and activation of ascorbic acid. Several pathological conditions such as Helicobacter pylori-related gastritis, corpus atrophic gastritis, as well as antisecretory drugs, and gastric surgery may interfere with the normal functioning of gastric oxyntic mucosa and micronutrients homeostasis. Investigation of the stomach by gastroscopy plus biopsies should always be considered in the management of patients with micronutrient deficiencies. The current review focuses on the physiological and pathophysiological aspects of gastric acid secretion and the role of the stomach in iron, cobalamin, calcium, and magnesium deficiency and ascorbate homeostasis.

Autoimmune gastritis, with or without pernicious anemia: epidemiology, risk factors, and clinical management.

Autoimmune gastritis (AIG) is a chronic immune-mediated, inflammatory condition that involves the destruction of the gastric oxyntic mucosa through the autoimmune-mediated loss of parietal cells, with replacement by atrophic and metaplastic tissue. Diagnosing AIG is important, given the need for ongoing clinical management and vigilance with respect to downstream complications, the most serious of which is gastric adenocarcinoma. Other clinical consequences include gastric neuroendocrine tumors, consequences related to decreased gastric acid and decreased intrinsic factor due to parietal cell destruction and antibodies against intrinsic factor (e.g. micronutrient deficiencies), as well as concomitant autoimmune disorders. Considering the prevalence of AIG and the potential for severe clinical outcomes, it is important to engage in efforts to reduce practice pattern variability related to diagnosis and management. Accordingly, herein, we review of the epidemiology, pathogenesis, clinical presentation of AIG, including both gastric and extragastric manifestations, and provide an overview of clinical management.

Review: Pathogenesis of Helicobacter pylori infection.

The original strategies developed by Helicobacter pylori to persistently colonise its host and to deregulate its cellular functions make this bacterium an outstanding model to study host-pathogen interaction and the mechanisms responsible for bacterial-induced carcinogenesis. During the last year, significant results were obtained on the role of bacterial factors essential for gastric colonisation such as spiral shape maintenance, orientation through chemotaxis and the formation of bacteria clonal population islands inside the gastric glands. Particularities of the Hpylori cell surface, a structure important for immune escape, were demonstrated. New insights in the bacterial stress response revealed the importance of DNA methylation-mediated regulation. Further findings were reported on Hpylori components that mediate natural transformation and mechanisms of bacterial DNA horizontal transfer which maintain a high level of Hpylori genetic variability. Within-host evolution was found to be niche-specific and probably associated with physiological differences between the antral and oxyntic gastric mucosa. In addition, with the progress of CryoEM, high-resolution structures of the major virulence factors, VacA and CagT4SS, were obtained. The use of gastric organoid models fostered research revealing, preferential accumulation of bacteria at the site of injury during infection. Several studies further characterised the role of CagA in the oncogenic properties of Hpylori, identifying the activation of novel CagA-dependent pathways, leading to the promotion of genetic instabilities, epithelial-to-mesenchymal transition and finally carcinogenesis. Recent studies also highlight that microRNA-mediated regulation and epigenetic modifications, through DNA methylation, are key events in the Hpylori-induced tumorigenesis process.

Histological changes associated with pyloric and pseudopyloric metaplasia after Helicobacter pylori eradication.

Pyloric metaplasia (PM) and pseudopyloric metaplasia (PPM) are metaplastic changes resulting in pyloric-type glands in the gastric oxyntic mucosa that mainly occur in chronic gastritis caused by Helicobacter pylori (H. pylori) infection. Focusing on PM and PPM, we classified the histological changes in gastric mucosa according to the Updated Sydney System, using 314 biopsy specimens of gastric greater curvature of the middle body before H. pylori eradication (HPE). Next, the numbers of PM and PPM glands were counted in 47 specimens, and subjects were followed up over 10years after HPE. PPM was recognized jointly with inflammation, activity, atrophy, and intestinal metaplasia, but PM was recognized more frequently than PPM as atrophy and intestinal metaplasia progressed. Both PM and PPM regressed significantly within 6years after HPE. Additionally, we demonstrated that PM and PPM are not always coincident with spasmolytic polypeptide-expressing metaplasia (SPEM). In conclusion, PM and PPM are considered different modulations of the same line of differentiation, which are both reversible, with PM potentially emerging from PPM upon progression.

Gastric Peptides-Gastrin and Somatostatin.

Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101-amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin-17 and gastrin-34. The C-terminal active site of gastrin (Trp-Met-Asp-Phe-NH2 ) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine-containing enterochromaffin-like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2 -receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid-peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197-228, 2020.

New evidence defining the pathology and pathogenesis of lower esophageal sphincter damage

SummaryBackgroundPresent diagnosis and management of gastroesophageal reflux disease (GERD) has resulted in a dramatic increase in the incidence of esophageal adenocarcinoma. This is due to failure to identify pathologic changes of early GERD; at present, pathology is limited to management of Barrett esophagus (BE).MethodsConvincing evidence have confirmed that cardiac mucosa distal to the squamocolumnar junction in the endoscopically normal person is a metaplastic GERD-induced esophageal epithelium, and not a normal proximal gastric epithelium.ResultsWhen cardiac mucosa is recognized as a metaplastic esophageal epithelium, it becomes self-evident that the present endoscopic definition of the gastro-esophageal junction is incorrect, and there exists a dilated distal esophagus (DDE) in what is incorrectly termed the “gastric cardia” presently mistaken for proximal stomach. It also becomes clear that the length of the DDE correlates with the presence and severity of GERD and represents the pathology of the entire spectrum of GERD. Further, it allows recognition that the DDE, measured as the gap between esophageal squamous epithelium and gastric oxyntic mucosa that is composed of cardiac mucosa, represents the pathologic anatomy of damage to the abdominal segment of the lower esophageal sphincter (LES).ConclusionThe new understanding of the significance of cardiac mucosa provides a new and highly accurate histologic method of assessment of LES damage, the primary cause of GERD. This opens a new door to complete histologic assessment of GERD from its etiologic standpoint and to new research that permit early diagnosis of GERD at its outset. Ultimately, such early diagnosis has the potential to reverse the increasing trend of esophageal adenocarcinoma.

Natural history of autoimmune atrophic gastritis: a prospective, single centre, long-term experience.

Autoimmune atrophic gastritis (AAG) is an immune-mediated disorder characterised by destruction of gastric oxyntic mucosa AIM: To explore gastric histopathological evolution in a cohort of AAG patients over a prolonged follow-up METHODS: Single centre prospective study enrolling consecutive patients with histologically confirmed AAG between 2000 and 2018. All AAG patients undergoing endoscopic follow-up every 1-3years were classified as having stages 1, 2 or 3 according to atrophy severity (mild, moderate and severe). AAG patients with either glandular or neuroendocrine dysplasia/neoplasia were classified as having stage 4. Disease stage progression, and changes in serum anti-parietal cell antibody (PCA), chromogranin A and gastrin-17 were assessed. In total, 282 AAG patients (mean age 60.3years; F:M ratio 2.4:1; median follow-up 3years, interquartile range 1-7) were enrolled. All patients with stages 1 or 2 progressed to stage 2 or 3 over time with a steady trend (P=.243) and regression from a severe to a milder stage was never noticed. Disease progression of patients with stages 1 or 2 occurred within the first 3years. PCA positivity rate did not change over time. Stage 3 patients had higher gastrin-17 levels compared to patients with stages 1 and 2 (median 606 vs 295pg/mL; P<.001). In stage 3, the hazard ratio for the risk of developing stage 4 was 6.6 (95% CI 1.5-29; P=.001). AAG is a steadily progressive disease, in which stages 1 and 2 always progress to stage 3. The risk of developing a complicated disease stage is greater in patients with more severe gastric lesions.

Expression of cell adhesion molecule 1 in gastric neck and base glandular cells: Possible involvement in peritoneal dissemination of signet ring cells

AimsTo determine cellular distribution of cell adhesion molecule 1 (CADM1), an immunoglobulin superfamily member, in the human oxyntic gastric mucosa, and to explore possible involvement in the development and peritoneal dissemination of signet ring cell (SRC) gastric carcinoma, which often develops in the oxyntic mucosa. Main methodsImmunohistochemistry and double immunofluorescence were conducted on surgical specimens of normal and SRC-bearing stomachs and peritoneal metastatic foci of SRCs. KATO-III (lacking CADM1) and HSC-43 (expressing CADM1) SRC cell lines were cocultured on a Met-5A mesothelial or TIG-1 fibroblastic cell monolayer. Key findingsIn the oxyntic gland, some neck and nearly all base glandular cells were CADM1-positive, and mucin 5AC-positive cells were CADM1-negative, while some mucin 6-positive neck cells were CADM1-positive. Foveolar-epithelial, parietal, and endocrine cells were CADM1-negative. CADM1 was negative in all SRC carcinomas that were confined within the submucosa (n = 11) and all but one of those invading deeper (n = 15). In contrast, peritoneal metastatic foci of SRCs were CADM1-positive in five out of eleven cases (P < 0.01). In the cocultures, exogenous CADM1 made KATO-III cells adhere more and grow faster on a Met-5A monolayer, not on TIG-1 monolayers. HSC-43 cells adhered more and grew faster on Met-5A than on TIG-1 monolayers, which were partly counteracted by a function-neutralizing anti-CADM1 antibody. SignificanceNearly all chief cells and a part of mucous neck cells express CADM1. SRC gastric carcinoma appears to emerge as a CADM1-negative tumor, but CADM1 may help SRCs develop peritoneal dissemination through promoting their adhesion and growth in the serosal tissue.

Activation of mTORC1 Signaling in Gastric X/A-Like Cells Induces Spontaneous Pancreatic Fibrosis and Derangement of Glucose Metabolism

Background: Pancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear. Methods: We established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1flox/flox mice were bred with Ghrl-cre mice to generate Ghrl-TSC1-/- (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice. Findings: Activation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis. Interpretation: Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin. Funding Statement: This research was supported by grants from the National Key R&D Program of China (2017YFC0908900), and the National Natural Science Foundation of China (81730020, 81330010, 81390354). Declaration of Interests: All authors declare no conflict of interests. Ethics Approval Statement: All experimental protocols were approved by the Animal Care and Use Committee of Peking University (Permit Number: LA2012-60).

Asymptomatic Gastric Heterotopia in the Rectum? A Rare Finding with Unclear Malignant Risk

Introduction Gastric heterotopia (GHT) is the presence of normal gastric mucosa in extra-gastric regions in the gastrointestinal tract (GIT). The most common locations are the esophagus, duodenum, and Meckel's diverticulum, but rarely it may occur in the rectum resulting in symptoms and unclear long-term risk. Detailed Case Description We describe a case of a 27 year old, healthy woman, with a long-standing history of loose stools, up to 8 bowel movements per day, and bloating. After diagnostic workup including lactose-breath test, celiac screen, microbiologic, and endocrinologic work up as well as colonoscopy for microscopic colitis; the presumptive diagnosis was irritable bowel syndrome (IBS) - diarrhea subtype. Her colonoscopy revealed normal biopsies of the cecum, transverse colon; however, the rectum contained a well demarcated, erythematous region of approximately 1 inch diameter, adjacent to a prominent fold and resembling a flat polyp. Pathologic biopsy of the folds identified benign gastric mucosa and benign large intestinal mucosa respectively. The diagnosis of rectal GHT was made based on the presence of gastric oxyntic mucosa with chief, parietal, and foveolar cells. Hpylori was not seen. The patient's IBS was treated with diet and lifestyle intervention. Loperamide was used to reduce stool frequency. Repeat sigmoidoscopy 2 years later confirmed stable GHT in rectum. The patient responded well to a reduced gluten diet, and had resolution of her longstanding IBS. She remains stable 8 years after diagnosis with no active IBS symptoms, and no clinical concerns about her GHT. Discussion GHT distal to the foregut is believed to be caused by pluripotent stem cells abnormally differentiating into gastric mucosa. Common symptoms of GHT include abdominal pain and gastrointestinal bleeding but many cases are asymptomatic. A literature review demonstrates higher prevalence in males with a younger median age at diagnosis. Complications are more common in the pediatric population, while risk of malignant transformation is higher in adults. Treatment is with H2-receptor antagonists or proton-pump inhibitors for bleeding, or complete excision for refractory symptoms. Few cases of neoplastic changes are reported in the literature but further observation is needed to appreciate the risk and benefit of pre-emptive excision by surgery or endoscopic submucosal dissection.1614 Figure 1. Heterotopic gastric tissue in rectum

Activation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and derangement of glucose metabolism by reducing ghrelin production.

BackgroundPancreatic fibrosis is a pathophysiological process associated with excessive deposition of extracellular matrix in pancreas, leading to reduced insulin secretion and derangement of glucose metabolism. X/A-like cells, a group of unique endocrine cells in gastric oxyntic mucosa, produce and secret ghrelin to influence energy balance. Whether gastric X/A-like cells affect pancreatic fibrosis and subsequent glucose homeostasis remains unclear.MethodsWe established a Ghrl-cre transgene in which the cre enzyme is expressed in X/A-like cells under the control of ghrelin-promoter. TSC1flox/flox mice were bred with Ghrl-cre mice to generate Ghrl-TSC1−/− (TG) mice, within which mTORC1 signaling was activated in X/A-like cells. Pancreatic fibrosis and insulin secretion were analyzed in the TG mice.FindingsActivation of mTORC1 signaling by deletion of TSC1 gene in gastric X/A-like cells induced spontaneous pancreatic fibrosis. This alteration was associated with reduced insulin expression and secretion, as well as impaired glucose metabolism. Activation of mTORC1 signaling in gastric X/A-like cells reduced gastric and circulating ghrelin levels. Exogenous ghrelin reversed pancreatic fibrosis and glucose intolerance induced by activation of mTORC1 signaling in these cells. Rapamycin, an inhibitor of mTOR, reversed the decrease of ghrelin levels and pancreatic fibrosis.InterpretationActivation of mTORC1 signaling in gastric X/A-like cells induces spontaneous pancreatic fibrosis and subsequently impairs glucose homeostasis via suppression of ghrelin.

Esophageal Neuroendocrine Carcinoma Presenting as a Rare Cause of Dysphagia

Introduction: Neuroendocrine carcinomas comprise 0.4-2.0% of all esophageal malignancies and are a rare cause of dysphagia. The prognosis is generally poor as the tumor is usually advanced at the time of symptomology and diagnosis. The following is a case of a 60-year-old male patient with solid food dysphagia found to have a large, friable, gastroesophageal junction tumor during esophagogastroduodenoscopy (EGD). Biopsies confirmed a high-grade neuroendocrine carcinoma with a Ki-67 (proliferative index) of 90%.Figure: Frond-like esophageal tumor seen in the distal esophagus.Figure: Large ulcerated tumor extending into the gastric cardia, retroflex view.Figure: Neuroendocrine carcinoma consisting of a poorly differentiated, high-grade malignant neoplasm of intermediate to large cells with a trabecular architecture resembling neuroendocrine tumor within gastric mucosa (magnification 100x).Case: A 60-year-old male presented with a six-month history of daily solid food dysphagia and a 10lb intentional weight loss. His past medical history was significant for stage 1 squamous cell carcinoma of the larynx diagnosed four years prior and treated with chemotherapy. He had a 30 pack-year smoking history and continued to smoke half a pack of cigarettes daily. His only medication was an ipratropium/albuterol 20-100mg inhaler for chronic obstructive pulmonary disease. EGD demonstrated a large frond-like villous tumor occupying 50% of the circumference of the distal third of the esophagus extending 3cm proximal of the Z-line (figure 1). There was a pseudo lumen within the tumor that led into the stomach, and on retroflexed view there was a 5 cm ulcerated tumor extending into the cardia (figure 2). Biopsy results showed squamous and oxyntic-gastric mucosa containing sheets and packets of pleomorphic cells (figure 3). The cells demonstrated variable immunohistochemical positivity for synaptophysin, chromogranin and CD56. Immunohistochemistry for Ki-67 revealed a proliferation index of greater than 90%, classifying the tumor as Grade 3 or high-grade neuroendocrine carcinoma, denoting poor prognosis per the current National Comprehensive Cancer Network guidelines. Subsequent computed tomography supported findings of a 7.1 x 6.8 x 4.8 cm gastroesophageal junction mass with prominent regional lymph nodes without distant metastasis. The patient was treated with neoadjuvant chemotherapy of cisplatin, etoposide, and dexamethasone and concurrent radiation therapy prior to surgical resection. Discussion: Esophageal neuroendocrine tumors are a very rare cause of dysphagia and represent 0.4-2.0% of all esophageal malignancies. They are not well known by gastroenterologists and present as a mimicker of esophageal adenocarcinoma. Poorly differentiated (high-grade) extrapulmonary neuroendocrine carcinomas are not well-defined or documented frequently within the medical literature. National cancer guidelines suggest a treatment similar to small-cell lung cancer with platinum-based chemotherapy and radiation therapy either as neoadjuvant therapy or palliative therapy if metastatic disease is present. Generally, there is a poor prognosis of esophageal neuroendocrine tumors due to the advanced nature at diagnosis, but in the absence of metastatic disease, are treated with curative intent.

The cytoprotective protein clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and promotes gastric cancer cell survival

The cytoprotective protein clusterin is often dysregulated during tumorigenesis, and in the stomach, upregulation of clusterin marks emergence of the oxyntic atrophy (loss of acid-producing parietal cells)-associated spasmolytic polypeptide-expressing metaplasia (SPEM). The hormone gastrin is important for normal function and maturation of the gastric oxyntic mucosa and hypergastrinemia might be involved in gastric carcinogenesis. Gastrin induces expression of clusterin in adenocarcinoma cells. In the present study, we examined the expression patterns and gastrin-mediated regulation of clusterin in gastric tissue from: humans; rats treated with proton pump (H+/K+-ATPase) inhibitors and/or a gastrin receptor (CCK2R) antagonist; H+/K+-ATPase β-subunit knockout (H/K-β KO) mice; and Mongolian gerbils infected with Helicobacter pylori and given a CCK2R antagonist. Biological function of secretory clusterin was studied in human gastric cancer cells. Clusterin was highly expressed in neuroendocrine cells in normal oxyntic mucosa of humans and rodents. In response to hypergastrinemia, expression of clusterin increased significantly and its localization shifted to basal groups of proliferative cells in the mucous neck cell-chief cell lineage in all animal models. That shift was partially inhibited by antagonizing the CCK2R in rats and gerbils. The oxyntic mucosa of H/K-β KO mice contained areas with clusterin-positive mucous cells resembling SPEM. In gastric adenocarcinomas, clusterin mRNA expression was higher in diffuse tumors containing signet ring cells compared with diffuse tumors without signet ring cells, and clusterin seemed to be secreted by tumor cells. In gastric cancer cell lines, gastrin increased secretion of clusterin, and both gastrin and secretory clusterin promoted survival after starvation- and chemotherapy-induced stress. Overall, our results indicate that clusterin is overexpressed in hypergastrinemic rodent models of oxyntic preneoplasia and stimulates gastric cancer cell survival.

Long-term administration of formic acid to weaners: Influence on intestinal microbiota, immunity parameters and growth performance

The use of organic acids in diets for livestock animals is interest due to their being potentially beneficial in maintaining gut homeostasis and controlling pathogenic bacterial growth. The objective of this study was to evaluate the influence of two doses of formic acid supplementation for six weeks to weaner pigs. The long-term effects of formic acid were tested for growth performance, microbiota composition in the jejunum using 16S_rRNA, expression of marker genes of inflammation in the jejunum, and quantification of acid-secreting cells in the gastric oxyntic mucosa using immunohistochemistry. Three diets containing no (control; CO), 1.4g/kg (low formic acid; LFA) or 6.4g/kg (high formic acid; HFA) free formic acid were fed to 36 pigs for 42 d from 7 d post-weaning (7.1±1.0kg live weight) until the end of the trial (27.7±5.5kg live weight); they were housed in individual cages for six weeks. During the first three weeks, formic acid supplementation, at any of the dosage above, increased average daily gain (ADG) (P=0.004), tended to increase average daily feed intake (ADFI) (P=0.08) and tended to decrease g of feed to g of gain (F:G) (P=0.08) while no effect was observed during the last three weeks. At the end of the trial, formic acid supplementation had only a minor effect on the microbiota composition in the jejunum. A higher microbiota diversity (Chao1 index P<0.05) was found in the HFA group than in the CO group. The Control group showed a higher abundance (P<0.05) of Gemella, Lactobacillus and Parvimimoas than the HFA and LFA groups, higher levels of Acinetobacter, Fusobactrium, Leuconostoc respect to the HFA group and of Turcibacter as compared to the LFA group. The abundance of Streptococcus was lower in the CO group than in the HFA group and higher than in the LFA group. The jejunal expression of C-C Motif Chemokine Ligand 2 (CCL20) was higher in the HFA group respect to the LFA group. Formic acid intake did not affect the thickness of the gastric mucosa, the number of parietal cells and stomach weight. This study showed that the addition of formic acid to piglet diets improved growth performance during the first period after weaning and that the long-term supplementation of formic slightly affected the microbiota composition according to the dose.