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Gastroenterology Feb 2022The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface... (Review)
Review
The mucosa of the body of the stomach (ie, the gastric corpus) uses 2 overlapping, depth-dependent mechanisms to respond to injury. Superficial injury heals via surface cells with histopathologic changes like foveolar hyperplasia. Deeper, usually chronic, injury/inflammation, most frequently induced by the carcinogenic bacteria Helicobacter pylori, elicits glandular histopathologic alterations, initially manifesting as pyloric (also known as pseudopyloric) metaplasia. In this pyloric metaplasia, corpus glands become antrum (pylorus)-like with loss of acid-secreting parietal cells (atrophic gastritis), expansion of foveolar cells, and reprogramming of digestive enzyme-secreting chief cells into deep antral gland-like mucous cells. After acute parietal cell loss, chief cells can reprogram through an orderly stepwise progression (paligenosis) initiated by interleukin-13-secreting innate lymphoid cells (ILC2s). First, massive lysosomal activation helps mitigate reactive oxygen species and remove damaged organelles. Second, mucus and wound-healing proteins (eg, TFF2) and other transcriptional alterations are induced, at which point the reprogrammed chief cells are recognized as mucus-secreting spasmolytic polypeptide-expressing metaplasia cells. In chronic severe injury, glands with pyloric metaplasia can harbor both actively proliferating spasmolytic polypeptide-expressing metaplasia cells and eventually intestine-like cells. Gastric glands with such lineage confusion (mixed incomplete intestinal metaplasia and proliferative spasmolytic polypeptide-expressing metaplasia) may be at particular risk for progression to dysplasia and cancer. A pyloric-like pattern of metaplasia after injury also occurs in other gastrointestinal organs including esophagus, pancreas, and intestines, and the paligenosis program itself seems broadly conserved across tissues and species. Here we discuss aspects of metaplasia in stomach, incorporating data derived from animal models and work on human cells and tissues in correlation with diagnostic and clinical implications.
Topics: Animals; Cell Plasticity; Cellular Reprogramming; Gastric Mucosa; Helicobacter Infections; Humans; Hyperplasia; Metaplasia; Parietal Cells, Gastric; Regeneration; Stomach
PubMed: 34728185
DOI: 10.1053/j.gastro.2021.10.036 -
Veterinary Journal (London, England :... 2022Many domesticated horses have gastric ulcers which can be diagnosed and graded during gastroscopy. A distinction should be made between equine squamous gastric disease... (Review)
Review
Many domesticated horses have gastric ulcers which can be diagnosed and graded during gastroscopy. A distinction should be made between equine squamous gastric disease (ESGD), which is caused by exposure of the mucosa to acid, and equine glandular gastric disease (EGGD), thought to occur when mucosal defence mechanisms are compromised. Horses with gastric ulcers may, but do not always, show clinical signs such as poor appetite, mild colic, discomfort during girthing, behavioural changes and reduced performance. The mainstay of treatment is blocking acid production using the proton pump inhibitor omeprazole. Treatment is usually successful in cases of ESGD, but less so for EGGD, where treatment duration is longer and for which sucralfate may be added or alternatives necessary, such as misoprostol, a prostaglandin analogue. To prevent recurrence of ulcers known risk factors, such as high concentrate diets, intense exercise and stress should be avoided or minimized.
Topics: Animals; Gastric Mucosa; Gastroscopy; Horse Diseases; Horses; Omeprazole; Stomach Ulcer
PubMed: 35472513
DOI: 10.1016/j.tvjl.2022.105830 -
Animals : An Open Access Journal From... Apr 2023Equine Gastric Ulcer Syndrome (EGUS) is a term that has been used since 1999, initially being used to describe all gastric mucosal disease in horses. Since this time,... (Review)
Review
Equine Gastric Ulcer Syndrome (EGUS) is a term that has been used since 1999, initially being used to describe all gastric mucosal disease in horses. Since this time, the identification of two distinct main disease entities of the equine gastric mucosa have been described under the umbrella of EGUS; these are Equine Squamous Gastric Disease (ESGD) and Equine Glandular Gastric Disease (EGGD). In 2015 the European College of Equine Internal Medicine (ECEIM) released a consensus statement defining these disease entities. This document highlighted the lack of evidence surrounding EGGD compared to ESGD, and identified knowledge gaps for further research to be directed. Subsequently, many studies on EGGD have been published, especially on pathophysiology, diagnosis, and treatment. This article updates current knowledge on both ESGD and EGGD as understanding has evolved since the last large-scale review.
PubMed: 37048517
DOI: 10.3390/ani13071261 -
Neuron Jul 2021The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there...
The vagus nerve innervates many organs, and most, if not all, of its motor fibers are cholinergic. However, no one knows its organizing principles-whether or not there are dedicated neurons with restricted targets that act as "labeled lines" to perform certain functions, including two opposing ones (gastric contraction versus relaxation). By performing unbiased transcriptional profiling of DMV cholinergic neurons, we discovered seven molecularly distinct subtypes of motor neurons. Then, by using subtype-specific Cre driver mice, we show that two of these subtypes exclusively innervate the glandular domain of the stomach where, remarkably, they contact different enteric neurons releasing functionally opposing neurotransmitters (acetylcholine versus nitric oxide). Thus, the vagus motor nerve communicates via genetically defined labeled lines to control functionally unique enteric neurons within discrete subregions of the gastrointestinal tract. This discovery reveals that the parasympathetic nervous system utilizes a striking division of labor to control autonomic function.
Topics: Animals; Brain; Cholinergic Neurons; Enteric Nervous System; Gastric Mucosa; Gene Expression Profiling; Male; Mice, Inbred C57BL; Mice, Transgenic; Motor Neurons; Neural Pathways; Stomach; Vagus Nerve; Mice
PubMed: 34077742
DOI: 10.1016/j.neuron.2021.05.004 -
Gastroenterology Dec 2019Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes.
BACKGROUND & AIMS
Patterns of genetic alterations characterize different molecular subtypes of human gastric cancer. We aimed to establish mouse models of these subtypes.
METHODS
We searched databases to identify genes with unique expression in the stomach epithelium, resulting in the identification of Anxa10. We generated mice with tamoxifen-inducible Cre recombinase (CreERT2) in the Anxa10 gene locus. We created 3 mouse models with alterations in pathways that characterize the chromosomal instability (CIN) and the genomically stable (GS) subtypes of human gastric cancer: Anxa10-CreER;Kras;Tp53;Smad4 (CIN mice), Anxa10-CreER;Cdh1;Kras;Smad4 (GS-TGBF mice), and Anxa10-CreER;Cdh1;Kras;Apc (GS-Wnt mice). We analyzed tumors that developed in these mice by histology for cell types and metastatic potential. We derived organoids from the tumors and tested their response to chemotherapeutic agents and the epithelial growth factor receptor signaling pathway inhibitor trametinib.
RESULTS
The gastric tumors from the CIN mice had an invasive phenotype and formed liver and lung metastases. The tumor cells had a glandular morphology, similar to human intestinal-type gastric cancer. The gastric tumors from the GS-TGFB mice were poorly differentiated with diffuse morphology and signet ring cells, resembling human diffuse-type gastric cancer. Cells from these tumors were invasive, and mice developed peritoneal carcinomatosis and lung metastases. GS-Wnt mice developed adenomatous tooth-like gastric cancer. Organoids derived from tumors of GS-TGBF and GS-Wnt mice were more resistant to docetaxel, whereas organoids from the CIN tumors were more resistant to trametinib.
CONCLUSIONS
Using a stomach-specific CreERT2 system, we created mice that develop tumors with morphologic similarities to subtypes of human gastric cancer. These tumors have different patterns of local growth, metastasis, and response to therapeutic agents. They can be used to study different subtypes of human gastric cancer.
Topics: Adenomatous Polyposis Coli Protein; Animals; Annexins; Antineoplastic Agents; Cell Transformation, Neoplastic; Disease Models, Animal; Drug Resistance, Neoplasm; Female; Gastric Mucosa; Genetic Loci; Humans; Integrases; Male; Mice; Mice, Transgenic; Mutation; Proto-Oncogene Proteins p21(ras); Smad4 Protein; Stomach Neoplasms; Tumor Suppressor Protein p53
PubMed: 31585123
DOI: 10.1053/j.gastro.2019.09.026 -
The New England Journal of Medicine Mar 2018Patients with early gastric cancers that are limited to gastric mucosa or submucosa usually have an advanced loss of mucosal glandular tissue (glandular atrophy) and are... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Patients with early gastric cancers that are limited to gastric mucosa or submucosa usually have an advanced loss of mucosal glandular tissue (glandular atrophy) and are at high risk for subsequent (metachronous) development of new gastric cancer. The long-term effects of treatment to eradicate Helicobacter pylori on histologic improvement and the prevention of metachronous gastric cancer remain unclear.
METHODS
In this prospective, double-blind, placebo-controlled, randomized trial, we assigned 470 patients who had undergone endoscopic resection of early gastric cancer or high-grade adenoma to receive either H. pylori eradication therapy with antibiotics or placebo. Two primary outcomes were the incidence of metachronous gastric cancer detected on endoscopy performed at the 1-year follow-up or later and improvement from baseline in the grade of glandular atrophy in the gastric corpus lesser curvature at the 3-year follow-up.
RESULTS
A total of 396 patients were included in the modified intention-to-treat analysis population (194 in the treatment group and 202 in placebo group). During a median follow-up of 5.9 years, metachronous gastric cancer developed in 14 patients (7.2%) in the treatment group and in 27 patients (13.4%) in the placebo group (hazard ratio in the treatment group, 0.50; 95% confidence interval, 0.26 to 0.94; P=0.03). Among the 327 patients in the subgroup that underwent histologic analysis, improvement from baseline in the atrophy grade at the gastric corpus lesser curvature was observed in 48.4% of the patients in the treatment group and in 15.0% of those in the placebo group (P<0.001). There were no serious adverse events; mild adverse events were more common in the treatment group (42.0% vs. 10.2%, P<0.001).
CONCLUSIONS
Patients with early gastric cancer who received H. pylori treatment had lower rates of metachronous gastric cancer and more improvement from baseline in the grade of gastric corpus atrophy than patients who received placebo. (Funded by the National Cancer Center, South Korea; ClinicalTrials.gov number, NCT02407119 .).
Topics: Adenoma; Adult; Aged; Amoxicillin; Anti-Bacterial Agents; Clarithromycin; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Gastritis, Atrophic; Gastroscopy; Helicobacter Infections; Helicobacter pylori; Humans; Incidence; Intention to Treat Analysis; Kaplan-Meier Estimate; Male; Middle Aged; Neoplasm Recurrence, Local; Prospective Studies; Proton Pump Inhibitors; Rabeprazole; Stomach; Stomach Neoplasms
PubMed: 29562147
DOI: 10.1056/NEJMoa1708423 -
The Journal of Clinical Investigation Nov 2022The stomach corpus epithelium is organized into anatomical units that consist of glands and pits. Mechanisms that control the cellular organization of corpus glands and...
The stomach corpus epithelium is organized into anatomical units that consist of glands and pits. Mechanisms that control the cellular organization of corpus glands and enable their recovery upon injury are not well understood. R-spondin 3 (RSPO3) is a WNT-signaling enhancer that regulates stem cell behavior in different organs. Here, we investigated the function of RSPO3 in the corpus during homeostasis, upon chief and/or parietal cell loss, and during chronic Helicobacter pylori infection. Using organoid culture and conditional mouse models, we demonstrate that RSPO3 is a critical driver of secretory cell differentiation in the corpus gland toward parietal and chief cells, while its absence promoted pit cell differentiation. Acute loss of chief and parietal cells induced by high dose tamoxifen - or merely the depletion of LGR5+ chief cells - caused an upregulation of RSPO3 expression, which was required for the initiation of a coordinated regenerative response via the activation of yes-associated protein (YAP) signaling. This response enabled a rapid recovery of the injured secretory gland cells. However, in the context of chronic H. pylori infection, the R-spondin-driven regeneration was maintained long term, promoting severe glandular hyperproliferation and the development of premalignant metaplasia.
Topics: Mice; Animals; Helicobacter pylori; Helicobacter Infections; Receptors, G-Protein-Coupled; Gastric Mucosa; Metaplasia; Stomach; Regeneration; Stomach Neoplasms
PubMed: 36099044
DOI: 10.1172/JCI151363 -
Journal of the American Veterinary... Sep 2022The purpose of this study was to characterize the relationship of diet and management factors with the glandular gastric mucosal microbiome. We hypothesize that the...
OBJECTIVE
The purpose of this study was to characterize the relationship of diet and management factors with the glandular gastric mucosal microbiome. We hypothesize that the gastric mucosal microbial community is influenced by diet and management factors. Our specific objective is to characterize the gastric mucosal microbiome in relation to these factors.
ANIMALS
57 client-owned horses in the southern Louisiana region with and without equine glandular gastric disease.
PROCEDURES
Diet and management data were collected via a questionnaire. Gastroscopy was used for evaluation of equine gastric ulcer syndrome and collection of glandular mucosal pinch biopsies. 16S rRNA amplicon sequencing was used for microbiome analysis. Similarity and diversity indices and sequence read counts of individual taxa were compared between diet and management factors.
RESULTS
Differences were detected in association with offering hay, type of hay, sweet feed, turnout, and stalling. Offering hay and stalling showed differences in similarity indices, whereas hay type, sweet feed, and turnout showed differences in similarity and diversity indices. Offering hay, hay type, and sweet feed were also associated with differences in individual sequence read counts.
CLINICAL RELEVANCE
This study provides preliminary characterization of the complex relationship between the glandular gastric microbiome and diet/management factors. The ideal microbiome to promote a healthy glandular gastric environment remains unknown.
Topics: Horses; Animals; Gastrointestinal Microbiome; RNA, Ribosomal, 16S; Stomach Ulcer; Gastric Mucosa; Horse Diseases; Diet
PubMed: 36108099
DOI: 10.2460/javma.22.07.0277 -
Veterinary Medicine (Auckland, N.Z.) 2019Equine glandular gastric disease (EGGD) is an increasingly recognized disease of the glandular mucosa of the equine stomach. Diagnosis is confirmed by gastric endoscopy... (Review)
Review
Equine glandular gastric disease (EGGD) is an increasingly recognized disease of the glandular mucosa of the equine stomach. Diagnosis is confirmed by gastric endoscopy and scored based upon one of several different endoscopic scoring systems. Prevalence appears to be variable, depending upon breed and discipline. Primary identified risk factors include exercise frequency, and stress; therefore, management strategies are focused on reducing exercise and stress. Limiting grain intake and increasing pasture turnout may also be helpful preventative measures. Pharmacologic treatment consists primarily of an approved omeprazole product with or without misoprostol or sucralfate. Further research into the pathophysiology of EGGD may allow for identification of other targeted treatments.
PubMed: 31406687
DOI: 10.2147/VMRR.S174427