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Immunological Investigations Nov 2023Autoimmune gastritis (AIG) is an autoimmune disease of the stomach characterized by the destruction of the oxyntic mucosa, which stops producing acid and becomes both...
BACKGROUND
Autoimmune gastritis (AIG) is an autoimmune disease of the stomach characterized by the destruction of the oxyntic mucosa, which stops producing acid and becomes both functionally and morphologically atrophic. The pathogenic mechanisms behind the disease are still poorly understood. There is no early diagnosis and specific AIG therapy. To elucidate the pathogenesis of AIG, to search for early diagnostic markers, as well as to test new therapeutic approaches, an adequate and easily reproducible experimental model for autoimmune gastritis (EAG) is needed. Existing EAG models have some limitations, including slow development of signs, absence of advanced gastritis, irrational use of animals to obtain antigen. The aim was to find out whether it is possible to cause autoimmune gastritis similar to human disease in Wistar rats through immunization with a homologous gastric mucosa extract.
METHODS
Wistar rats were immunized with gastric mucosa extract. Histology studies and evaluation of serological parameters were performed 56 and 91 days later.
RESULTS
Destruction of oxyntic glands by infiltrating T lymphocytes were detected in rats on 56 and 91 days after initial immunization with gastric mucosa extract. Hyperplasia of enterochromaffin-like (ECL) cells was detected on the 91st day. Antral mucosa remained unchanged.
CONCLUSION
Wistar rats, immunized with gastric mucosa extract, developed EAG similar to human AIG. The advantages of received EAG model are the ease of obtaining, the rapid development of oxyntic mucosa damage, which may progress to ECL cell hyperplasia.
Topics: Humans; Rats; Animals; Hyperplasia; Rats, Wistar; Gastritis; Gastric Mucosa; Autoimmune Diseases
PubMed: 37962068
DOI: 10.1080/08820139.2023.2283103 -
European Journal of Pediatrics Feb 2024We would like to provide an updated comprehensive perspective and identify the components linked to chronic spontaneous urticaria (CSU) without specific triggers in... (Review)
Review
UNLABELLED
We would like to provide an updated comprehensive perspective and identify the components linked to chronic spontaneous urticaria (CSU) without specific triggers in autoimmune atrophic gastritis (AAG). AAG is an organ-specific autoimmune disease that affects the corpus-fundus gastric mucosa. Although we lack a unified explanation of the underlying pathways, when considering all paediatric patients reported in the literature, alterations result in gastric neuroendocrine enterochromaffin-like (ECL) cell proliferation and paracrine release of histamine. Several mechanisms have been proposed for the pathogenesis of CSU, with much evidence pointing towards AAG and ECL cell responses, which may be implicated as potential factors contributing to CSU. The excessive production/release of histamine into the bloodstream could cause or trigger exacerbations of CSU in AAG, independent of Helicobacter pylori; thus, the release of histamine from ECL cells may be the primary modulator.
CONCLUSION
Considering the understanding of these interactions, recognising the respective roles of AAG in the pathogenesis of CSU may strongly impact the diagnostic workup and management of unexplained/refractory CSU and may inform future research and interventions in the paediatric population.
WHAT IS KNOWN
• Autoimmune atrophic gastritis is a chronic immune-mediated inflammatory disease characterised by the destruction of the oxyntic mucosa in the gastric body and fundus, mucosal atrophy, and metaplastic changes. • Autoimmune atrophic gastritis in paediatric patients is important because of the poor outcome and risk of malignancy and possibly underestimated entities primarily reported in single-case reports.
WHAT IS NEW
• Upper gastrointestinal inflammatory disorders, independent of H. pylori, have been implicated as potential inducing factors in the development of chronic spontaneous urticaria. • If a paediatric patient presents with symptoms such as anaemia, reduced vitamin B12 levels, recurrent urticaria with no other detectable aetiology, positive anti-parietal cell antibodies, and elevated gastrin levels, autoimmune atrophic gastritis should be considered a possible cause of chronic urticaria.
Topics: Humans; Child; Gastritis, Atrophic; Histamine; Gastritis; Gastric Mucosa; Chronic Urticaria; Autoimmune Diseases; Chronic Disease; Helicobacter pylori; Helicobacter Infections
PubMed: 37947925
DOI: 10.1007/s00431-023-05324-2 -
Frontiers in Oncology 2023The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred... (Review)
Review
The prevalence of gastric cancer has markedly declined, but due to the high mortality rates associated with gastric cancer, it is still a serious disease. The preferred classification of gastric cancer is according to Lauren into either the intestinal type, which has a glandular growth pattern, or the diffuse type, which does not have glandular structures. Both types have been classified as adenocarcinomas, with the latter type based on periodic acid-Schiff (PAS) positivity presumed to reflect mucin. However, the presence of mucin in the diffuse type, in contrast to neuroendocrine/enterochromaffin-like (ECL) cell markers, has not been confirmed by immunohistochemistry and hybridization. The ECL cells are probably prone to becoming cancerous because they do not express E-cadherin. Gastric cancer is unique in that a bacterium, , is thought to be its main cause. predisposes infected individuals to cancer only after having caused oxyntic atrophy leading to gastric hypoacidity and hypergastrinemia. No single factor has been convincingly proved to be carcinogenic. It is probable that gastrin is the pathogenetic factor for gastric cancer due to , autoimmune gastritis, and long-term prolonged inhibition of gastric acid secretion. Hypergastrinemia induces ECL cell hyperplasia, which develops into neuroendocrine tumors (NETs) and then into neuroendocrine carcinomas in rodents, a sequence that has also been described in humans. During carcinogenesis, the tumor cells lose specific traits, requiring that sensitive methods be used to recognize their origin. Gastric cancer occurrence may hopefully be prevented by eradication at a young age, and by the reduced use of inhibitors of acid secretion and use of a gastrin antagonist in those with previous long-term infection and those with autoimmune gastritis.
PubMed: 37941554
DOI: 10.3389/fonc.2023.1176673 -
European Journal of Pharmacology Dec 2023Hormone-producing enteroendocrine cells (EECs) are present throughout the gastrointestinal tract and respond to various nutrient and gut microbiota produced metabolites...
Hormone-producing enteroendocrine cells (EECs) are present throughout the gastrointestinal tract and respond to various nutrient and gut microbiota produced metabolites stimuli. Two important EEC subtypes, Glucagon like peptide-1 (GLP-1) producing L-cells and serotonin (5-HT) producing enterochromaffin (EC) cells interact via paracrine signaling and exhibit bidirectional regulation of expression and secretion of produced hormones. Accordingly, in vitro studies suggest potential to modulate 5-HT secretion by GLP-1 receptor agonism, and L-cell differentiation via serotonin receptor 4 agonism. However, the importance of this cellular signaling on host metabolism is poorly understood. In this study, we found that two weeks of high fat diet (HFD) feeding reduced RNA expression of gut hormones, including proglucagon (Gcg) gene encoding GLP-1 and Tryptophan hydroxylase1 (Tph1) gene encoding rate limiting enzyme in 5-HT synthesis, specifically in the colon and reduced plasma GLP-1 levels. Levels of propionate and butyrate were also reduced following HFD. However, supplementation of sodium propionate did not improve HFD induced reduction in GLP-1. In contrast, chemical induction of serotonin receptor 4 promoted GLP-1 levels, colonic Gcg RNA expression accompanied by improvement in glucose tolerance in HFD-fed mouse. Thus, this study suggests a novel mechanism to improve glucose tolerance via serotonin receptor 4 stimulation in the HFD induced obese mouse model.
Topics: Mice; Animals; Glucagon-Like Peptide 1; Diet, High-Fat; Serotonin; Glucose; Receptors, Serotonin; RNA; Mice, Inbred C57BL
PubMed: 37926275
DOI: 10.1016/j.ejphar.2023.176181 -
Science (New York, N.Y.) Oct 2023Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic...
Enteroendocrine cells (EECs) are hormone-producing cells residing in the epithelium of stomach, small intestine (SI), and colon. EECs regulate aspects of metabolic activity, including insulin levels, satiety, gastrointestinal secretion, and motility. The generation of different EEC lineages is not completely understood. In this work, we report a CRISPR knockout screen of the entire repertoire of transcription factors (TFs) in adult human SI organoids to identify dominant TFs controlling EEC differentiation. We discovered ZNF800 as a master repressor for endocrine lineage commitment, which particularly restricts enterochromaffin cell differentiation by directly controlling an endocrine TF network centered on PAX4. Thus, organoid models allow unbiased functional CRISPR screens for genes that program cell fate.
Topics: Humans; Cell Differentiation; CRISPR-Cas Systems; Enteroendocrine Cells; Gene Expression Regulation; Organoids; Zinc Fingers; Adult; Cell Lineage; Repressor Proteins
PubMed: 37883554
DOI: 10.1126/science.adi2246 -
Pharmacological Reviews Dec 2023Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord.... (Review)
Review
Pain perception involves current stimulation in peripheral nociceptive nerves and the subsequent stimulation of postsynaptic excitatory neurons in the spinal cord. Importantly, in chronic pain, the neural activity of both peripheral nociceptors and postsynaptic neurons in the central nervous system is influenced by several inflammatory mediators produced by the immune system. Growing evidence has indicated that the commensal microbiota plays an active role in regulating pain perception by either acting directly on nociceptors or indirectly through the modulation of the inflammatory activity on immune cells. This symbiotic relationship is mediated by soluble bacterial mediators or intrinsic structural components of bacteria that act on eukaryotic cells, including neurons, microglia, astrocytes, macrophages, T cells, enterochromaffin cells, and enteric glial cells. The molecular mechanisms involve bacterial molecules that act directly on neurons, affecting their excitability, or indirectly on non-neuronal cells, inducing changes in the production of proinflammatory or anti-inflammatory mediators. Importantly, Parkinson disease, a neurodegenerative and inflammatory disorder that affects mainly the dopaminergic neurons implicated in the control of voluntary movements, involves not only a motor decline but also nonmotor symptomatology, including chronic pain. Of note, several recent studies have shown that Parkinson disease involves a dysbiosis in the composition of the gut microbiota. In this review, we first summarize, integrate, and classify the molecular mechanisms implicated in the microbiota-mediated regulation of chronic pain. Second, we analyze the changes on the commensal microbiota associated to Parkinson disease and propose how these changes affect the development of chronic pain in this pathology. SIGNIFICANCE STATEMENT: The microbiota regulates chronic pain through the action of bacterial signals into two main locations: the peripheral nociceptors and the postsynaptic excitatory neurons in the spinal cord. The dysbiosis associated to Parkinson disease reveals increased representation of commensals that potentially exacerbate chronic pain and reduced levels of bacteria with beneficial effects on pain. This review encourages further research to better understand the signals involved in bacteria-bacteria and bacteria-host communication to get the clues for the development of probiotics with therapeutic potential.
Topics: Humans; Chronic Pain; Parkinson Disease; Dysbiosis; Pain Perception; Gastrointestinal Microbiome; Dopaminergic Neurons
PubMed: 37863655
DOI: 10.1124/pharmrev.122.000674 -
The Journal of Biological Chemistry Dec 2023Adhesion G protein-coupled receptors (aGPCRs) feature large extracellular regions with modular domains that often resemble protein classes of various function. The...
Adhesion G protein-coupled receptors (aGPCRs) feature large extracellular regions with modular domains that often resemble protein classes of various function. The pentraxin (PTX) domain, which is predicted by sequence homology within the extracellular region of four different aGPCR members, is well known to form pentamers and other oligomers. Oligomerization of GPCRs is frequently reported and mainly driven by interactions of the seven-transmembrane region and N or C termini. While the functional importance of dimers is well-established for some class C GPCRs, relatively little is known about aGPCR multimerization. Here, we showcase the example of ADGRG4, an orphan aGPCR that possesses a PTX-like domain at its very N-terminal tip, followed by an extremely long stalk containing serine-threonine repeats. Using X-ray crystallography and biophysical methods, we determined the structure of this unusual PTX-like domain and provide experimental evidence for a homodimer equilibrium of this domain which is Ca-independent and driven by intermolecular contacts that differ vastly from the known soluble PTXs. The formation of this dimer seems to be conserved in mammalian ADGRG4 indicating functional relevance. Our data alongside of theoretical considerations lead to the hypothesis that ADGRG4 acts as an in vivo sensor for shear forces in enterochromaffin and Paneth cells of the small intestine.
Topics: Animals; Mammals; Protein Domains; Receptors, G-Protein-Coupled; Signal Transduction; Enterochromaffin Cells; Paneth Cells; Crystallography, X-Ray; Biophysical Phenomena; Models, Molecular; Protein Structure, Tertiary; Protein Folding; Sequence Alignment; Amino Acid Sequence; HEK293 Cells; Humans
PubMed: 37863265
DOI: 10.1016/j.jbc.2023.105356 -
Veterinary Pathology Mar 2024Rhesus macaques () are used extensively in biomedical research, often with a focus on the gastrointestinal tract, and yet a full characterization of their normal...
Rhesus macaques () are used extensively in biomedical research, often with a focus on the gastrointestinal tract, and yet a full characterization of their normal resident intestinal cell populations has not been published. In addition, chronic enterocolitis (CE), also known as idiopathic chronic diarrhea, affects up to 25% of colony-housed rhesus macaques, often requiring euthanasia for welfare concerns and severely limiting their value as a breeding animal or research subject. We aimed to characterize subjective and objective variables in sections of the ileum, cecum, colon, and rectum in 16 healthy rhesus macaques and compare these results with a cohort of 37 animals euthanized for CE to produce relevant diagnostic thresholds and to improve case definitions for future studies. We found neutrophils to be an infrequent but expected component of the large intestinal leukocyte population. Animals with CE had significantly increased total leukocyte populations between crypts in the cecum, colon, and rectum; variable increases in specific cell populations across all levels of the distal intestinal tract; and significantly increased intraepithelial CD3+ T cells in the colon and rectum. Concentrations of enteroendocrine cells, enterochromaffin cells, and intestinal mast cells were not significantly different between healthy and affected individuals. This study characterizes individual leukocyte populations in the rhesus macaque lower intestinal tract, is the first to evaluate rhesus macaque intestinal mast cells, and provides key diagnostic thresholds for evaluating animals with potential CE.
Topics: Humans; Animals; Macaca mulatta; Enterocolitis; Diarrhea; Ileum; Enterochromaffin Cells
PubMed: 37818978
DOI: 10.1177/03009858231203315 -
Clinical Nuclear Medicine Dec 2023Neuroendocrine tumors (NETs) are rare neoplasms arising from enterochromaffin cells, which are predominantly noted in the gastrointestinal tract and lung; metastases of...
Neuroendocrine tumors (NETs) are rare neoplasms arising from enterochromaffin cells, which are predominantly noted in the gastrointestinal tract and lung; metastases of NETs to the testes in NET are further uncommon. Testicular NET usually has no symptoms and/or presents with painless swelling of the scrotum. Detection of testicular lesion can be challenging and frequently missed on conventional radiological imaging. We present testicular NET missed on conventional radiological imaging, where 68 Ga-DOTATATE PET/CT imaging detected the testicular lesion, and further evident on 177 Lu-DOTATATE-based post-peptide receptor radionuclide therapy theranostic imaging.
Topics: Male; Humans; Positron Emission Tomography Computed Tomography; Neuroendocrine Tumors; Precision Medicine; Organometallic Compounds; Radioisotopes; Receptors, Peptide
PubMed: 37793184
DOI: 10.1097/RLU.0000000000004846 -
The Journal of Histochemistry and... Nov 2023The communication between the intestinal epithelium and the enteric nervous system has been considered indirect. Mechanical or chemical stimuli activate enteroendocrine...
The communication between the intestinal epithelium and the enteric nervous system has been considered indirect. Mechanical or chemical stimuli activate enteroendocrine cells inducing hormone secretion, which act on sub-epithelial nerve ends, activating the enteric nervous system. However, we identified an epithelial cell that expresses NKAIN4, a neuronal protein associated with the β-subunit of Na/K-ATPase. This cell overexpresses Na/K-ATPase and ouabain-insensitive Na-ATPase, enzymes involved in active sodium transport. NKAIN4-positive cells also express neuronal markers as NeuN, acetylcholine-esterase, acetylcholine-transferase, α3- and α7-subunits of ACh receptors, glutamic-decarboxylase, and serotonin-receptor-7, suggesting they are neurons. NKAIN4-positive cells show a polarized shape with an oval body, an apical process finished in a knob-like terminal in contact with the lumen, a basal cilia body at the base of the apical extension, and basal axon-like soma projections connecting sub-epithelial nerve terminals, lymphoid nodules, glial cells, and enterochromaffin cells, forming a network that reaches the epithelial surface. We also showed, using retrograde labeling and immunofluorescence, that these cells receive afferent signals from the enteric nervous system. Finally, we demonstrated that acetylcholine activates NKAIN4-positive cells inducing Ca mobilization and probably serotonin secretion in enterochromaffin cells. NKAIN4-positive cells are neurons that would form a part of a duodenal sensory network for physiological or noxious luminal stimuli.
Topics: Serotonin; Acetylcholine; Neurons; Intestinal Mucosa; Enteric Nervous System; Epithelium; Adenosine Triphosphatases; Sodium-Potassium-Exchanging ATPase
PubMed: 37791513
DOI: 10.1369/00221554231203038