Sodium-Permeable Ion Channels TRPM4 and TRPM5 are Functional in Human Gastric Parietal Cells in Culture and Modulate the Cellular Response to Bitter-Tasting Food Constituents.

Gastric parietal cells secrete chloride ions and protons to form hydrochloric acid. Besides endogenous stimulants, e.g., acetylcholine, bitter-tasting food constituents, e.g., caffeine, induce proton secretion via interaction with bitter taste receptors (TAS2Rs), leading to increased cytosolic Ca2+ and cAMP concentrations. We hypothesized TAS2R activation by bitter tastants to result in proton secretion via cellular Na+ influx mediated by transient receptor potential channels (TRP) M4 and M5 in immortalized human parietal HGT-1 cells. Using the food-derived TAS2R agonists caffeine and l-arginine, we demonstrate both bitter compounds to induce a TRPM4/M5-mediated Na+ influx, with EC50 values of 0.65 and 10.38 mM, respectively, that stimulates cellular proton secretion. Functional involvement of TAS2Rs in the caffeine-evoked effect was demonstrated by means of the TAS2R antagonist homoeriodictyol, and stably CRISPR-Cas9-edited TAS2R43ko cells. Building on previous results, these data further support the suitability of HGT-1 cells as a surrogate cell model for taste cells. In addition, TRPM4/M5 mediated a Na+ influx after stimulating HGT-1 cells with the acetylcholine analogue carbachol, indicating an interaction of the digestion-associated cholinergic pathway with a taste-signaling pathway in parietal cells.

Transforming Growth Factor α Evokes Aromatase Expression in Gastric Parietal Cells during Rat Postnatal Development.

Estrogen, well known as a female hormone, is synthesized primarily by ovarian aromatase. However, extra-glandular tissues also express aromatase and produce estrogen. It is noteworthy that aromatase in gastric parietal cells begins expression around 20 days after birth and continues secreting considerable amounts of estrogen into the portal vein throughout life, supplying it to the liver. Estrogen, which is secreted from the stomach, is speculated to play a monitoring role in blood triglyceride, and its importance is expected to increase. Nevertheless, the regulatory mechanisms of the aromatase expression remain unclear. This study investigated the influence of transforming growth factor α (TGFα) on gastric aromatase expression during postnatal development. The administration of TGFα (50 µg/kg BW) to male Wistar rats in the weaning period resulted in enhanced aromatase expression and increased phosphorylated ERK1+2 in the gastric mucosa. By contrast, administration of AG1478 (5 mg/kg BW), a protein tyrosine kinase inhibitor with high selectivity for the epidermal growth factor receptor and acting as an antagonist of TGFα, led to the suppression of aromatase expression. In fact, TGFα expression in the gastric fundic gland isthmus began around 20 days after birth in normal rats as did that of aromatase, which indicates that TGFα might induce the expression of aromatase in the parietal cells concomitantly.

Autoimmune gastritis serological biomarkers in gastric cancer patients.

The role of autoimmunity in the pathogenesis of gastric cancer remains controversial. We studied antiparietal cell antibody (anti-PCA) and anti-intrinsic factor antibody (anti-IFA) levels and their associations with pepsinogen I/pepsinogen II levels in patients with gastric adenocarcinoma compared to a control group with mild or no atrophy of the stomach mucosa. Plasma levels of anti-PCA and anti-IFA were measured by ELISA (Inova Diagnostics Inc, San Diego, California, USA). The cutoff value for anti-PCA and anti-IFA positivity was ≥25 units. Altogether 214 patients (126 men, 88 women, median age 64.46, range: 35-86) with confirmed gastric adenocarcinoma and 214 control cases paired for age and sex were included in the study. Positive anti-PCA was present in 22 (10.3%) gastric cancer patients and controls (P ≥ 0.999); positive anti-IFA in 6 (2.8%) and 4 (1.9.%), P < 0.232, respectively. We did not find significant differences in anti-PCA and anti-IFA positivity between gastric cancer patients and the control group; further investigation is required to better understand the potential involvement of autoimmune gastritis in the development of gastric cancer.

[Intracellular Mechanism of Gastric Acid Secretion: What is the True Switch?]

In 1985, I was accepted as postdoc by Professor Forte of UC Berkeley. He discovered H+,K+-ATPase and established the membrane recycling theory as the activation mechanism for acid secretion using whole animals. H+,K+-ATPase is an enzyme that exchanges H+ with K+. In resting state, it locates on the tubulovesicles and the pump does not work because the membrane lacks K+ permeability. Upon stimulation, the tubulovesicles fuse to the apical membrane and acquire K+ permeability, turning the pump on. The main route was known to be protein kinase A (PKA), but its specific targets remained unknown. Right after I joined Forte's lab, I was fortunate enough to reproduce the above mechanism in vitro, and I discovered proteins of molecular weight 120 kDa and 80 kDa that were specifically phosphorylated in stimulated parietal cells. After I returned to Japan, the former was cloned and named as parchorin, which is one of the chloride intracellular channels. Although no progress was made on ezrin, I found out the importance of PIP2 and Arf6 using permeabilized gland models. After I left parietal cell research, the link between ezrin and Arf6 was revealed. PKA phosphorylates S66 of ezrin and also MST4. The former changes the N-terminal structure of ezrin to bind syntaxin3, and the latter phosphorylates ACAP4, an Arf6-GAP, to accelerate binding to ezrin. Subsequently, H+,K+-ATPase, SNAREs, ezrin, and Arf6-GAP are aligned on the apical membrane. However, there are still many unsolved questions and the intracellular mechanism of parietal cells remains an attractive research area.

SOX9 Governs Gastric Mucous Neck Cell Identity and Is Required for Injury-Induced Metaplasia.

BACKGROUND & AIMS: Acute and chronic gastric injury induces alterations in differentiation within the corpus of the stomach called pyloric metaplasia. Pyloric metaplasia is characterized by the death of parietal cells and reprogramming of mitotically quiescent zymogenic chief cells into proliferative, mucin-rich spasmolytic polypeptide-expressing metaplasia (SPEM) cells. Overall, pyloric metaplastic units show increased proliferation and specific expansion of mucous lineages, both by proliferation of normal mucous neck cells and recruitment of SPEM cells. Here, we identify Sox9 as a potential gene of interest in the regulation of mucous neck and SPEM cell identity in the stomach. METHODS: We used immunostaining and electron microscopy to characterize the expression pattern of SRY-box transcription factor 9 (SOX9) during murine gastric development, homeostasis, and injury in homeostasis, after genetic deletion of Sox9 and after targeted genetic misexpression of Sox9 in the gastric epithelium and chief cells. RESULTS: SOX9 is expressed in all early gastric progenitors and strongly expressed in mature mucous neck cells with minor expression in the other principal gastric lineages during adult homeostasis. After injury, strong SOX9 expression was induced in the neck and base of corpus units in SPEM cells. Adult corpus units derived from Sox9-deficient gastric progenitors lacked normal mucous neck cells. Misexpression of Sox9 during postnatal development and adult homeostasis expanded mucous gene expression throughout corpus units including within the chief cell zone in the base. Sox9 deletion specifically in chief cells blunts their reprogramming into SPEM. CONCLUSIONS: Sox9 is a master regulator of mucous neck cell differentiation during gastric development. Sox9 also is required for chief cells to fully reprogram into SPEM after injury.

Neuroendocrine mechanism of gastric acid secretion: Historical perspectives and recent developments in physiology and pharmacology.

The physiology of gastric acid secretion is one of the earliest subjects in medical literature and has been continuously studied since 1833. Starting with the notion that neural stimulation alone drives acid secretion, progress in understanding the physiology and pathophysiology of this process has led to the development of therapeutic strategies for patients with acid-related diseases. For instance, understanding the physiology of parietal cells led to the developments of histamine 2 receptor blockers, proton pump inhibitors (PPIs), and recently, potassium-competitive acid blockers. Furthermore, understanding the physiology and pathophysiology of gastrin has led to the development of gastrin/CCK2 receptor (CCK2 R) antagonists. The need for refinement of existing drugs in patients have led to second and third generation drugs with better efficacy at blocking acid secretion. Further understanding of the mechanism of acid secretion by gene targeting in mice has enabled us to dissect the unique role for each regulator to leverage and justify the development of new targeted therapeutics for acid-related disorders. Further research on the mechanism of stimulation of gastric acid secretion and the physiological significances of gastric acidity in gut microbiome is needed in the future.

Critical influence of cytokines and immune cells in autoimmune gastritis.

Gastric cancer (GC) is a type of the most common cancers. Autoimmune gastritis (AIG) and infection with Helicobacter pylori (HP) are the risk factors of triggering GC. With the emphasis on the treatment of HP, the incidence and prevalence of HP infection in population is decreasing. However, AIG lacks accurate diagnosis and treatment methods, which occupies high cancer risk factors. AIG is controlled by the immune environment of the stomach, including immune cells, inflammatory cells, and infiltrating intercellular material. Various immune cells or cytokines play a central role in the process of regulating gastric parietal cells. Abnormal expression levels of cytokines involved in immunity are bound to face the risk of tumorigenesis. Therefore, it is particularly important for preventing or treating AIG and avoiding the risk of gastric cancer to clarify the confirmed action mode of immune cells and cytokines in the gastric system. Herein, we briefly reviewed the role of the immune environment under AIG, focussing on describing these double-edged effects between immune cells and cytokines, and pointing out potential research challenges.

Vitamin B12 deficiency may play an etiological role in atrophic glossitis and its grading: A clinical case-control study.

BACKGROUND: Existing studies have reported the significant association between atrophic glossitis (AG) and hematinic deficiencies, including iron, folate and vitamin B12 deficiency. However, these findings were inconsistent. AG can be graded as partial or complete atrophy. It is still unclear whether hematinic deficiencies are associated with the grading of AG. METHODS: 236 AG patients and 208 sex- and age-matched healthy controls were enrolled in this study. Hematological tests including complete blood count, and serum levels of folate, ferritin and vitamin B12 were performed. The AG group was divided into those with partial AG and those with complete AG according to the extent of papillary atrophy. Statistical analysis was performed to assess whether hematinic deficiencies are risk factors for AG and its grading. RESULTS: Compared with the healthy controls, AG patients had significantly higher frequencies of vitamin B12 deficiency (68.22%), ferritin deficiency (13.98%) and anemia (21.61%). The differences in hematinic deficiencies and anemia between AG patients and healthy controls changed according to gender and age. The frequencies of serum vitamin B12 deficiency and anemia in the complete AG subgroup were significantly higher than those in the partial AG subgroup. Logistic regression analysis revealed that vitamin B12 deficiency and anemia were significantly correlated with AG and its grading. The AG patients with vitamin B12 deficiency responded well to supplement therapy. CONCLUSION: AG could be an important clinical indicator for potential vitamin B12 deficiency, especially when the degree of tongue atrophy more than 50% and complete atrophy. Vitamin B12 deficiency might play an etiological role in the development of AG.

Gastric Neuroendocrine Tumors With Parietal Cell Atrophy in a Long-term Carcinogenicity Study in Rats.

Malignant neuroendocrine tumors were diagnosed in the stomach of two out of sixty female Sprague-Dawley rats treated for 89 weeks with a high dose of a novel, small molecule, cannabinoid-1 antagonist. The tumors were associated with parietal cell atrophy accompanied by foveolar hyperplasia of the glandular stomach mucosa. Parietal cell atrophy/foveolar hyperplasia was considered test article related at the high dose, given the higher incidence and severity relative to untreated controls, although the precise mechanism of the parietal cell atrophy was undetermined. Spontaneous gastric neuroendocrine tumors are very rare in rats, and the current cases were considered secondary to parietal cell atrophy causing reduced gastric acid secretion and subsequent overstimulation of gastrin release through a feedback loop.

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.

Expression alteration and dysfunction of ion channels/transporters in the parietal cells induces gastric diffused mucosal injury.

Gastric mucosal injuries include focal and diffused injuries, which do and do not change the cell differentiation pattern. Parietal cells loss is related to the occurrence of gastric mucosal diffused injury, with two phenotypes of spasmolytic polypeptide-expressing metaplasia and neuroendocrine cell hyperplasia, which is the basis of gastric cancer and gastric neuroendocrine tumor respectively. Multiple ion channels and transporters are located and expressed in the parietal cells, which is not only regulate the gastric acid-base homeostasis, but also regulate the growth and development of parietal cells. Therefore, alteration and dysregulation of ion channels and transporters in the parietal cells impairs the morphology and physiological functions of stomach, resulted in gastric diffused mucosal damage. In this review, multiple ion channels and transporters in parietal cells, including K+ channels, aquaporins, Cl- channels, Na+/H+ transporters, and Cl-/HCO3- transporters are described, and their roles in gastric diffused mucosal injury are discussed. We hope to drive researcher's attention to focus on the role of ion channels/transporters loss in the parietal cells induced gastric diffused mucosal injury.

Parietal Cell Dysfunction: A Rare Cause of Gastric Neuroendocrine Neoplasm with Achlorhydria and Extreme Hypergastrinemia.

A 69-year-old woman with multiple neuroendocrine neoplasms (NENs) was referred to our hospital. Although she had extreme hypergastrinemia (11,675 pg/mL), no findings that indicated types I to III gastric NENs were found. Although gastric corpus atrophy was suspected on conventional white-light imaging, findings on magnifying endoscopy with narrow-band imaging indicated no severe atrophy. A biopsy from the background fundic gland mucosa revealed no atrophic changes, parietal cells with vacuolated cytoplasm and negative findings for H+K+-ATPase. Thus, this case was diagnosed as multiple NENs with parietal cell dysfunction. Neither progression nor metastasis has been confirmed during two-year follow-up.

Anemia ferropénica como inicio de gastritis atrófica en un paciente con diabetes mellitus tipo 1 / Iron deficiency anaemia as a first manifestation of atrophic gastritis in a patient with type 1 diabetes mellitus

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Fundic gland polyps related to diverse aetiologies show subtle morphological differences: a multicentre retrospective study.

AIMS: Fundic gland polyps (FGPs) comprise 66% of all gastric polyps. Although they are usually non-syndromic, they may be associated with various syndromes, including familial adenomatous polyposis (FAP) or gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). We aimed to evaluate how histological features relate to distinct FGP subtypes. METHODS AND RESULTS: We performed a retrospective analysis of 118 FGPs from 109 patients for the architecture of fundic glands, microcyst lining, parietal cell hyperplasia and surface foveolar epithelial changes. Age, gender and history of FAP or GAPPS were collected. Based on combinations of histological features, three distinct patterns (A, B and C) of FGPs were delineated and correlated to the aetiologies. Non-syndromic FGPs were well-formed polyps composed of disordered fundic glands with intermediate-sized microcysts typically lined by a mixture of oxyntic and mucin-secreting cells (73%). Parietal cell hyperplasia (80%) and foveolar surface hyperplasia (78%) were common. FAP-associated cases demonstrated small microcysts that were predominantly lined by fundic epithelium (77%), with limited parietal cell hyperplasia (27%); foveolar hyperplasia was uncommon. GAPPS-related polyps were the largest, with prominent, mucin-secreting epithelium-lined microcysts (73%). Hyperproliferative aberrant pits were universally present, whereas parietal cell hyperplasia was uncommon. Pattern A was identified in most non-syndromic FGPs (74%) and in a minority of FAP-related FGPs (26%). The majority (82%) of FAP-related FGPs showed pattern B, but only 18% of non-syndromic FGPs did. Pattern C consisted exclusively of GAPPS-associated polyps. CONCLUSIONS: We conclude that, although FGPs share similar histomorphology, subtle differences exist between polyps of different aetiology. In the appropriate clinical setting, the recognition of these variations may help to consider syndromic aetiologies.

Decreased anti-parietal cell antibody titer in the advanced phase of autoimmune gastritis.

BACKGROUND: Autoimmune gastritis (AIG) is histologically classified into three phases according to the severity of oxyntic mucosal atrophy: early, florid, and end phases. This study aimed to clarify the relationship between the AIG phase and the anti-parietal cell antibody titer. METHODS: Patients who underwent upper gastrointestinal endoscopy were retrospectively reviewed in this study. We enrolled patients who were histologically diagnosed with AIG and serologically tested for anti-parietal cell antibody (APCA). AIG patients were classified into three groups: early, florid, and end phase groups. Clinical characteristics, including APCA titers, were compared among these three groups. RESULTS: A total of 44 AIG patients were enrolled. There were two patients in the early phase, 11 in the florid phase, and 31 in the end phase. APCA-positive rates were 100% in the early phase, 90.9% in the florid phase, and 90.3% in the end phase. The mean APCA titer was 480 U in the early phase, 220 U in the florid phase, and 150 U in the end phase. There was a stepwise decrease in the APCA titer from the early phase to the end phase. The mean APCA titer for the end phase was significantly lower than that of the early phase or florid phase. Additionally, there was a stepwise decrease in serum gastrin levels from the early phase to the end phase. CONCLUSION: AIG progresses from the early phase to the end phase, and the APCA titer shows a decrease. The negativity of APCA could occur, especially in the end phase.

Cellular Plasticity, Reprogramming, and Regeneration: Metaplasia in the Stomach and Beyond.

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.

Age-related alterations of gastric mucosa and estrogen synthesis in rat parietal cells.

The stomach has diverse functions other than gastric acid secretion. Multifaceted studies have investigated age-related changes of the gastrointestinal tract. Nevertheless, little is known about estrogen production changes in gastric parietal cells in rats aged over 3 months. We investigated age-related changes in gastric estrogen synthesis and the accompanying changes in liver estrogen receptor from 3 to 24 months. Weights of the body, stomach, and liver increased linearly from 3 to 18 months, then maintained a constant proportion up to 24 months. The gastric mucosa area (in mm2/1 mm muscularis mucosa) showed a constant proportion throughout the rats' life. The population of parietal cells immunostained area with H+/K+-ATPase decreased gradually with advancing age. Cells that were immunopositive to aromatase antibody were observed at 3-24 months. The expressions of aromatase mRNA and its protein were somewhat lower at 18 and 24 months than at 3 months. The portal venous estradiol concentration at 12 months was 1.5 times higher than that at 3 months, and that at 18 months was a half of that at 3 months. The expression of estrogen receptor mRNA in the liver at 18 and 24 months was about 80% of that at 3 months. Results suggest that the gastric estrogen production declines with aging, and the liver estrogen receptor is also affected accordingly. Simultaneously, the gastric mucosa continues to express aromatase to maintain liver function(s) throughout the animal's life.

Interplay of potassium channel, gastric parietal cell and proton pump in gastrointestinal physiology, pathology and pharmacology.

Gastric acid secretion plays a pivotal role in the physiology of gastrointestinal tract. The functioning of the system encompasses a P2 ATPase pump (which shuttles electroneutral function at low pH) along with different voltage sensitive/neutral ion channels, cytosolic proteins, acid sensor receptors as well hormonal regulators. The increased acid secretion is a pathological marker of several diseases like peptic ulcer, gastroesophageal reflux disease (GERD), chronic gastritis, and the bug Helicobacter pylori (H. pylori) has also a critical role, which altogether affects the patient's quality of life. This review comprehensively described the nature of potassium ion channel and its mediators, the different clinical strategy to control acid rebound, and some basic experimental observations performed to study the interplay of ion channels, pumps, as well as mediators during acid secretion. Different aspects of regulation of gastric acid secretion have been focused either in terms of physiology of secretion or molecular interactions. The importance of H pylori infection and its treatment has also been discussed. Furthermore, the relevance of calcium signaling during acid secretion has been reviewed. The entire theme will make anyone understand in detail the gastric secretion machinery in general.