Role of Gastric Microorganisms Other than Helicobacter pylori in the Development and Treatment of Gastric Diseases.

The microenvironment in the stomach is different from other digestive tracts, mainly because of the secretion of gastric acid and digestive enzymes, bile reflux, special mucus barrier, gastric peristalsis, and so on, which all contribute to the formation of antibacterial environment. Microecological disorders can lead to gastric immune disorders or lead to the decrease of dominant bacteria and the increase of the abundance and virulence of pathogenic microorganisms and then promote the occurrence of diseases. The body performs its immune function through innate and adaptive immunity and maintains microbial balance through the mechanism of immune homeostasis. Microecological imbalance can lead to the invasion of pathogenic microorganisms and damage mucosal barrier and immune system. The coexistence of gastric microorganisms (including viruses and fungi) may play a synergistic or antagonistic role in the pathogenesis of gastric diseases. Probiotics have the ability to compete with intestinal pathogens, increase the secretion of immunoglobulin A (IgA), stimulate the production of mucin, bacteriocin, and lactic acid, regulate the expression and secretion of cytokines, and regulate the growth of microbiota, which all have beneficial effects on the host microbial environment. At present, most studies focused on Helicobacter pylori, ignoring other stomach microbes and the overall stomach microecology. So, in this article, we reviewed advances in human gastric microecology, the relationship between gastric microecology and immunity or gastric diseases, and the treatment of probiotics in gastric diseases, in order to explore new area for further study of gastric microorganisms and treatment of gastric diseases.

Autophagy-lysosome dysfunction is involved in gastric ischemia-reperfusion injury by promoting microglial activation in the paraventricular nucleus.

The hypothalamic paraventricular nucleus (PVN) is a specific center in the brain that regulates gastric mucosal injury following gastric ischemia-reperfusion (GI-R) injury. This study aimed to investigate whether autophagy-lysosome dysfunction in the PVN tissues of GI-R rats is involved in the gastric injury, and the underlying molecular mechanisms. The rat model of GI-R was established by clamping the celiac artery for 30 min and reperfusion for different hours (1, 3, and 6 h). The gastric injury was evaluated by hematoxylin and eosin staining of the stomach and the gastric mucosal index. The autophagy-lysosome dysfunction in the PVN was evaluated by the protein levels of LC3 II and Beclin-1 (markers for autophagosome activity) and the activity of acid phosphatase (a representative lysosomal enzyme). Immunohistochemical staining of ionized calcium-binding adaptor molecule 1 in the PVN was performed to evaluate microglial activation. Reactive oxygen species (ROS) content and phosphorylated γ-aminobutyric acid B receptor (p-GABAB R) expression in the PVN were also examined. The results revealed that, in GI-R rats, the shorter the reperfusion duration, the more severe the gastric mucosal damage. The autophagy-lysosome dysfunction exhibited by GI-R rats further enhanced microglial activation, ROS production, p-GABAB R expression, and gastric injury. In addition, activating microglial cells increased ROS production, p-GABAB R expression, and gastric injury in GI-R rats, while inhibiting microglial activation resulted in the opposite results. Taken together, autophagy-lysosome dysfunction induced by GI-R aggravated the gastric injury by inducing microglia activation.

Role of the posterior mucosal defense barrier in portal hypertensive gastropathy.

Portal hypertensive gastropathy (PHG) is a complication of cirrhotic or noncirrhotic portal hypertension. PHG is very important in the clinic because it can cause acute or even massive blood loss, and its treatment efficacy and prognosis are poor. Currently, the incidence of PHG in patients with cirrhosis is 20-80%, but its pathogenesis is complicated and poorly understood. Studies have shown that portal hypertension can cause changes in gastric mucosal microcirculation hemodynamics, leading to changes in gastric mucosal histology and function and thereby weakening the mucosal defense barrier. However, no specific drug treatment plans are currently available. This article reviews the current literature to further our understanding of the mechanism underlying PHG and the relationship between PHG and the posterior mucosal defense barrier and to explore new therapeutic targets.

The gastric conduction system in health and disease: a translational review.

Gastric peristalsis is critically dependent on an underlying electrical conduction system. Recent years have witnessed substantial progress in clarifying the operations of this system, including its pacemaking units, its cellular architecture, and slow-wave propagation patterns. Advanced techniques have been developed for assessing its functions at high spatiotemporal resolutions. This review synthesizes and evaluates this progress, with a focus on human and translational physiology. A current conception of the initiation and conduction of slow-wave activity in the human stomach is provided first, followed by a detailed discussion of its organization at the cellular and tissue level. Particular emphasis is then given to how gastric electrical disorders may contribute to disease states. Gastric dysfunction continues to grow in their prevalence and impact, and while gastric dysrhythmia is established as a clear and pervasive feature in several major gastric disorders, its role in explaining pathophysiology and informing therapy is still emerging. New insights from high-resolution gastric mapping are evaluated, together with historical data from electrogastrography, and the physiological relevance of emerging biomarkers from body surface mapping such as retrograde propagating slow waves. Knowledge gaps requiring further physiological research are highlighted.

Investigating Helicobacter pylori-related pyloric hypomotility: functional, histological, and molecular alterations.

Multiple theories have been proposed describing the pathogenic mechanisms of Helicobacter pylori (H. pylori)-associated gastric motility disorders. We assessed ex vivo pyloric activity in H. pylori-infected rats, and tried to explore the associated ghrelin hormone alteration and pyloric fibrogenesis. In addition, miR-1 was assessed in pyloric tissue samples, being recently accused of having a role in smooth muscle dysfunction. Ninety adult male Wistar albino rats were assigned into nine groups: 1) control group, 2) sterile broth (vehicle group), 3) amoxicillin control, 4) omeperazole control, 5) clarithromycin control, 6) triple therapy control, 7) H. pylori- group, 8) H. pylori-clarithromycin group, and 9) H. pylori-triple therapy group. Urease enzyme activity was applied as an indicator of H. pylori infection. Ex vivo pyloric contractility was evaluated. Serum ghrelin was assessed, and histological tissue evaluation was performed. Besides, pyloric muscle miR-1 expression was measured. The immunological epithelial to mesenchymal transition (EMT) markers; transforming growth factor ß (TGFß), α-smooth muscle actin (α-SMA), and E-cadherin-3 were also evaluated. By H. pylori infection, a significant (P < 0.001) reduced pyloric contractility index was recorded. The miR-1 expression was decreased (P < 0.001) in the H. pylori-infected group, associated with reduced serum ghrelin, elevated TGFß, and α-SMA levels and reduced E-cadherin levels. Decreased miR-1 and disturbed molecular pattern were improved by treatment. In conclusion, H. pylori infection was associated with reduced miR-1, epithelial to mesenchymal transition, and pyloric hypomotility. The miR-1 may be a target for further studies to assess its possible involvement in H. pylori-associated pyloric dysfunction, which might help in the management of human H. pylori manifestations and complications.NEW & NOTEWORTHY This work is investigating functional, histopathological, and molecular changes underlying Helicobacter pylori hypomotility and is correlating these with miR-1, whose disturbance is supposed to be involved in smooth muscle dysfunction and cell proliferation according to literature. Epithelial to mesenchymal transition and reduced ghrelin hormone may contribute to H. pylori infection-associated hypomotility. H. pylori infection was associated with reduced pyloric miR-1 expression. Targeting miR-1 could be valuable in the clinical management of pyloric hypofunction.

ANKRD22 Drives Rapid Proliferation of Lgr5+ Cells and Acts as a Promising Therapeutic Target in Gastric Mucosal Injury.

BACKGROUND & AIMS: Rapid gastric epithelial progenitor cell (EPC) proliferation and inflammatory response inhibition play key roles in promoting the repair of gastric mucosal damage. However, specific targets inducing these effects are unknown. In this study, we explored the effects of a potential target, Ankyrin repeat domain 22 (ANKRD22). METHODS: An acute gastric mucosal injury model was established with Ankrd22-/- and Ankrd22+/+ mice by intragastric administration of acidified ethanol. Organoid culture and flow cytometry were performed to evaluate the effects of ANKRD22 on leucine-rich repeat-containing G-protein-coupled receptor 5-positive (Lgr5+) gastric EPC proliferation. The mechanisms by which ANKRD22 affects gastric EPC proliferation and inflammatory responses were explored by mitochondrial Ca2+ influx and immunoblotting. Candidate ANKRD22 inhibitors then were screened virtually and validated in vitro and in vivo. RESULTS: After acute gastric mucosal injury, the number of Lgr5+ gastric EPCs was increased significantly in Ankrd22-/- mice compared with that in Ankrd22+/+ mice. Moreover, Ankrd22 knockout attenuated inflammatory cell infiltration into damaged gastric tissues. ANKRD22 deletion also reduced mitochondrial Ca2+ influx and cytoplasmic nuclear factor of activated T cells in gastric epithelial cells and macrophages, which further induced Lgr5+ gastric EPC proliferation and decreased macrophage release of tumor necrosis factor-α and interleukin 1α. In addition, a small molecule, AV023, was found to show similar effects to those produced by ANKRD22 deletion in vitro. Intraperitoneal injection of AV023 into the mouse model promoted the repair of gastric mucosal damage, with increased proliferation of Lgr5+ gastric EPCs and visible relief of inflammation. CONCLUSIONS: ANKRD22 inhibition is a potential target-based therapeutic approach for promoting the repair of gastric mucosal damage.

Helicobacter pylori Outer Membrane Vesicles and Extracellular Vesicles from Helicobacter pylori-Infected Cells in Gastric Disease Development.

Extracellular vesicles (EVs) are cell-derived vesicles important in intercellular communication that play an essential role in host-pathogen interactions, spreading pathogen-derived as well as host-derived molecules during infection. Pathogens can induce changes in the composition of EVs derived from the infected cells and use them to manipulate their microenvironment and, for instance, modulate innate and adaptive inflammatory immune responses, both in a stimulatory or suppressive manner. Gastric cancer is one of the leading causes of cancer-related deaths worldwide and infection with Helicobacter pylori (H. pylori) is considered the main risk factor for developing this disease, which is characterized by a strong inflammatory component. EVs released by host cells infected with H. pylori contribute significantly to inflammation, and in doing so promote the development of disease. Additionally, H. pylori liberates vesicles, called outer membrane vesicles (H. pylori-OMVs), which contribute to atrophia and cell transformation in the gastric epithelium. In this review, the participation of both EVs from cells infected with H. pylori and H. pylori-OMVs associated with the development of gastric cancer will be discussed. By deciphering which functions of these external vesicles during H. pylori infection benefit the host or the pathogen, novel treatment strategies may become available to prevent disease.

Liver transcriptome response to periparturient hormonal and metabolic changes depends on the postpartum occurrence of subacute ruminal acidosis in Holstein cows.

We investigated changes in rumen fermentation, peripheral blood metabolites and hormones, and hepatic transcriptomic dynamics in Holstein cows with and those without subacute ruminal acidosis (SARA) during the periparturient period. Sixteen multiparous Holstein cows were categorized in the SARA (n = 8) or non-SARA (n = 8) groups depending on whether they developed SARA during the 2 wk after parturition. Reticulo-ruminal pH was measured continuously throughout the study. Rumen fluid, blood, and liver tissue samples were collected at 3 wk prepartum and 2 and 6 wk postpartum, with an additional blood sample collected at 0 and 4 wk postpartum. The 1-h mean pH was depressed postpartum in both groups, whereas depression was more severe in the SARA group simultaneously with significantly longer duration of time (for pH <5.6 and 5.8). Significant expression of differentially expressed genes in liver tissue (DEGs; false discovery rate corrected P < 0.1) were identified only in the non-SARA group and were further analyzed by Ingenuity Pathway Analysis software. Among the top expressed DEGs, the hepatic genes encoding lipid and cholesterol secretion (APOA1, APOA4, and G0S2) and gluconeogenesis (PC, G6PC, and PCK1) were upregulated postpartum. In silico analysis revealed the significant postpartum activation of upstream regulators, such as INSR, PPARG, and PPARGC1A. These results suggested that hepatic transcriptomic responsiveness to postpartum metabolic load and hormones were likely discouraged in cows with SARA when compared with the significant activation of genes and signaling pathways for adequate metabolic adaption to postpartum high-grain diet feeding in Holstein cows without SARA.

Neurons and Astrocytes in Ventrolateral Periaqueductal Gray Contribute to Restraint Water Immersion Stress-Induced Gastric Mucosal Damage via the ERK1/2 Signaling Pathway.

BACKGROUND: The restraint water immersion stress (RWIS) model includes both psychological and physical stimulation, which may lead to gastrointestinal disorders and cause gastric mucosal damage. The ventrolateral periaqueductal gray (VLPAG) contributes to gastrointestinal function, but whether it is involved in RWIS-induced gastric mucosal damage has not yet been reported. METHODS: The expression of glial fibrillary acidic protein, neuronal c-Fos, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG after RWIS was assessed using western blotting and immunocytochemical staining methods. Lateral ventricle injection of astrocytic toxin L-a-aminoadipate and treatment with extracellular signal-regulated kinase (ERK)1/2 signaling pathway inhibitor PD98059 were further used to study protein expression and distribution in the VLPAG after RWIS. RESULTS: The expression of c-Fos, glial fibrillary acidic protein, and phosphorylated extracellular signal regulated kinase 1/2 in the VLPAG significantly increased following RWIS and peaked at 1 hour after RWIS. Lateral ventricle injection of the astrocytic toxin L-a-aminoadipate significantly alleviated gastric mucosal injury and decreased the activation of neurons and astrocytes. Treatment with the ERK1/2 signaling pathway inhibitor PD98059 obviously suppressed gastric mucosal damage as well as the RWIS-induced activation of neurons and astrocytes in the VLPAG. CONCLUSIONS: These results suggested that activation of VLPAG neurons and astrocytes induced by RWIS through the ERK1/2 signaling pathway may play a critical role in RWIS-induced gastric mucosa damage.

Zuojin Pill ameliorates inflammation in indomethacin-induced gastric injury via inhibition of MAPK pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Zuojin Pill (ZJP) has been a classic prescription for the treatment of gastrointestinal diseases in China since ancient times. But its effect on non-steroidal anti-inflammatory drugs (NSAIDs) induced gastric injury (GI) is still uncharted. AIM OF THE STUDY: This study aims to investigate the therapeutic effect and molecular mechanism of ZJP on indomethacin (IDO) induced gastric injury. MATERIALS AND METHODS: GI was induced in rat by oral administration of 5 mg/kg IDO. Then the rats were treated with ZJP (1.26, 2.52, 5.04 g/kg, ig). The changes of food intake, body weight, gastric pH and general state observation were carried out to determine the improvement of ZJP in IDO-induced GI: HE staining and AB-PAS staining was analyzed to characterize the thickness of gastric mucosa and micro mucosal injury; in order to elucidate the effect of ZJP on IDO-induced inflammatory injury, the inflammatory infiltration of gastric tissue was observed by MPO immunohistochemical method, and the contents of TNF-α, IL-6 and IL-10 were measured. Furthermore, the regulatory mechanism of ZJP in treating IDO-induced GI was predicted with the help of network pharmacology, and the expression levels of key proteins ERK, p-ERK, P38, p-P38, JNK, p-JNK were determined to elucidate the molecular mechanism of ZJP. RESULTS: Current data strongly demonstrated that ZJP alleviated food intake reduction, weight loss and gastric injury caused by IDO and made gastric pH and mucosal thickness return to normal. In addition, ZJP could reduce the level of MPO to alleviate the inflammatory infiltration of gastric tissue. Simultaneously, ZJP could down regulate the expression of TNF-α and IL-6 and up regulate the expression of IL-10 to reduce the damage caused by inflammatory, and create a healing environment. Furthermore, ZJP could significantly inhibit the phosphorylation of ERK, p38 and JNK, which leaded to the increase of inflammatory factors and the damage of gastric mucosa. CONCLUSION: ZJP improved local inflammation by inhibiting MAPK signaling pathway, and had a good therapeutic effect on IDO-induced GI. This study has reference significance for the study of ZJP in the prevention and treatment of NSAID induced gastric injury. In addition, ZJP may be a new treatment option for the prevention and treatment of NSAID induced gastric disease.

Helicobacter pylori type 4 secretion systems as gastroduodenal disease markers.

Although the type 4 secretion system of the integrating and conjugative elements (tfs ICE) is common in Helicobacter pylori, its clinical association with the cag pathogenicity island (cagPAI) have not yet been well-investigated. In this study, Vietnamese patient H. pylori samples (46 duodenal ulcer (DU), 51 non-cardia gastric cancer (NCGC), 39 chronic gastritis (CG)) were fully sequenced using next-generation sequencing and assembled into contigs. tfs3, tfs4, and cagPAI genes were compared with the public database. Most (94%) H. pylori strains possessed a complete cagPAI, which was the greatest risk factor for clinical outcomes, while the prevalences of tfs3 and tfs4 were 45% and 77%, respectively. Complete tfs3 and tfs4 were found in 18.3% and 17.6% of strains, respectively. The prevalence of H. pylori strains with complete tfs3 ICE in DU patients was significantly higher than that in NCGC patients (30.4% vs 11.7%, P < 0.05). In addition, the prevalence of strains with complete tfs3 ICE and cagPAI was significantly higher in DU patients than that in NCGC (28.4% vs 9.8%, P = 0.038) and CG patients (28.2% vs 7.7%, P = 0.024). cagPAI and complete tfs3 increased the risk of DU compared to NCGC (OR = 3.56, 95%CI: 1.1-14.1, P = 0.038) and CG (OR = 4.64, 95%CI: 1.1-27.6, P = 0.024). A complete cluster of tfs3 ICE was associated with gastroduodenal diseases in Vietnam. However, there was a low prevalence of the dupA/complete dupA cluster (15.4%) in the Vietnam strains. The prevalence of cagPAI in Vietnam strains was significantly higher than in US (P = 0.01) and Indonesia (P < 0.0001); the prevalence of the dupA cluster was also higher in the Vietnam strains than in the Indonesian strains (P < 0.05). In addition, the prevalence of ctkA, an accessory gene of tfs3, was significantly different between Vietnam and US strains (28% vs 2%, P = 0.0002). In summary, the acquisition of tfs3/4 ICE was common in H. pylori strains in patients with gastroduodenal disease in Vietnam, and the complete cluster of tfs3 ICE was a reliable marker for the severity of disease in the H. pylori infected population.

Role of nucleotide binding oligomerization domain-like receptor protein 3 inflammasome in stress-induced gastric injury.

BACKGROUND AND AIM: The inflammasomes promote pro-caspase-1 cleavage, leading to processing of pro-interleukin (IL)-1ß into its mature form. We investigated the role of the IL-1ß and nucleotide binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome in gastric injury in mice receiving water-immersion restraint stress (WIRS), focusing on the cyclooxygenase (COX)-2/prostaglandin (PG) E2 axis. METHODS: To induce gastric injury, the mice were placed in a restraint cage and immersed in the water bath to the level of the xiphoid process. Protein levels of mature caspase-1 and IL-1ß were assessed by western blotting. RESULTS: Water-immersion restraint stress induced gastric injury with increase in IL-1ß expression by activation of NLRP3 inflammasome. Exogenous IL-1ß attenuated the injury, whereas anti-IL-1ß neutralizing antibody and IL-1ß receptor antibody aggravated it. NLRP3-/- and caspase-1-/- mice enhanced the injury with reducing of mature IL-1ß, and this aggravation was reduced by exogenous IL-1ß supplementation. Toll-like receptor 4-/- mice were hyporesponsive to WIRS in terms of mature IL-1ß production. Rabeprazole attenuated the injury with preventing inflammasome activation. WIRS injured the stomach with promotion of COX-2 mRNA and PGE2 production, and exogenous IL-1ß enhanced these molecules, while IL-1ß immunoneutralization exerted opposite effect. PGE2 supplementation abolished the hypersensitivity in NLRP3-/- and caspase-1-/- mice through negative regulation of inflammatory cytokines. CONCLUSION: These results suggest that NLRP3 inflammasome-derived IL-1ß plays a protective role in stress-induced gastric injury via activation of the COX-2/PGE2 axis. Toll-like receptor 4 signaling and gastric acid may be involved in NLRP3 inflammasome activation.

Sustained Helicobacter pylori infection accelerates gastric dysplasia in a mouse model.

More than 80% of gastric cancer is attributable to stomach infection with Helicobacter pylori (Hp). Gastric preneoplastic progression involves sequential tissue changes, including loss of parietal cells, metaplasia and dysplasia. In transgenic mice, active KRAS expression recapitulates these tissue changes in the absence of Hp infection. This model provides an experimental system to investigate additional roles of Hp in preneoplastic progression, beyond its known role in initiating inflammation. Tissue histology, gene expression, the immune cell repertoire, and metaplasia and dysplasia marker expression were assessed in KRAS+ mice +/-Hp infection. Hp+/KRAS+ mice had severe T-cell infiltration and altered macrophage polarization; a different trajectory of metaplasia; more dysplastic glands; and greater proliferation of metaplastic and dysplastic glands. Eradication of Hp with antibiotics, even after onset of metaplasia, prevented or reversed these tissue phenotypes. These results suggest that gastric preneoplastic progression differs between Hp+ and Hp- cases, and that sustained Hp infection can promote the later stages of gastric preneoplastic progression.

Self-Emulsifying Drug Delivery System of Celecoxib for Avoiding Delayed Oral Absorption in Rats with Impaired Gastric Motility.

This study aimed to develop a self-emulsifying drug delivery system (SEDDS) of celecoxib (CEL) for suppressed delay in oral absorption under impaired gastric motility. A pseudo-ternary phase diagram was constructed for the determination of the optimal component ratio in SEDDS of CEL (SEDDS/CEL), and the SEDDS/CEL was physicochemically characterized. A pharmacokinetic study on orally dosed CEL samples (5-mg CEL/kg) was carried out in normal and propantheline (PPT)-treated rats to mimic impaired gastric motility. SEDDS/CEL rapidly formed a fine emulsion with a mean size of 147 nm in distilled water and significantly improved the dissolution behavior of CEL under pH 1.2 condition with a 20-fold higher dissolved amount than crystalline CEL. In normal rats, orally dosed SEDDS/CEL provided a 4.6-fold higher systemic exposure than that of crystalline CEL, due to the improved dissolution properties of CEL. Crystalline CEL showed delayed and decreased oral absorption of CEL in PPT-treated rats as evidenced by a 6.9-h-delayed mean absorption time and only 12% of the systemic exposure of CEL compared with those in normal rats. In contrast, SEDDS/CEL enhanced the oral absorption of CEL with a 14.6-fold higher systemic exposure with significant suppression of delay in absorption than crystalline CEL even in PPT-treated rats. SEDDS/CEL could be an efficacious option for suppressing delay in CEL absorption even under impairment of gastric motility, possibly leading to rapid and reproducible management of severe acute pain.

Transcriptomic Changes in the Rumen Epithelium of Cattle after the Induction of Acidosis.

The transition from normal forage to a highly fermentable diet to achieve rapid weight gain in the cattle industry can induce ruminal acidosis. The molecular host mechanisms that occur in acidosis are largely unknown. Therefore, the histology and transcriptome profiling of rumen epithelium was investigated in normal and acidosis animals to understand the molecular mechanisms involved in the disease. The rumen epithelial transcriptome from acidosis (n=3) and control (n=3) Holstein steers was obtained using RNA-sequencing. The mean values of clean reads were 70,975,460&plusmn;984,046 and 71,142,189&plusmn;834,526 in normal and acidosis samples, respectively. In total, 1,074 differentially expressed genes were identified in the two groups (P&lt;0.05), of which 624 and 450 genes were up- and down-regulated in the acidosis samples, respectively. Functional analysis indicated that the majority of the up-regulated genes had a function in filament organization, positive regulation of epithelial and muscle fiber concentration, biomineral tissue development, negative regulation of fat cell differential, regulation of ion transmembrane transport, regulation of cell adhesion and butyrate, as well as short-chain fatty acid absorption that was metabolized as an energy source. Functional analysis of the down-regulated genes revealed effects in immune response, positive regulation of T-cell migration, regulation of metabolic processes, and localization. Furthermore, the results showed a differential expression of genes involved in the Map Kinase and Toll-like receptor signaling pathways. The IL1B, CXCL5, IL36A, and IL36B were significantly down-regulated in acidosis rumen tissue samples. The results suggest that rapid shifts to rich fermentable carbohydrates diets cause an increase in the concentration of ruminal volatile fatty acids, tissue damage, and significant changes in transcriptome profiles of rumen epithelial.

John Goodsir: discovering Sarcina ventriculi and diagnosing Darwin's dyspepsia.

In 1842, when John Goodsir was Conservator to the Museum of the RCSEd, he saw a 19-year-old male patient who vomited a large volume of acidic, fermented-smelling, watery fluid every morning. Under his microscope, Goodsir found the vomitus to be populated with a micro-organism he named Sarcina ventriculi, which he considered to be causative. In so-doing, Goodsir became one of the first people to link a specific micro-organism with a disease. Goodsir recommended small doses of creosote as an antiseptic and claimed that the boy was eventually cured of the vomiting condition. In August of 1863 Charles Darwin was hugely celebrated by the scientific community and the public, but he had suffered from severe stomach problems all his adult life and at this point, he was vomiting daily. He read Goodsir's paper and contacted him and asked if he could send some vomitus samples to Edinburgh in the hope that Goodsir might find Sarcina in it and solve the mystery of his debilitating stomach symptoms and perhaps cure them with creosote. Goodsir examined samples in his microscope, but failed to find Sarcina. Sadly, Darwin went on to suffer constantly from severe stomach problems, recently attributed to lactose intolerance, until he died in 1882, some 20 years later.

Prophylactic effect of Lactobacillus plantarum KSFY06 on HCl/ethanol-induced gastric injury in mice.

The present study was conducted to determine the prophylactic effect of Lactobacillus plantarum KSFY06 (LP-KSFY06) on HCl/ethanol-induced gastric injury in Kunming mice. The experimental mice were allocated into six groups: the normal group, HCl/ethanol treated group, HCl/ethanol + ranitidine treated group, HCl/ethanol + Lactobacillus delbrueckii subsp. Bulgaricus (LB) treated group, HCl/ethanol + low concentration of Lactobacillus plantans KSFY06 (LP-KSFY06-L) treated group, and HCl/ethanol + high concentration of Lactobacillus plantans KSFY06 (LP-KSFY06-H) treated group. The changes in daily body weight and food intake of the mice in the HCl/ethanol + LP-KSFY06-H treated group were the closest to those of the HCl/ethanol + ranitidine treated and normal groups. LP-KSFY06 significantly inhibited the formation of gastric mucosal lesions, reduced the area of gastric lesions, inhibited gastric-juice secretion, and increased pH compared with the HCl/ethanol treated group. After the treatment, the serum interleukin-6 (IL)-6, IL-12, tumor necrosis factor-α (TNF-α), and interferon-γ levels and the gastric-tissue IL-6 and IL-12 levels in the LP-KSFY06 (including LP-KSFY06-L and LP-KSFY06-H) group decreased compared with those in the HCl/ethanol treated group. The level of serum and gastric tissue malondialdehyde was lower and the nitric oxide, total superoxide dismutase, and glutathione activities in the LP-KSFY06 treated mice were higher than those in the HCl/ethanol treated mice. Quantitative polymerase chain reaction analysis and western blot analysis showed that LP-KSFY06 increased the mRNA and protein expression of the epidermal growth factor, epidermal growth factor receptor, vascular endothelial growth factor, inhibitor kappaB-α, neuronal nitric oxide synthase, and endothelial NOS and reduced the mRNA and protein expression of nuclear factor kappaB, inducible NOS, cyclooxygenase-2, TNF-α, and IL-1ß in gastric tissues compared with the HCl/ethanol treated mice. These experimental results showed that a high concentration (1.0 × 109 CFU per kg B.W.) of LP-KSFY06 had a stronger effect on preventing gastric injury than a low concentration (1.0 × 108 CFU per kg B.W.) of LP-KSFY06. These results suggest that LP-KSFY06 has a potential probiotic effect in preventing gastric injury.

Infiltration of Immunoinflammatory Cells and Related Chemokine/Interleukin Expression in Different Gastric Immune Microenvironments.

Gastric mucosal immune microenvironment plays an important role in the occurrence and development of diseases such as inflammation and cancer. In the present study, single-sample gene set enrichment analysis (ssGSEA) was used to evaluate the expression of cytokines and the degree of immune cell infiltration in four different gastric mucosa tissues from normal gastric mucosa, simple gastritis, and atrophic gastritis to gastric cancer. Here, we show the immune microenvironments of these four gastric mucosae were significantly different. From inflammation to gastric cancer, most immunoinflammatory cells showed a downward trend such as central memory CD4 T cell. Instead, several cells showed an upward trend such as macrophage. Additionally, we found some chemokines/interleukins were illustrated to be low expressed (or highly expressed) in precancerous stage and highly expressed (or low expressed) in postcancerous stage, which demonstrated an opposite expression characteristic in pre-/postcancerous stage.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.