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Gastric acid-related disorders are commonly encountered in clinical practice. Acetylcholine, gastrin, and histamine are physiological agonists that stimulate acid secretion from parietal cells. Histamine plays a decisive role in the transformation of parietal cells into acid-secreting forms. The H+, K+- ATPase proton pump, which represents the final step of acid secretion, translocates from cytoplasmic tubulovesicles to secretory canaliculi upon parietal cell stimulation and facilitates exchange of intracellular H+ with extracellular K+ in a 1:1 ratio. Histamine-2 receptor antagonists and proton pump inhibitors (PPIs) are widely used in clinical practice, and potassium-competitive acid blockers (P-CABs) have gained attention in recent times. P-CABs address the unmet needs of patients who receive conventional PPIs and have broadened the spectrum of drug choices; however, further research is warranted to confirm long-term safety of these drugs. Comprehensive understanding of the mechanisms of actions, characteristics, advantages and disadvantages, and the adverse effect profile is essential for appropriate prescription of gastric acid-suppressive drugs. In this review, we provide a developing history and outline the pharmacological mechanisms underlying various gastric acid-suppressive drugs used in clinical settings.
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Patients frequently report that stress causes or exacerbates gastrointestinal (GI) symptoms, indicating a functional relationship between the brain and the GI tract. The brain and GI tract are closely related embryologically and functionally, interacting in various ways. The concept of the brain–gut axis was originally established in the 19th and early 20th centuries based on physiological observations and experiments conducted in animals and humans. In recent years, with the growing recognition that gut microbiota plays a vital role in human health and disease, this concept has been expanded to the brain–gut–microbiota axis. The brain influences the motility, secretion, and immunity of the GI tract, with consequent effects on the composition and function of the gut microbiota. On the other hand, gut microbiota plays an essential role in the development and function of the brain and enteric nervous system. Although knowledge of the mechanisms through which the gut microbiota influences distant brain function is incomplete, studies have demonstrated communication between these organs through the neuronal, immune, and endocrine systems. The brain–gut–microbiota axis is an essential aspect of the pathophysiology of functional GI disorders such as irritable bowel syndrome, and is also involved in other GI diseases, including inflammatory bowel disease. This review summarizes the evolving concept of the brain–gut–microbiota axis and its implications for GI diseases, providing clinicians with new knowledge to apply in clinical practice.
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BACKGROUND/OBJECTIVES@#Consumption of certain protective foods may help inhibit Helicobacter pylori (H. pylori) associated gastric pathologies. However, studies conducted to assess the efficacy of protective foods in H. pylori-infected subjects are either limited or inconsistent. This study evaluated the association of individual or a combination of protective foods on the incidence of gastric cancer (GC) in H. pylori-positive subjects through a casecontrol study.MATERIALS/METHODS: Subjects aged 20–79 years were selected from 2 hospitals between December 2002 and September 2006. In total, 134 patients and 212 controls tested positive for H. pylori infection. Among these, we included 82 pairs of cases and controls matched by sex, age (± 5 years), enrollment period (± 1 years), and hospital. @*RESULTS@#A higher intake of soy products was associated with a significantly lower risk of GC than a lower intake of soy products (odds ratio [OR] = 0.37, 95% confidence interval [CI] = 0.14–0.96). Additionally, a higher fruit intake resulted in a significantly lower risk of GC than a lower fruit intake (OR = 0.35, 95% CI = 0.13–0.94). A combination of food groups was evaluated, and a lower risk of GC was observed with a high intake of both soy products and fruits (OR = 0.20, 95% CI = 0.06–0.67), high intake of soy and dairy products (OR = 0.28, 95% CI = 0.10–0.78) and high intake of fruits and dairy products (OR = 0.28, 95% CI = 0.09–0.83). @*CONCLUSIONS@#A high intake of soy products or fruits was associated with a lower risk of GC.A combination of soy products or fruits with dairy products was associated with a lower risk of GC. A balanced intake of soy products, fruits, and dairy products may help reduce GC risk.
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Gastrointestinal (GI) prokinetic agents are drugs that increase GI motility and promote the movement of contents in the GI tract by amplifying and controlling the contraction of GI smooth muscle. Currently used prokinetics increase GI motility by acting as a dopamine D2 receptor antagonist (e.g., metoclopramide, domperidone, levosulpiride) and 5-HT4 receptor agonist (e.g., mosapride, prucalopride). Some prokinetics also have a cholinesterase inhibitory property (e.g., itopride), and herb-derived prokinetics (e.g., motilitone) affect multiple receptors. Depending on the type and distribution of receptors on which the prokinetics bind, the effect(s) may be regional or throughout the GI tract. Most prokinetics have been used for functional dyspepsia and gastroparesis because they mainly affect upper GI motility. However, prucalopride, a highly selective 5-HT4 receptor agonist, is used primarily to treat chronic constipation and pseudo-obstruction. Dopamine D2 receptor antagonists also inhibit the D2 receptor in the medulla oblongata chemoreceptor trigger zone; therefore, they can treat nausea and vomiting. However, short term use of dopamine D2 antagonists at an appropriate dose is recommended because of their potential for central nervous system side effects by penetrating the blood-brain barrier. It is necessary to know the mechanism of action, each clinical trial’s characteristics, and the side effects of prokinetics to obtain the best clinical outcomes. This article aims to summarize the results of clinical studies related to the impact of currently available prokinetic agents in Korea on GI motility.
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Sensory Guillain-Barré syndrome (GBS) is a rare heterogeneous subgroup of GBS characterized by the primary involvement of sensory neurons resulting in a distinctive clinical presentation. Sensory GBS usually occurs with acute and monophasic sensory symptoms, and no or minimal muscle weakness. Sensory GBS patient show hypo- or areflexia, distal paresthesia, and normal cerebrospinal fluid finding or albumino-cytologic dissociation which are suggesting that these conditions are a GBS variant. Autonomic dysfunctions have rarely been reported in sensory GBS patient presenting with postural hypotension, abnormal heart rate response to respiration. In this case, we demonstrate a patient with autonomic symptoms dominant sensory GBS in systemic lupus erythematosus.
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KRAS activating mutations, which are present in more than 90% of pancreatic cancers, drive tumor dependency on the RAS/ mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT signaling pathways. Therefore, combined targeting of RAS/MAPK and PI3K/AKT signaling pathways may be required for optimal therapeutic effect in pancreatic cancer.However, the therapeutic efficacy of combined MAPK and PI3K/AKT signaling target inhibitors is unsatisfactory in pancreatic cancer treatment, because it is often accompanied by MAPK pathway reactivation by PI3K/AKT inhibitor. Therefore, we developed an inRas37 antibody, which directly targets the intra-cellularly activated GTP-bound form of oncogenic RAS mutation and investigated its synergistic effect in the presence of the PI3K inhibitor BEZ-235 in pancreatic cancer. In this study, inRas37 remarkably increased the drug response of BEZ-235 to pancreatic cancer cells by inhibiting MAPK reactivation. Moreover, the co-treatment synergistically inhibited cell proliferation, migration, and invasion and exhibited synergistic anticancer activity by inhibiting the MAPK and PI3K pathways. The combined administration of inRas37and BEZ-235 significantly inhibited tumor growth in mouse models. Our results demonstrated that inRas37 synergistically increased the antitumor activity of BEZ-235 by inhibiting MAPK reactivation, suggesting that inRas37 and BEZ-235 co-treatment could be a potential treatment approach for pancreatic cancer patients with KRAS mutations.
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Purpose@#Owing to differences in the general characteristics of gastric cancer (GC) according to histological type, the association of GC risk factors, such as diet, may also differ depending on the histological type. We investigated the associations between individual and combined intake of soy products, vegetables, and dairy products and GC mortality by following up cases of death among Korean GC cases and whether these associations differ according to the histological type. @*Materials and Methods@#A total of 508 GC cases were enrolled from two hospitals between 2002 and 2006. Their survival or death was prospectively followed up until December 31, 2016, through a review of medical records and telephonic surveys. Finally, 300 GC cases classified as intestinal- or diffuse-type GC cases were included. The median follow-up period was 7.1 years. @*Results@#In the fully adjusted model, a high intake of soy products (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.19–0.96) and the combination of soy products and vegetables (HR, 0.34; 95% CI, 0.12–0.96) or soy products and dairy products (HR, 0.37; 95% CI, 0.14–0.98) decreased the mortality from intestinal-type GC. In particular, patients consuming various potentially protective foods (HR, 0.23; 95% CI, 0.06–0.83) showed a highly significant association with a lower mortality from intestinal-type GC. However, no significant association was found with diffuse-type GC. @*Conclusions@#High intake of potentially protective foods, including soy products, vegetables, and dairy products, may help increase survival in intestinal-type GC.
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Eradication of Helicobacter pylori has contributed to the treatment of peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Moreover, it has possibly decreased the prevalence of gastric cancer. However, eradication therapy is associated with various adverse effects, of which diarrhea is the most common. The incidence of diarrhea after eradication treatment varies from 8% to 48%. In particular, the incidence is higher in patients who receive first-line standard triple therapy compared with those who receive second-line therapy. Both antibiotics and proton pump inhibitors, components of eradication therapy, have short-term and long-term impacts on gut microbiota. The alterations of gut microbiota may not recover until 1 year after eradication therapy. Most cases of diarrhea that occur after eradication therapy are antibiotic-associated diarrhea caused by the destruction of the normal gut microbiota. In some cases, Clostridioides difficile-associated diarrhea occurs after eradication therapy. If bloody diarrhea occurs after eradication therapy and the Clostridioides difficile toxin is not detected, antibiotic-associated hemorrhagic colitis associated with Klebsiella oxytoca infection should be suspected. It is crucial to explain the possibility of diarrhea before initiating eradication therapy to increase compliance. Furthermore, probiotics may be administered to reduce diarrhea. If severe diarrhea or symptoms other than the usual antibiotic-associated diarrhea occur during or after eradication therapy, antibiotics should be discontinued. In addition, appropriate tests to determine the cause of diarrhea should be performed. This review summarizes the alteration of the gut microbiota, the causes of diarrhea after Helicobacter pylori eradication therapy, and its management.
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Background/Aims@#Studies in healthy humans have reported that the addition of mosapride to acid suppressants resulted in higher intragastric pH than acid suppressant administration alone. We investigated the effect of the addition of mosapride to famotidine on the intragastric pH and gastric emptying rate (GER) in rats. @*Materials and Methods@#Sixty male Wistar rats were used in this study. Experimental groups were divided into control, famotidine-only, mosapride-only, and famotidine with mosapride (combination). The first experiment was performed in non-stressed rats. Mosapride was administered by oral gavage 1 hour before the meal, and famotidine was administered just before the meal. The rats were provided with food for 30 minutes. The intragastric pH was measured under isoflurane anesthesia, and the GER was measured after harvesting the stomach. In the stress experiment, rats were exposed to 1-hour restraint stress immediately after mosapride administration and subjected to the same process as in the experiment with the non-stressed rats. @*Results@#The famotidine-only and combination groups showed significantly higher gastric pH levels than the control group in non-stressed (P<0.01 and P<0.001, respectively) and stressed (P<0.001 and P<0.001, respectively) rats. The combination group also showed significantly higher intragastric pH levels than the famotidine-only group in non-stressed (P<0.01) and stressed (P<0.05) rats. Additionally, combination groups showed a significantly higher GER than the famotidine-only group in non-stressed (P<0.001) and stressed (P<0.01) rats. @*Conclusions@#The combination of mosapride with famotidine significantly increased intragastric pH compared to famotidine alone in the non-stressed and stressed rats.
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Background/Aims@#The incidence of peptic ulcer disease has decreased in past decades; however, the trends in peptic ulcer bleeding (PUB) are inconsistent among regions. This study aimed to investigate the trends in PUB incidence and the effect of risk factors on PUB in Korea. @*Methods@#The records of patients hospitalized with PUB from 2006 to 2015 were retrieved from the Korean National Health Insurance Service Database. Standardized incidences of PUB were calculated, and the clinical characteristics such as age, sex, Helicobacter pylori infection, drug exposure, comorbidities, and mortality were obtained. @*Results@#In total, 151,507 hospitalizations with PUB were identified. The overall annual hospitalization rate was 34.98 per 100,000 person-years. The incidence of PUB showed no significant change from 2006 to 2008 and decreased from 2008 to 2015, with an annual change of –2.7% (p<0.05); however, this change was only significant in men. The incidence of PUB was higher in men than in women between 40 and 70 years old and higher in women than in men older than 80 years. From 2006 to 2015, the H. pylori infection rate increased significantly in patients with PUB;however, there was no significant change in exposure to nonsteroidal anti-inflammatory drugs or other drugs that increase the risk of PUB. @*Conclusions@#Over the past decade, the incidence of PUB has decreased in a sex-specific manner. There has been a decreasing trend in the H. pylori infection rate and no change in exposure to drugs that increase the risk of PUB in Korea.
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Eradication of Helicobacter pylori has contributed to the treatment of peptic ulcers and mucosa-associated lymphoid tissue lymphoma. Moreover, it has possibly decreased the prevalence of gastric cancer. However, eradication therapy is associated with various adverse effects, of which diarrhea is the most common. The incidence of diarrhea after eradication treatment varies from 8% to 48%. In particular, the incidence is higher in patients who receive first-line standard triple therapy compared with those who receive second-line therapy. Both antibiotics and proton pump inhibitors, components of eradication therapy, have short-term and long-term impacts on gut microbiota. The alterations of gut microbiota may not recover until 1 year after eradication therapy. Most cases of diarrhea that occur after eradication therapy are antibiotic-associated diarrhea caused by the destruction of the normal gut microbiota. In some cases, Clostridioides difficile-associated diarrhea occurs after eradication therapy. If bloody diarrhea occurs after eradication therapy and the Clostridioides difficile toxin is not detected, antibiotic-associated hemorrhagic colitis associated with Klebsiella oxytoca infection should be suspected. It is crucial to explain the possibility of diarrhea before initiating eradication therapy to increase compliance. Furthermore, probiotics may be administered to reduce diarrhea. If severe diarrhea or symptoms other than the usual antibiotic-associated diarrhea occur during or after eradication therapy, antibiotics should be discontinued. In addition, appropriate tests to determine the cause of diarrhea should be performed. This review summarizes the alteration of the gut microbiota, the causes of diarrhea after Helicobacter pylori eradication therapy, and its management.
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Background/Aims@#Studies in healthy humans have reported that the addition of mosapride to acid suppressants resulted in higher intragastric pH than acid suppressant administration alone. We investigated the effect of the addition of mosapride to famotidine on the intragastric pH and gastric emptying rate (GER) in rats. @*Materials and Methods@#Sixty male Wistar rats were used in this study. Experimental groups were divided into control, famotidine-only, mosapride-only, and famotidine with mosapride (combination). The first experiment was performed in non-stressed rats. Mosapride was administered by oral gavage 1 hour before the meal, and famotidine was administered just before the meal. The rats were provided with food for 30 minutes. The intragastric pH was measured under isoflurane anesthesia, and the GER was measured after harvesting the stomach. In the stress experiment, rats were exposed to 1-hour restraint stress immediately after mosapride administration and subjected to the same process as in the experiment with the non-stressed rats. @*Results@#The famotidine-only and combination groups showed significantly higher gastric pH levels than the control group in non-stressed (P<0.01 and P<0.001, respectively) and stressed (P<0.001 and P<0.001, respectively) rats. The combination group also showed significantly higher intragastric pH levels than the famotidine-only group in non-stressed (P<0.01) and stressed (P<0.05) rats. Additionally, combination groups showed a significantly higher GER than the famotidine-only group in non-stressed (P<0.001) and stressed (P<0.01) rats. @*Conclusions@#The combination of mosapride with famotidine significantly increased intragastric pH compared to famotidine alone in the non-stressed and stressed rats.
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Men and women are different, but this difference has not been well reflected in clinical trials and preclinical studies of biomedical science. Gender medicine, which systematically analyzes research results according to sex and gender, has been emphasized to overcome this problem. On the other hand, researchers still have difficulty in applying gender medicine to their research. To perform rigorous gender medicine, using correct terms, a thorough literature review during research planning, appropriate statistical analysis and reporting, and cautious interpretation of the results are necessary. Applying gender medicine will increase the reproducibility of studies, promote discoveries, expand the study relevance, and ultimately improve patient care in both men and women. Here, this study reviewed the practical issues on applying gender medicine to both preclinical and clinical studies in the field of biomedical science.
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Background/Aims@#Gastroparesis is identified as a subject that is understudied in Asia. The scientific committee of the Asian Neurogastroenterology and Motility Association performed a Knowledge, Attitude, and Practices survey on gastroparesis among doctors in Asia. @*Methods@#The questionnaire was created and developed through a literature review of current gastroparesis works of literature by the scientific committee of Asian Neurogastroenterology and Motility Association. @*Results@#A total of 490 doctors from across Asia (including Bangladesh, China, Hong Kong, Indonesia, Japan, Malaysia, Myanmar, the Philippines, Singapore, South Korea, Taiwan, Thailand, and Vietnam) participated in the survey. Gastroparesis is a significant gastrointestinal condition. However, a substantial proportion of respondents was unable to give the correct definition and accurate diagnostic test. The main reason for lack of interest in diagnosing gastroparesis was “the lack of reliable diagnostic tests” (46.8%) or “a lack of effective treatment” (41.5%). Only 41.7% of respondents had access to gastric emptying scintigraphy. Most doctors had never diagnosed gastroparesis at all (25.2%) or diagnosed fewer than 5 patients a year (52.1%). @*Conclusions@#Gastroparesis can be challenging to diagnose due to the lack of instrument, standardized method, and paucity of research data on normative value, risk factors, and treatment studies in Asian patients. Future strategies should concentrate on how to disseminate the latest knowledge of gastroparesis in Asia. In particular, there is an urgent need to estimate the magnitude of the problems in high risk and idiopathic patients as well as a standardized diagnostic procedure in Asia.
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Background/Aims@#The gut microbiota regulates intestinal immune homeostasis through host-microbiota interactions. Multiple factors affect the gut microbiota, including age, sex, diet, and use of drugs. In addition, information on gut microbiota differs depending on the samples.The aim of this study is to investigate whether changes in cecal microbiota depend on aging. @*Methods@#Gut microbiota in cecal contents of 6-, 31-, and 74-week-old and 2-year-old male Fischer-344 rats (corresponding to 5-, 30-, 60-, and 80-year-old humans in terms of age) were analyzed using 16S ribosomal RNA metagenome sequencing and phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) based on the Kyoto Encyclopedia of Genes and Genomes orthology.Moreover, short-chain fatty acid (SCFA) level in cecum and inflammation related factors were measured using real-time quantitative polymerase chain reaction and enzyme linked immunosorbent assay. @*Results@#Alpha and beta diversity did not change significantly with age. At the family level, Lachnospiraceae and Ruminococcaceae, which produce SCFAs, showed significant change in 31-week-old rats: Lachnospiraceae significantly increased at 31 weeks of age, compared to other age groups, while Ruminococcaceae decreased. Butyrate levels in cecum were significantly increased in 31-week-old rats, and the expression of inflammation related genes was increased followed aging. Especially, EU622775_s and EU622773_s, which were highly abundance species in 31-week-old rats, showed significant relationship with butyrate concentration. Enzymes required for producing butyrate—acetyl-CoA transferase, butyryl-CoA dehydrogenase, and butyrate kinase—were not predicted by PICRUSt. @*Conclusions@#Major bacterial taxa in the cecal lumen, such as Lachnospiraceae, well-known SCFAs-producing family, changed in 31-week-old rats.Moreover, unknown species EU622775_s and EU622773_s showed strong association with cecal butyrate level at 31 weeks of age.
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Background/Aims@#This study aimed to characterize the changes in the gut microbiota of irritable bowel syndrome (IBS) patients and to investigate the consequent alterations in bacterial functions. @*Methods@#We performed 16S rRNA metagenomic sequencing and a phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt) analyses using fecal samples from control (n=12) and diarrhea-dominant IBS patients (n=7). @*Results@#The samples were clustered by the principal coordinates analysis depending on the presence of IBS (p=0.003). In the IBS patients, the abundances of Acidaminococcaceae, Sutterellaceae, and Desulfovibrionaceae were significantly increased, while those of Enterococcaceae, Leuconostocaceae, Clostridiaceae, Peptostreptococcaceae, and Lachnospiraceae were significantly decreased. The PICRUSt results indicated that two orthologues involved in secondary bile acid biosynthesis were significantly decreased in IBS patients. Modules involved in multidrug resistance, lipopolysaccharide biosynthesis, the reductive citrate cycle, and the citrate cycle were significantly increased in the IBS patients. In contrast, modules involved in cationic antimicrobial peptide resistance, and some transport systems were more abundant in controls than in IBS patients. @*Conclusions@#Changes in the gut microbiota composition in IBS patients lead to alterations in bacterial functions, such as bile acid transformation and the induction of inflammation, which is a known pathophysiological mechanism of IBS.
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Background/Aims@#The incidence of peptic ulcer disease has decreased in past decades; however, the trends in peptic ulcer bleeding (PUB) are inconsistent among regions. This study aimed to investigate the trends in PUB incidence and the effect of risk factors on PUB in Korea. @*Methods@#The records of patients hospitalized with PUB from 2006 to 2015 were retrieved from the Korean National Health Insurance Service Database. Standardized incidences of PUB were calculated, and the clinical characteristics such as age, sex, Helicobacter pylori infection, drug exposure, comorbidities, and mortality were obtained. @*Results@#In total, 151,507 hospitalizations with PUB were identified. The overall annual hospitalization rate was 34.98 per 100,000 person-years. The incidence of PUB showed no significant change from 2006 to 2008 and decreased from 2008 to 2015, with an annual change of –2.7% (p<0.05); however, this change was only significant in men. The incidence of PUB was higher in men than in women between 40 and 70 years old and higher in women than in men older than 80 years. From 2006 to 2015, the H. pylori infection rate increased significantly in patients with PUB;however, there was no significant change in exposure to nonsteroidal anti-inflammatory drugs or other drugs that increase the risk of PUB. @*Conclusions@#Over the past decade, the incidence of PUB has decreased in a sex-specific manner. There has been a decreasing trend in the H. pylori infection rate and no change in exposure to drugs that increase the risk of PUB in Korea.
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Background/Aims@#Effect of proton pump inhibitor (PPI) use on the risk of hipfracture is controversial. This study aimed to clarify the association between PPIuse and hip fracture risk using a large cohort. @*Methods@#This study recruited participants from the nationwide cohort (n =1,025,340). After exclusion of participants who had hip fractures or were aged less than 40 years during the baseline period (2002 to 2004), 371,806 participants were followed to 2013. Participants prescribed PPIs for more than 90 days during baseline period were defined as users. Fracture cases were defined when participants were hospitalized with claims of a hip fracture. @*Results@#During 4,159,343 person-years of follow-up, fractures developed more oftenin PPI users than in nonusers (relative risk [RR], 1.787; 95% confidence interval [CI], 1.260 to 2.534; p = 0.002). The results persisted after adjusting for age, sex, andmany drugs relevant to osteoporosis or influential in bone health. Furthermore,fracture risk associated with PPI use increased with duration of use ( p trend 180-day users. The positive association between PPI use and fracture was also confirmed in a subgroup with health screening data where further adjustment for body mass index, smoking status, alcohol consumption, and physical activity was available (adjusted RR, 2.025; 95% CI, 1.151 to 3.564, p = 0.014). Conclusions: PPI use is associated with hip fracture development.
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