Correlation of Probe-Based Confocal Laser Endomicroscopy (pCLE) and Mucosal Integrity Testing (MIT) with Epithelial Barrier Function and Presence of Gastroesophageal Reflux Disease (GERD).

INTRODUCTION: Epithelial barrier function (EBF) disruption is a key mechanism underlying gastroesophageal reflux disease (GERD). Our aim was to assess whether two novel technologies, probe-based confocal laser endomicroscopy (pCLE) and mucosal integrity testing (MIT), could assess EBF. METHODS: We prospectively enrolled patients undergoing upper endoscopy for refractory GERD or non-GERD conditions. Patients underwent esophagogastroduodenoscopy, pCLE, MIT, esophageal biopsy at 2 cm and 6 cm above the esophagogastric junction, and wireless pH testing. To assess EBF in vitro, biopsies were mounted in a mini-Ussing chamber, 1 ml of fluorescein was instilled on the mucosal side, and concentration of fluorescein on the serosal side was measured at 3 h. RESULTS: We enrolled 54 subjects (28 GERD, 26 non-GERD based on Lyon consensus criteria). In vivo permeability assessed by pCLE did not differ significantly between GERD vs. non-GERD patients and did not correlate with in vitro permeability. Mean MIT at 2 cm was lower in GERD compared to non-GERD (1914 vs. 3727 ohms). MIT correlated inversely with in vitro permeability at 2 cm and at 6 cm. Using a predictive model that used slope and intercept of MIT at 2 cm and 6 cm, sensitivity and specificity of MIT at identifying GERD was 76% and 72%, respectively. CONCLUSION: pCLE did not differentiate GERD vs non-GERD and did not correlate with EBF measured in vitro. MIT, on the other hand, may be more promising as it differentiated GERD vs non-GERD and correlated with EBF measured in vitro.

Proton pump inhibitors: misconceptions and proper prescribing practice.

PURPOSE OF REVIEW: The current review summarizes and attempts to place in proper perspective the past year's literature regarding purported adverse effects of proton pump inhibitors (PPIs). RECENT FINDINGS: Although generally considered safe, physicians are inundated with retrospective database-driven epidemiologic studies, and meta-analyses on the same studies, claiming a panoply of serious adverse effects associated with long-term use of PPIs. The quality of the evidence underlying most of these associations is very low and cannot ascribe cause and effect. Nonetheless, these reports have stoked fears, in both prescribers and patients. As a result, patients are being harmed. Physicians are not prescribing PPIs when medically indicated and patients are stopping PPIs without consulting their caregivers. It is reassuring that a cross-sectional analysis of data from the National Ambulatory Medical Care Survey as well as a double-blinded, placebo-controlled trial report no safety concerns with PPIs, other than a possible small association with enteric infection. SUMMARY: Most of the publicized serious putative adverse effects attributed to PPIs have been debunked in more recent and properly designed studies. Nevertheless, PPIs should be prescribed for valid indications and, when prescribed long-term, they should be used at the lowest effective dose and their ongoing need periodically assessed.

Proton pump inhibitors: placing putative adverse effects in proper perspective.

PURPOSE OF REVIEW: This review summarizes the past year's literature, both clinical and basic science, regarding potential adverse effects of proton pump inhibitors (PPIs). RECENT FINDINGS: PPIs are amongst the most widely prescribed and over-prescribed medications worldwide. Although generally considered well tolerated, epidemiologic studies that mine large databases have reported a panoply of putative adverse effects associated with PPIs. It should be emphasized that the quality of the evidence underlying most of these associations is very low and the studies, by design, cannot ascribe cause and effect. These associations continue to be sensationalized in the media and misinterpreted by providers and patients. The unintended consequences are that patients who require PPIs, such as those taking dual antiplatelet agents, are not being prescribed or taking these necessary medications. In addition, physicians are spending an inordinate amount of additional time placing these findings into proper perspective for their patients and reassuring them upon initiating PPI treatment as well as at every follow-up visit. SUMMARY: Most of the recent publicized putative serious adverse effects attributed to PPIs rely on observational data and have not been confirmed in prospective randomized trials. Nevertheless, PPIs should be prescribed for valid indications and when prescribed long-term, they should be used at the lowest effective dose and the need for their use periodically reassessed.

Proton Pump Inhibitor Initiation and Withdrawal affects Gut Microbiota and Readmission Risk in Cirrhosis.

OBJECTIVES: Cirrhosis is associated with gut microbial dysbiosis, high readmissions and proton pump inhibitor (PPI) overuse, which could be inter-linked. Our aim was to determine the effect of PPI use, initiation and withdrawl on gut microbiota and readmissions in cirrhosis. METHODS: Four cohorts were enrolled. Readmissions study: Cirrhotic inpatients were followed throughout the hospitalization and 30/90-days post-discharge. PPI initiation, withdrawal/continuation patterns were analyzed between those with/without readmissions. Cross-sectional microbiota study: Cirrhotic outpatients and controls underwent stool microbiota analysis. Beneficial autochthonous and oral-origin taxa analysis vis-à-vis PPI use was performed. Longitudinal studies: Two cohorts of decompensated cirrhotic outpatients were enrolled. Patients on chronic unindicated PPI use were withdrawn for 14 days. Patients not on PPI were started on omeprazole for 14 days. Microbial analysis for oral-origin taxa was performed pre/post-intervention. RESULTS: Readmissions study: 343 inpatients (151 on admission PPI) were enrolled. 21 were withdrawn and 45 were initiated on PPI resulting in a PPI use increase of 21%. PPIs were associated with higher 30 (p = 0.002) and 90-day readmissions (p = 0.008) independent of comorbidities, medications, MELD and age. Cross-sectional microbiota: 137 cirrhotics (59 on PPI) and 45 controls (17 on PPI) were included. PPI users regardless of cirrhosis had higher oral-origin microbiota while cirrhotics on PPI had lower autochthonous taxa compared to the rest. Longitudinal studies: Fifteen decompensated cirrhotics tolerated omeprazole initiation with an increase in oral-origin microbial taxa compared to baseline. PPIs were withdrawn from an additional 15 outpatients, which resulted in a significant reduction of oral-origin taxa compared to baseline. CONCLUSIONS: PPIs modulate readmission risk and microbiota composition in cirrhosis, which responds to withdrawal. The systematic withdrawal and judicious use of PPIs is needed from a clinical and microbiological perspective in decompensated cirrhosis.

Helicobacter pylori-Induced Changes in Gastric Acid Secretion and Upper Gastrointestinal Disease.

Appropriate management of Helicobacter pylori infection of the human stomach is evolving and remains a significant clinical challenge. Acute infection results in hypochlorhydria, whereas chronic infection results in either hypo- or hyperchlorhydria, depending upon the anatomic site of infection. Acute hypochlorhydria facilitates survival of the bacterium and its infection of the stomach. Interestingly, most patients chronically infected with H. pylori manifest a pangastritis with reduced acid secretion due to bacterial virulence factors, inflammatory cytokines, and various degrees of gastric atrophy. While these patients are predisposed to develop gastric adenocarcinoma (~1%), there is increasing evidence from population studies that they are also protected from gastroesophageal reflux disease (GERD), Barrett's esophagus (BE), and esophageal adenocarcinoma (EAC). Eradication of H. pylori, in these patients, may provoke GERD in predisposed individuals and may be a contributory factor for the rising incidence of refractory GERD, BE, and EAC observed in Westernized societies. Only ~10% of chronically infected patients, mainly the young, manifest an antral predominant gastritis with increased acid secretion due to a decrease in somatostatin and increase in gastrin secretion; these patients are predisposed to develop peptic ulcer disease. H. pylori-induced changes in acid secretion, in particular hypochlorhydria, may allow ingested microorganisms to survive transit through the stomach and colonize the distal intestine and colon. Such perturbation of gut microbiota, i.e. dysbiosis, may influence human health and disease.

Adverse effects of proton pump inhibitors: fact or fake news?

PURPOSE OF REVIEW: The present review summarizes the past year's literature, both clinical and basic science, regarding potential adverse effects of proton pump inhibitors. RECENT FINDINGS: Proton pump inhibitors are amongst the most widely prescribed and overprescribed medications worldwide. Although generally considered well tolerated, epidemiologic studies mining large databases have reported a panoply of purported serious adverse effects associated with proton pump inhibitors, including chronic kidney disease, cognitive decline, myocardial infarction, stroke, bone fracture and even death. It should be noted that the quality of the evidence underlying these associations is very low and these studies, by design, cannot ascribe cause and effect. Nonetheless, these associations have been sensationalized in the media and misinterpreted by patients and providers. Unintended consequences of the fake news are that patients are not being prescribed and/or taking clinical guideline-recommended proton pump inhibitors to prevent and treat complications from gastroesophageal reflux disease and upper gastrointestinal bleeding precipitated by NSAIDs and dual antiplatelet therapies. In addition, physicians, who already have limited time to interact with their patients, are spending an inordinate amount of additional time placing these findings into proper perspective and reassuring their patients when initiating treatment as well as on every follow-up visit. SUMMARY: Most of the recent highly publicized serious adverse effects ascribed to proton pump inhibitors are not based on demonstrable evidence. Nevertheless, when proton pump inhibitors are prescribed long-term, they should be used at the lowest effective dose and the need for their use periodically reassessed.

Physiologic, pathophysiologic, and pharmacologic regulation of gastric acid secretion.

PURPOSE OF REVIEW: The present review summarizes the past year's literature, both clinical and basic science, regarding physiologic and pharmacologic regulation of gastric acid secretion in health and disease. RECENT FINDINGS: Gastric acid kills microorganisms, assists digestion, and facilitates absorption of iron, calcium, and vitamin B12. The main stimulants of acid secretion are the hormone gastrin, released from antral G cells; paracrine agent histamine, released from oxyntic enterochromaffin-like cells; and neuropeptide acetylcholine, released from antral and oxyntic intramural neurons. Gastrin is also a trophic hormone that participates in carcinogenesis. Helicobacter pylori may increase or decrease acid secretion depending upon the acuity and predominant anatomic focus of infection; most patients manifest hypochlorhydria. Despite the fact that proton pump inhibitors (PPIs) are amongst the most widely prescribed drugs, they are underutilized in patients at high risk for UGI bleeding. Although generally considered well tolerated, concerns have been raised regarding associations between PPI use and dementia, kidney disease, myocardial infarction, pneumonia, osteoporosis, dysbiosis, small bowel injury, micronutrient deficiency, and fundic gland polyps. SUMMARY: Our understanding of the physiologic, pathophysiologic, and pharmacologic regulation of gastric secretion continues to advance. Such knowledge is crucial for improved and safe management of acid-peptic disorders.

Gastric acid secretion.

PURPOSE OF REVIEW: The present review summarizes the past year's literature, both clinical and basic science, regarding neuroendocrine and intracellular regulation of gastric acid secretion and proper use of antisecretory medications. RECENT FINDINGS: Gastric acid kills microorganisms, modulates the gut microbiome, assists in digestion of protein, and facilitates absorption of iron, calcium, and vitamin B12. The main stimulants of acid secretion are gastrin, released from antral G cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Other stimulants include ghrelin, motilin, and hydrogen sulfide. The main inhibitor of acid secretion is somatostatin, released from oxyntic and antral D cells. Glucagon-like peptide-1 also inhibits acid secretion. Proton pump inhibitors (PPIs) reduce acid secretion and, as a result, decrease somatostatin and thus stimulate gastrin secretion. Although considered well tolerated drugs, concerns have been raised this past year regarding associations between PPI use and kidney disease, dementia, and myocardial infarction; the quality of evidence, however, is very low. SUMMARY: Our understanding of the physiology of gastric secretion and proper use of PPIs continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders.

Functional anatomy and physiology of gastric secretion.

PURPOSE OF REVIEW: This review summarizes the past year's literature regarding the neuroendocrine and intracellular regulation of gastric acid secretion, discussing both basic and clinical aspects. RECENT FINDINGS: Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High acidity kills ingested microorganisms and limits bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. The main stimulants of acid secretion are gastrin, released from antral gastrin cells; histamine, released from oxyntic enterochromaffin-like cells; and acetylcholine, released from antral and oxyntic intramural neurons. Ghrelin and coffee also stimulate acid secretion whereas somatostatin, cholecystokinin, glucagon-like peptide-1, and atrial natriuretic peptide inhibit acid secretion. Although 95% of parietal cells are contained within the oxyntic mucosa (fundus and body), 50% of human antral glands contain parietal cells. Proton pump inhibitors are considered well tolerated drugs, but concerns have been raised regarding dysbiosis, atrophic gastritis, hypergastrinemia, hypomagnesemia, and enteritis/colitis. SUMMARY: Our understanding of the functional anatomy and physiology of gastric secretion continues to advance. Such knowledge is crucial for improved management of acid-peptic disorders, prevention and management of neoplasia, and the development of novel medications.

Systems biology analysis of omeprazole therapy in cirrhosis demonstrates significant shifts in gut microbiota composition and function.

Proton pump inhibitors (PPI) have been associated with infectious complications in cirrhosis, but their impact on distal gut microbiota composition and function is unclear. We aimed to evaluate changes in stool microbiota composition and function in patients with cirrhosis and healthy controls after omeprazole therapy. Both 15 compensated cirrhotic patients and 15 age-matched controls underwent serum gastrin measurement, stool microbiota profiling with multitagged pyrosequencing, and urinary metabolic profiling with NMR spectroscopy to assess microbial cometabolites before/after a 14-day course of 40 mg/day omeprazole under constant diet conditions. Results before (pre) and after PPI were compared in both groups, compared with baseline by systems biology techniques. Adherence was >95% without changes in diet or MELD (model for end-stage liver disease) score during the study. Serum gastrin concentrations significantly increased after PPI in cirrhosis (pre 38.3 ± 35.8 vs. 115.6 ± 79.3 pg/ml P < 0.0001) and controls (pre 29.9 ± 14.5 vs. 116.0 ± 74.0 pg/ml, P = 0.001). A significant microbiota change was seen in both controls and cirrhosis after omeprazole (QIIME P < 0.0001). Relative Streptococcaceae abundance, normally abundant in saliva, significantly increased postomeprazole in controls (1 vs. 5%) and cirrhosis (0 vs. 9%) and was correlated with serum gastrin levels (r = 0.4, P = 0.005). We found significantly reduced hippurate in cirrhosis vs. controls both pre- and postomeprazole and increased lactate in both groups post vs. preomeprazole, whereas dimethylamine (DMA) decreased in cirrhosis only. On correlation network analysis, significant changes in linkages of bacteria with metabolites (hippurate/DMA/lactate) were found postomeprazole, compared with pre-PPI in cirrhosis patients. In conclusion, omeprazole is associated with a microbiota shift and functional change in the distal gut in patients with compensated cirrhosis that could set the stage for bacterial overgrowth.

Gastric secretion.

PURPOSE OF REVIEW: This review summarizes the past year's literature regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. RECENT FINDINGS: Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications. High gastric acidity, in combination with pepsin and lipase, kills ingested microorganisms and may play a role in preventing bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis, community-acquired pneumonia, and infection with Mycobacterium tuberculosis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, gastric inhibitory polypeptide, calcitonin gene-related peptide, and adrenomedullin. Helicobacter pylori stimulates or inhibits depending upon the time course of infection and the area of the stomach predominantly infected. Proteins implicated in H-K-ATPase membrane trafficking include myosin IIB, F-actin, ezrin, and Rab GTPases. SUMMARY: Our understanding of the regulation of gastric acid secretion continues to advance. Such knowledge is crucial for the management of acid-peptic disorders and the development of novel medications, such as cholecystokinin-2 receptor antagonists.

H. pylori acutely inhibits gastric secretion by activating CGRP sensory neurons coupled to stimulation of somatostatin and inhibition of histamine secretion.

Acute Helicobacter pylori infection produces hypochlorhydria. The decrease in acid facilitates survival of the bacterium and its colonization of the stomach. The present study was designed to identify the pathways in oxyntic mucosa by which acute H. pylori infection inhibits acid secretion. In rat fundic sheets in an Ussing chamber, perfusion of the luminal surface with H. pylori in spent broth (10(3)-10(8) cfu/ml) or spent broth alone (1:10(5) to 1:10(0) final dilution) caused a concentration-dependent increase in somatostatin (SST; maximal: 200 ± 20 and 194 ± 9% above basal; P < 0.001) and decrease in histamine secretion (maximal: 45 ± 5 and 48 ± 2% below basal; P < 0.001); the latter was abolished by SST antibody, implying that changes in histamine secretion reflected changes in SST secretion. Both responses were abolished by the axonal blocker tetrodotoxin (TTX), the sensory neurotoxin capsaicin, or the CGRP antagonist CGRP8-37, implying that the reciprocal changes in SST and histamine secretion were due to release of CGRP from sensory neurons. In isolated rabbit oxyntic glands, H. pylori inhibited basal and histamine-stimulated acid secretion in a concentration-dependent manner; the responses were not affected by TTX or SST antibody, implying that H. pylori can directly inhibit parietal cell function. In conclusion, acute administration of H. pylori is capable of inhibiting acid secretion directly as well as indirectly by activating intramural CGRP sensory neurons coupled to stimulation of SST and inhibition of histamine secretion. Activation of neural pathways provides one explanation as to how initial patchy colonization of the superficial gastric mucosa by H. pylori can acutely inhibit acid secretion.

Gastric secretion.

PURPOSE OF REVIEW: The review summarizes the past year's literature, basic science and clinical, regarding the neural, paracrine, hormonal, and intracellular regulation of gastric acid secretion. RECENT FINDINGS: Gastric acid facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B(12), and certain medications (e.g. thyroxin). It also kills ingested microorganisms and prevents bacterial overgrowth, enteric infection, and possibly spontaneous bacterial peritonitis. Stimulants of acid secretion include histamine, gastrin, acetylcholine, and ghrelin. Inhibitors include somatostatin, nefstatin-1, interleukin-11, and calcitonin gene-related peptide. Helicobacter pylori stimulates or inhibits acid secretion depending upon the time course of infection and the area of the stomach predominantly infected. Acute infection activates calcitonin gene-related peptide sensory neurons coupled to inhibition of histamine and acid secretion. Serum chromogranin A, a marker for neuroendocrine tumors, is elevated in patients taking proton pump inhibitors. SUMMARY: Progress continues in our understanding of the regulation of gastric acid secretion in health and disease, as well as the function of gastric neuroendocrine cells. The recognition that gastrin is not only a secretagogue but also a trophic hormone has led to new research into the role of gastrin and its receptor (cholecystokinin-2 receptor) in carcinogenesis and the development of cholecystokinin-2 receptor antagonists.

Gastric secretion.

PURPOSE OF REVIEW: This review summarizes the past year's literature regarding the regulation of gastric exocrine and endocrine secretion, both basic science and clinical. RECENT FINDINGS: Gastric acid secretion facilitates the digestion of protein as well as the absorption of iron, calcium, vitamin B12, and certain medications as well as prevents bacterial overgrowth, enteric infection, and possibly community-acquired pneumonia, spontaneous bacterial peritonitis, and IgE-mediated food allergy. It is regulated by neural (e.g., pituitary adenylate cyclase-activating peptide), hormonal (e.g., gastrin, ghrelin, and apelin), and paracrine (e.g., histamine) pathways as well as by chemical (e.g., amino acids) and bacterial stimuli (e.g., Helicobacter pylori). Novel peptides, which may possess physiologic function, have been identified in gastric mucosal neuroendocrine cells including parathyroid hormone-like hormone in histamine-secreting enterochromaffin-like cells and hepcidin in acid-secreting parietal cells. The secretion of hydrochloric acid by parietal cells involves translocation of the proton pump, HK-ATPase, to the apical membrane along with activation of apical chloride and potassium channels. Serum markers include chromogranin A for neuroendocrine tumors, pepsinogen I for gastric atrophy, and pepsinogen II for H. pylori infection. SUMMARY: We continue to make progress in our understanding of the regulation of gastric acid secretion in health and disease.

Gastric secretion.

PURPOSE OF REVIEW: The review summarizes the past year's literature regarding the regulation of gastric exocrine and endocrine secretion, both basic science and clinical. RECENT FINDINGS: Gastric acid secretion is an elaborate and dynamic process that is regulated by neural (efferent and afferent), hormonal (e.g. gastrin), and paracrine (e.g. histamine, ghrelin, somatostatin) pathways as well as mechanical (e.g. distension) and chemical (e.g. amino acids) stimuli. Secretion of hydrochloric acid (HCl) by parietal cells involves translocation of HK-ATPase-containing cytoplasmic tubulovesicles to the apical membrane with subsequent electroneutral transport of hydronium ions in exchange for potassium. The main apical potassium channel is KCNQ1 which, when activated, assembles with its ß-subunit KCNE2 to function as a constitutively open, voltage-insensitive, and acid-resistant luminal potassium channel. Proton pump inhibitors block acid secretion by covalently binding to cysteine residues accessible from the luminal surface of the HK-ATPase. Potassium-competitive ATPase blockers (P-CABs) act by competing for K on the luminal surface of HK-ATPase. As they are acid-stable and do not require acid-dependent activation, P-CABs hold promise for rapid and prolonged inhibition of acid secretion. SUMMARY: We continue to make progress in our understanding of the physiologic regulation of gastric acid secretion. A better understanding of the pathways and mechanisms regulating acid secretion should lead to improved management of patients with acid-induced disorders.