Impact of phospholipid digests and bile acid pool variations on the crystallization of atazanavir from supersaturated solutions.

Oral delivery of poorly water-soluble drugs (PWSDs), which predominate the development pipeline, poses significant challenges. Weakly basic compounds, such as atazanavir, represent a critical class of PWSDs as even the administration of the crystalline solid may invoke supersaturation during gastric-intestinal transfer. The absorption advantage afforded by this supersaturated state can be offset by inherent metastability and a tendency to revert to the lower energy crystalline state. Therefore, it is important to understand the physiological factors that can affect crystallization to improve in vitro-in vivo predictiveness and to regulate inter-individual responses. The first aim of this study was to elucidate the influence of lyso-phosphatidylcholine (lyso-PC) and sodium oleate on crystallization, as the products of phosphatidylcholine (PC) hydrolysis and the major lipid components of human intestinal fluid (HIF) and updated fasted state simulated intestinal fluid version 3 (FaSSIF-V3). Secondly, as an individual's bile acid pool is unique, dynamic and related to gut microbiome community structure, it was of interest to investigate the impact of bile acid pool variations on crystallization from supersaturated solutions. To study the effect of PC hydrolysis, media with 2.8 mM sodium glycocholate (GCA) and sodium taurocholate (TCA) (1:1) but varying concentrations of PC, lyso-PC or sodium oleate were prepared. To investigate the influence of inter-individual variations in intestinal bile acid pool size and composition, media simulating the profiles of six healthy Western volunteers were prepared based on previously published data. The crystalline and amorphous solubility of atazanavir, a weakly basic antiretroviral drug, was firstly determined in these media. Nucleation-induction time experiments were then performed at an equivalent extent of supersaturation in each medium (corresponding to the amorphous solubility). At a constant level of GCA/TCA, increasing concentrations of both PC and lyso-PC accelerated crystallization onset; however, this was at least 2-fold more pronounced with lyso-PC at a given molar concentration. The addition of sodium oleate was also observed to induce crystallization. Interestingly, substituting GCA/TCA with the bile salt fraction of other biorelevant media partially circumvented the crystallization-inducing effect of phospholipids and their digests. The presence of dihydroxy bile salts was found to be particularly significant in decelerating the crystallization process. Nucleation-induction times in simulated volunteer pools were found to be dependent upon bile salt concentration, with higher bile salt levels generally prolonging supersaturation. Differences of up to 6-fold were observed. This study demonstrates that the choice of biorelevant medium used to evaluate supersaturating formulations can influence the observed crystallization kinetics. While the presence of lyso-PC and sodium oleate in FaSSIF-V3 medium is more physiologically relevant, further attention should be paid to the bile salt fraction when designing a biorelevant medium for supersaturating formulations. In vivo, inter-individual differences in the amount and types of bile acids and phospholipids present may influence the behaviour of supersaturating formulations.

Physiology of Intestinal Absorption and Secretion.

Virtually all nutrients from the diet are absorbed into blood across the highly polarized epithelial cell layer forming the small and large intestinal mucosa. Anatomical, histological, and functional specializations along the gastrointestinal tract are responsible for the effective and regulated nutrient transport via both passive and active mechanisms. In this chapter, we summarize the current state of knowledge regarding the mechanism of intestinal absorption of key nutrients such as sodium, anions (chloride, sulfate, oxalate), carbohydrates, amino acids and peptides, lipids, lipid- and water-soluble vitamins, as well as the major minerals and micronutrients. This outline, including the molecular identity, specificity, and coordinated activities of key transport proteins and genes involved, serves as the background for the following chapters focused on the pathophysiology of acquired and congenital intestinal malabsorption, as well as clinical tools to test and treat malabsorptive symptoms.

Does Alkaline Colonic pH Predispose to Clostridium difficile Infection?

OBJECTIVES: Clostridium difficile caused nearly 500,000 infections and was associated with approximately 29,000 deaths in 2011, according to data from the Centers for Disease Control and Prevention. C. difficile is a bacterium that causes diarrhea and, often, severe illness in healthcare facilities, as well as the community. Our objective was to determine whether alkaline colonic pH predisposes to colonization and infection with C. difficile. METHODS: A total of 228 patients with diarrhea and/or abdominal pain, leukocytosis, and fever were included. Stool pH was measured, and C. difficile antigen and toxin in stool were detected. RESULTS: Of 228 patients, 30 (13.2%) tested positive for C. difficile (antigen+/toxin+) and 171 (75%) were C. difficile negative (antigen-/toxin-). Of 171 patients who tested negative, 93 (54.4%) had stool pH >7.0 and 78 (45.6%) had pH ≤7.0. Among the 30 patients who tested positive, 26 (86.7%) had stool pH >7.0 (P = 0.002). Among the 27 colonized patients (antigen+/toxin-), 12 (44.4%) had stool pH >7.0 (P = 0.34). For all patients with stool pH ≤7.0, 96% tested negative for C. difficile infection (P = 0.002). CONCLUSIONS: A strong association between C. difficile infection and alkaline stool pH was found.

A new method to measure intestinal secretion using fluorescein isothiocyanate-inulin in small bowel of rats.

BACKGROUND: Small intestine ischemia can be seen in various conditions such as intestinal transplantation. To further understand the pathologic disruption in ischemia-reperfusion injury, we have developed a method to measure fluid changes in the intestinal lumen of rats. METHODS: Two 10-cm rat intestine segments were procured, connected to the terminal apertures of a perfusion device, and continuously infused with 3 mL of HEPES solution (control solution) containing 50 µM of fluorescein isothiocyanate (FITC)-inulin. The perfusion device consists of concentric chambers that contain the perfused bowel segments, which are maintained at 37°C via H2O bath. The individual chamber has four apertures as follows: two fill and/or drain the surrounding HEPES solution on the blood side of the tissue. The others provide flow of HEPES solution containing FITC-inulin through the lumens. The experimental intestine was infused with the same solution with 100 µM of Forskolin. A pump continuously circulated solutions at 6 mL/min. Samples were collected at 15-min intervals until 150 min and were measured by the nanoflourospectrometer. RESULTS: A mean of 6-µM decrease in the FITC-inulin concentration in the Forskolin-treated experimental intestine was observed in comparison with that in the control intestine. The FITC-inulin count dilution in the experimental intestine is a result of an increase of fluid secretion produced by the effect of Forskolin, with P values <0.0001. CONCLUSIONS: We demonstrate that it is possible to measure luminal fluid changes over time using our new modified perfusion system along with FITC-inulin to allow real-time determinations of fluid and/or electrolyte movement along the small intestine.

Novel functional roles for enteric glia in the gastrointestinal tract.

Enteric glia are a unique class of peripheral glial cells within the gastrointestinal tract. Major populations of enteric glia are found in enteric ganglia in the myenteric and submucosal plexuses of the enteric nervous system (ENS); these cells are also found outside of the ENS, within the circular muscle and in the lamina propria of the mucosa. These different populations of cells probably represent unique classes of glial cells with differing functions. In the past few years, enteric glia have been found to be involved in almost every gut function including motility, mucosal secretion and host defence. Subepithelial glia seem to have a trophic and supporting relationship with intestinal epithelial cells, but the necessity of these roles in the maintenance of normal epithelial functions remains to be shown. Likewise, glia within enteric ganglia are activated by synaptic stimulation, suggesting an active role in synaptic transmission, but the precise role of glial activation in normal enteric network activity is unclear. Excitingly, enteric glia can also give rise to new neurons, but seemingly only under limited circumstances. In this Review, we discuss the current body of evidence supporting functional roles of enteric glia and identify key gaps in our understanding of the physiology of these unique cells.

The prebiotic source influences the growth, biochemical features and survival under simulated gastrointestinal conditions of the probiotic Lactobacillus acidophilus.

The viability of the probiotic strain Lactobacillus acidophilus DSM 20079, after its passage through the simulated gastric and pancreatic juices, was evaluated as function of its pre-growth in a medium containing the known prebiotics pectin or inulin, and was compared to glucose used as control. The presence of pectin or inulin did not affect the growth (12.11(log10) colony forming units/mL and 12.08(log10) colony forming units/mL for pectin and inulin respectively versus 12.22(log10) colony forming units/mL obtained for glucose). Pectin and inulin, in contrast to glucose, induced cell stress resistance against gastrointestinal juices (Δ(log10) 1 and 2 colony forming units/mL respectively, versus Δ(log10) 4.5 for glucose). The data were confirmed by the analysis of the protein pattern following stress treatments which, in the case of microbial cells grown with glucose, revealed a relevant protein degradation after the double passage through simulated gastric and intestinal juices. An impressive metabolic change, as function of the growth conditions, was demonstrated by analyzing the proteomic profile with a µ-2DE system, used herein for the first time as evaluation tool of prebiotic-probiotic interactions. The analysis revealed a different pH protein distribution that was mostly acidic in the presence of pectin and neutral-alkaline in the presence of inulin. Both prebiotics stimulated the production of butyrate, a relevant healthy bio-molecule not detectable in the presence of glucose, that was measured by HPLC analysis to be 14.5 fold higher after growth in the presence of inulin, as compared to pectin. Three specific proteins were detected at pH 6 after growth in the presence of pectin or inulin. They could be correlated to the stress resistance and/or to the production of butyrate, the common phenotypic characteristics induced in the bacterial strain by the two prebiotics.

Mechanisms of action of zinc on rat intestinal epithelial electrogenic ion secretion: insights into its antidiarrhoeal actions.

OBJECTIVES: Zinc is a useful addition to oral rehydration therapy for acute diarrhoea. We have assessed the mechanism of its epithelial antisecretory action when intestinal epithelial tight junctions were pharmacologically opened. METHODS: Rat isolated ileal and colonic mucosae were mounted in Ussing chambers and exposed to ZnSO(4) (Zn(2+) ) in the presence of secretagogues and inhibition of short circuit current (I(sc) ) was measured. KEY FINDINGS: Pre-incubation with basolateral but not apical Zn(2+) reduced I(sc) stimulated by forskolin, carbachol and A23187. In the presence of the tight junction-opener, cytochalasin D, antisecretory effects of apically-applied Zn(2+) were enabled in colon and ileum. The apparent permeability coefficient (P(app) ) of Zn(2+) was increased 1.4- and 2.4-fold across rat ileum and colon, respectively, by cytochalasin D. Basolateral addition of Zn(2+) also reduced the I(sc) stimulated by nystatin in rat colon, confirming K channel inhibition. In comparison with other inhibitors, Zn(2+) was a relatively weak blocker of basolateral K(ATP) and K (Ca2+) channels. Exposure of ileum and colon to Zn(2+) for 60 min had minimal effects on epithelial histology. CONCLUSIONS: Antisecretory effects of Zn(2+) on intestinal epithelia arose in part through nonselective blockade of basolateral K channels, which was enabled when tight junctions were open.

Intestinal secretory cell ER stress and inflammation.

Data from animal models and human inflammatory bowel diseases have implicated the ER (endoplasmic reticulum) stress pathway in intestinal inflammation. We have characterized the development of inflammation in Winnie mice in which ER stress arises due to a single missense mutation in the MUC2 mucin produced by intestinal goblet cells. This model has allowed us to explore the genesis of inflammation ensuing from a single gene polymorphism affecting secretory cells. In these mice, a proportion of MUC2 misfolds during biosynthesis, leading to ER stress and activation of the unfolded protein response. Winnie mice develop spontaneous complex progressive inflammation that is most severe in the distal colon. Inflammation involves TH1, TH2 and TH17 T-cells, with a progressive development of a TH17-dominated response, but also involves innate immunity, in a pattern not dissimilar to human colitis. Experimental inhibition of tolerance in this model severely exacerbates colitis, demonstrating active effective suppression of inflammation. Even though the misfolding of MUC2 is a consequence of an inherited mutation, as inflammation develops, the molecular markers of ER stress increase further and goblet cell pathology becomes worse, suggesting that inflammation itself exacerbates ER stress.

Differential roles of NHERF1, NHERF2, and PDZK1 in regulating CFTR-mediated intestinal anion secretion in mice.

The epithelial anion channel CFTR interacts with multiple PDZ domain-containing proteins. Heterologous expression studies have demonstrated that the Na+/H+ exchanger regulatory factors, NHERF1, NHERF2, and PDZK1 (NHERF3), modulate CFTR membrane retention, conductivity, and interactions with other transporters. To study their biological roles in vivo, we investigated CFTR-dependent duodenal HCO3- secretion in mouse models of Nherf1, Nherf2, and Pdzk1 loss of function. We found that Nherf1 ablation strongly reduced basal as well as forskolin-stimulated (FSK-stimulated) HCO3- secretory rates and blocked beta2-adrenergic receptor (beta2-AR) stimulation. Conversely, Nherf2-/- mice displayed augmented FSK-stimulated HCO3- secretion. Furthermore, although lysophosphatidic acid (LPA) inhibited FSK-stimulated HCO3- secretion in WT mice, this effect was lost in Nherf2-/- mice. Pdzk1 ablation reduced basal, but not FSK-stimulated, HCO3- secretion. In addition, laser microdissection and quantitative PCR revealed that the beta2-AR and the type 2 LPA receptor were expressed together with CFTR in duodenal crypts and that colocalization of the beta2-AR and CFTR was reduced in the Nherf1-/- mice. These data suggest that the NHERF proteins differentially modulate duodenal HCO3- secretion: while NHERF1 is an obligatory linker for beta2-AR stimulation of CFTR, NHERF2 confers inhibitory signals by coupling the LPA receptor to CFTR.

Development of simulated intestinal fluids containing nutrients as transport media in the Caco-2 cell culture model: assessment of cell viability, monolayer integrity and transport of a poorly aqueous soluble drug and a substrate of efflux mechanisms.

The purpose of this study was to identify simulated intestinal fluids (SIFs) containing nutrients compatible with the Caco-2 cell culture model and to examine the impact of the identified medium on the transport of a poorly aqueous soluble model compound, estradiol, and a substrate of efflux mechanisms, etoposide. Monolayer integrity was evaluated by transepithelial electrical resistance and cellular viability by release of lactate dehydrogenase to the apical compartment and cellular protein content. It was shown that the viability of Caco-2 cells was enhanced by use of the CO(2) independent nutritional medium, Leibovitz's L-15 compared to Hanks' balanced salt solution. SIF containing 5mM sodium taurocholate and 1.25 mM phosphatidylcholine or lysophosphatidylcholine in Leibovitz's L-15 induced less release of lactate dehydrogenase than the traditional transport medium, HBSS. Addition of lipolysis products, 0.5mM oleic acid and 0.25 mM monoolein, did only cause increase in lactate dehydrogenase in 3 of 12 comparisons. The presence of SIFs in the apical compartment was shown to decrease flux of estradiol due to incorporation of estradiol in micelles and hence a decreased fraction of free estradiol. Further, a concentration dependent increase in the apparent permeability of etoposide was observed from apical to basolateral compartment, which indicated that components in the SIFs affects efflux mechanisms.

Digestive enzyme compartmentalization and recycling and sites of absorption and secretion along the midgut of Dermestes maculatus (Coleoptera) larvae.

Bostrichiformia is the less known major series of Coleoptera regarding digestive physiology. The midgut of Dermestes maculatus has a cylindrical ventriculus with anterior caeca. There is no cell differentiation along the ventriculus, except for the predominance of cells undergoing apocrine secretion in the anterior region. Apocrine secretion affects a larger extension and a greater number of cells in caeca than in ventriculus. Ventricular cells putatively secrete digestive enzymes, whereas caecal cells are supposed to secrete peritrophic gel (PG) glycoproteins. Feeding larvae with dyes showed that caeca are water-absorbing, whereas the posterior ventriculus is water-secreting. Midgut dissection revealed a PG and a peritrophic membrane (PM) covering the contents in anterior and posterior ventriculus, respectively. This was confirmed by in situ chitin detection with FITC-WGA conjugates. Ion-exchange chromatography of midgut homogenates, associated with enzymatic assays with natural and synthetic substrates and specific inhibitors, showed that trypsin and chymotrypsin are the major proteinases, cysteine proteinase is absent, and aspartic proteinase probably is negligible. Amylase and trypsin occur in contents and decrease along the ventriculus; the contrary is true for cell-membrane-bound aminopeptidase. Maltase is cell-membrane-bound and predominates in anterior and middle midgut. Digestive enzyme activities in hindgut are negligible. This, together with dye data, indicates that enzymes are recovered from inside PM by a posterior-anterior flux of fluid outside PM before being excreted. The combined results suggest that protein digestion starts in anterior midgut and ends in the surface of posterior midgut cells. All glycogen digestion takes place in anterior midgut.

Feed withdrawal alters small-intestinal morphology and mucus of broilers.

In an effort to reduce carcass contamination and consequent reprocessing, market-age broilers are often subjected to feed withdrawal (FW) before processing to reduce intestinal content and intestinal ruptures during processing. However, little is known regarding the effects of FW on mucus content and intestinal morphology. Therefore, 2 experiments were conducted to determine the effects of FW on intestinal characteristics. Male broilers were raised in floor pens on standard industry diets to 42 and 39 d of age for Experiments (Exp.) 1 and 2, respectively. In Exp. 1, feed was removed 24, 12, 8, and 0 h before sampling, respectively (n = 5 birds/time). Birds remained on litter with access to water for the first 4-h of the FW period and were then placed in crates. Body weights, left pectoralis major weights, and distal ileal and jejunal segments were collected for determination of morphological characteristics. For Exp. 2, birds (n = 8 birds/time) were subjected to 0, 12, and 24 h of FW. Birds were injected with 5-bromo-2'-deoxyuridine and thymidine at 24 and 21 h, respectively, before sampling to determine epithelial cell migration rates. One-centimeter distal ileal segments were collected for mucus quantification at 0, 12, and 24 h. In Exp. 1, ileal villi heights were unaffected by FW, but villus width and crypt depth decreased with increasing FW time (P < or = 0.05). Jejunal villus height increased as FW progressed. Jejunal crypt depths increased until 12 h of FW and then declined at 24 h. Mucus content decreased linearly and was reduced by 46% from 0 to 24 h FW (P < 0.05). The intestinal morphology alterations and the depletion of intestinal mucus that occur during a short-term FW may reduce the integrity of the intestine.

Estudio comparativo de los inhibidores de la bomba de protones en la hemorragia digestiva alta / Proton pump inhibitors

El medio ácido disminuye la agregación plaquetaria y la formación del coágulo. El beneficio de los fármacos antisecretores en la hemorragia digestiva por enfermedad péptica (HDA-EP) se alcanzará, de forma ideal, al mantener un pH intragástrico superior 6 de forma constante. Los antagonistas H2 pierden su potencia antisecretora a partir del tercer día de tratamiento. Los inhibidores de la bomba de protones tienen una mayor capacidad antisecretora y más mantenida y han demostrado su eficacia en la prevención de la recidiva, necesidad de cirugía y mortalidad en la HDA-EP. Existen estudios demostrando la superioridad de omeprazol y pantoprazol frente a placebo, especialmente después de tratamiento endoscópico. Esomeprazol por vía intravenosa ha demostrado tener una mayor capacidad para inhibir la secreción ácida y elevar el pH intragástrico. Se recomienda un bolo de 80 mg, seguido de una infusión constante de 8 mg/hora durante tres días (AU)

In an acid environment platelet aggregation and clotting formation are reduced. Ideally, highest benefits in peptic disease- related digestive hemorrhages (PDRDH) could be reached if intragastric pH was continuously maintained above 6. The H2 antagonists lose their antisecretory potential after a three day treatment. The proton pump inhibitors have a higher and maintained antisecretory potential in comparison to H2 antagonists in PDRDH; their efficiency in the prevention of recurrent disease, reduction of surgery and mortality has been also demonstrated. Several studies have reported the superiority of omeprazole and pantoprazole compared to placebo, specially after endoscopic treatment. Intravenous esomeprazole has shown benefit preventing acid secretion and increasing intragastric pH. A bolus of 80 mg is the dose preferred, followed by constant infusion of esomeprazole 8 mg/hour throughout three days (AU)

Farmacología de someprazol / Pharmacology of esomeprazol

Esomeprazol es un enantiómero del omeprazol (S-omeprazol). Es más potente que omeprazol para inhibir la secreción gástrica y produce un aumento más rápido del pH, manteniéndolo durante más tiempo por encima de 4. Esto permite que pueda ser utilizado a demanda para tratar a enfermos con enfermedad por reflujo gastroesofágico. Actúa bloqueando la ATPasa-H+/Na+ de la membrana de las células parietales gástricas. Se absorbe rápidamente en intestino delgado y en hígado se transforma por acción de las isoformas del citocromo P450 CYP2C19 y, en menor grado CYP34A, que actúan de forma distinta a como lo hacen con omeprazol lo que da lugar a una biodisponibilidad de esomeprazol mayor y una mayor área bajo la curva de la concentración plasmática. Es bien tolerado y disponible por vía intravenosa para administrar en inyección en 3 minutos o en infusión (AU)

Esomeprazole is an enantiomer of omeprazole (S-omeprazole). The gastric secretion suppression is better for esomeprazole in comparison with omeprazole; esomeprazole increases the pH faster, maintaining it above 4 during more time. Thus, it can be used on demand in patients with gastroesophagic reflux disease. The esomeprazole action pattern includes the blockade of H+/Na+ ATPase in the gastric parietal cell membrane. It is absorbed rapidly in the small bowel and transformed in the liver by the action of P450 CYP2C19 cytochrome isoenzymes and, in lesser extent, by P450 CYP34A cytochrome isoenzymes, as they perform in a different way with esomeprazole. This feature increases the esomeprazole bioavailability and the area under the plasmatic concentration curve. Esomeprazole is well tolerated and it can be administrated by intravenous injection or infusion (AU)

Recurrent networks of submucous neurons controlling intestinal secretion: a modeling study.

Secretomotor neurons, immunoreactive for vasoactive intestinal peptide (VIP), are important in controlling chloride secretion in the small intestine. These neurons form functional synapses with other submucosal VIP neurons and transmit via slow excitatory postsynaptic potentials (EPSPs). Thus they form a recurrent network with positive feedback. Intrinsic sensory neurons within the submucosa are also likely to form recurrent networks with positive feedback, provide substantial output to VIP neurons, and receive input from VIP neurons. If positive feedback within recurrent networks is sufficiently large, then neurons in the network respond to even small stimuli by firing at their maximum possible rate, even after the stimulus is removed. However, it is not clear whether such a mechanism operates within the recurrent networks of submucous neurons. We investigated this question by performing computer simulations of realistic models of VIP and intrinsic sensory neuron networks. In the expected range of electrophysiological properties, we found that activity in the VIP neuron network decayed slowly after cessation of a stimulus, indicating that positive feedback is not strong enough to support the uncontrolled firing state. The addition of intrinsic sensory neurons produced a low stable firing rate consistent with the common finding that basal secretory activity is, in part, neurogenic. Changing electrophysiological properties enables these recurrent networks to support the uncontrolled firing state, which may have implications with hypersecretion in the presence of enterotoxins such as cholera-toxin.

Basic drug--enterosoluble polymer coevaporates: development of oral controlled release systems.

Precipitation of basic drugs within oral prolonged release systems, at the higher pH values of the intestine, would affect drug release. Coevaporates of a model basic drug verapamil HCl, in single or mixed polymer systems, containing Eudragit L100 (L100) and ethyl cellulose or Eudragit RS100, were prepared from ethanolic solution. XRD and DSC indicated loss of crystallinity of the drug in the coevaporates. The presence of the enterosoluble polymer in the system was found to aid in faster dissolution of the drug at higher pH values. This was affected by the presence and type of retarding polymer present in the system. Compression of the coevaporates resulted in either very slow release of the drug or undesirable changes in the release profile. Pelletization of a coevaporate containing drug and L100 yielded systems, which released the drug uniformly when studied by the buffer change method in simulated gastric (SGF) and intestinal (SIF) fluids. The presence of L100 in intimate contact with the drug was found to be essential for the desirable drug release properties of the system. The drug release occurred predominantly by diffusion in SGF and by a combination of diffusion and polymer dissolution/erosion in SIF. Appropriate choice of release modifiers and formulation variables and development of suitable formulations can yield systems which compensate for the reduced solubility of the drug in the higher pH environments of the intestine.

A pilot study on duodenal acid exposure and its relationship to symptoms in functional dyspepsia with prominent nausea.

BACKGROUND: Duodenal hypersensitivity to acid and decreased duodenal clearance of exogenous acid have been reported in functional dyspepsia (FD). However, the relevance of these abnormalities to spontaneous duodenal acid exposure and dyspeptic symptoms in FD is unknown. AIMS: To determine spontaneous duodenal acid exposure and its relationship with symptoms, duodenal sensitivity to acid, and the effects of a 5-HT(3) receptor antagonist on duodenal responses to acid in FD. METHODS: Eleven FD patients with prominent nausea and 11 healthy controls underwent 24-h ambulatory duodenal pH monitoring with assessment of dyspeptic symptoms. On the next day, duodenal bolus infusions of 5 ml of acid and normal saline were given in a randomized double-blind manner and repeated after ondansetron or a placebo. RESULTS: Nighttime duodenal acid exposure was similar, but FD patients had lower duodenal pH and higher duodenal % time (pH < 4) than controls during the daytime and in the second postprandial 2 h (p < 0.05). Seven patients (64%) with duodenal acid exposure above the normal range had higher severity scores for several dyspeptic symptoms including nausea. However, the symptom severity was poorly or weakly correlated to duodenal pH, and brief duodenal acid infusion did not affect any symptoms. Duodenal responses to exogenous acid were unaffected by 5-HT(3) receptor antagonism. CONCLUSIONS: Spontaneous duodenal acid exposure is increased in a subset of FD patients with prominent nausea, and this is associated with more severe dyspeptic symptoms. However, a direct relationship between duodenal acid exposure and symptom severity is lacking.

Acid in the duodenum.

Acid in the duodenum triggers many physiological responses. Also, acid in the duodenum elicits hyperalgesia of the foregut. In the article by Hobson et al. in this issue the reduction of the latencies in evoked potential in response to electrical stimulation of the esophagus after duodenal acidification is reported, which may explain the symptom development in functional dyspepsia. Microscopic damages of the duodenal epithelium might be responsible for such changes. Microscopic damages of the intestinal epithelium may come into the center stage of the pathogenesis of functional GI disorders.