Proabsorptive Effect Research Articles

Short Chain Fatty Acids Effect on Chloride Channel ClC-2 as a Possible Mechanism for Lubiprostone Intestinal Action.

Lubiprostone, a 20-carbon synthetic fatty acid used for the treatment of constipation, is thought to act through an action on Cl− channel ClC-2. Short chain fatty acids (SCFAs) are produced and absorbed in the distal intestine. We explore whether SCFAs affect ClC-2, re-examine a possible direct effect of lubiprostone on ClC-2, and use mice deficient in ClC-2 to stringently address the hypothesis that the epithelial effect of lubiprostone targets this anion channel. Patch-clamp whole cell recordings of ClC-2 expressed in mammalian cells are used to assay SCFA and lubiprostone effects. Using chamber measurements of ion current in mice deficient in ClC-2 or CFTR channels served to analyze the target of lubiprostone in the distal intestinal epithelium. Intracellular SCFAs had a dual action on ClC-2, partially inhibiting conduction but, importantly, facilitating the voltage activation of ClC-2. Intra- or extracellular lubiprostone had no effect on ClC-2 currents. Lubiprostone elicited a secretory current across colonic epithelia that was increased in mice deficient in ClC-2, consistent with the channel’s proposed proabsorptive function, but absent from those deficient in CFTR. Whilst SCFAs might exert a physiological effect on ClC-2 as part of their known proabsorptive effect, ClC-2 plays no part in the lubiprostone intestinal effect that appears mediated by CFTR activation.

Potency of Oral Rehydration Solution in Inducing Fluid Absorption is Related to Glucose Concentration

Oral rehydration solutions (ORSs) is the key treatment of acute diarrhea in children, as it restores the electrolyte balance by stimulating the intestinal sodium/glucose transporter SGLT1 to induce fluid absorption. The World Health Organization (WHO) and The European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) proposed ORSs with different chemical compositions. The main agent of childhood acute gastroenteritis is rotavirus (RV). We evaluate the effects of ORS with different concentration of glucose and sodium on RV induced secretion. Ussing chambers technique was used for electophysiology experiments to evaluate ion fluid flux. ESPGHAN ORS (sodium 60 mmol/L and glucose 111 mmol/L) induced a more potent proabsorptive effect in Caco-2 cells than WHO ORS, and this effect depended on the sodium/glucose ratio. Titration experiments showed that RV-induced fluid secretion can be reverted to a proabsorptive direction when sodium and glucose concentration fall in specific ranges, specifically 45–60 mEq/L and 80–110 mM respectively. The results were confirmed by testing commercial ORSs. These findings indicated that ORS proabsorptive potency depends on sodium and glucose concentrations. Optimal ORS composition should be tailored to reduce RV-induced ion secretion by also considering palatability. These in vitro data should be confirmed by clinical trials.

Origanum majorana L. extract exhibit positive cooperative effects on the main mechanisms involved in acute infectious diarrhea

Ethnopharmacological relevanceOriganum majorana L. (Lamiaceae) is commonly used in Moroccan folk medicine to treat infantile colic, abdominal discomfort and diarrhea. Liquid stools and abdominal discomfort observed in acute infectious diarrhea are the consequences of imbalance between intestinal water secretion and absorption in the lumen, and relaxation of smooth muscle surrounding the intestinal mucosa. Aim of the studyThe objective of our study was to see if aqueous extract of Origanum majorana L. (AEOM) may exhibit an effect on those deleterious mechanisms. Materials and methodsThe effect of AEOM on electrogenic Cl- secretion and Na+ absorption, the two main mechanisms underlying water movement in the intestine, was assessed on intestinal pieces of mice intestine mounted, in vitro, in Ussing chambers. AEOM effect on muscle relaxation was measured on rat intestinal smooth muscle mounted in an isotonic transducer. Results1) AEOM placed on the serosal (i.e. blood) side of the piece of jejunum entirely inhibited in a concentration-dependent manner the Forskolin-induced electrogenic chloride secretion, with an IC50 = 654 ± 8 µg/mL. 2) AEOM placed on the mucosal (i.e. luminal) side stimulated in a concentration-dependent manner an electrogenic Na+ absorption, with an IC50 = 476.9 ± 1 µg/mL. 3) AEOM (1 mg/mL) inhibition of Forskolin-induced electrogenic secretion was almost entirely prevented by prior exposure to Ca++ channels or neurotransmitters inhibitors. 4) AEOM (1 mg/mL) proabsorptive effect was greater in the ileum and progressively declined in the jejunum, distal colon and proximal colon (minimal). 5) AEOM inhibited in a concentration-dependent manner smooth muscle Carbachol or KCl induced contraction, with an IC50 = 1.64 ± 0.2 mg/mL or 1.92 ± 0.8 mg/mL, respectively. Conclusionthe present results indicate that aqueous extract of Origanum majorana L. exhibit positive cooperative effects on the main mechanisms that are involved in acute infectious diarrhea.

MECHANISMS OF ANTIDIARRHEAL EFFECT BY PROBIOTICS

Gastroenteritis is a major cause of morbidity and mortality worldwide. Several microbial pathogens cause secretory diarrhea such as Vibrio cholerae and enterotoxigenic Escherichia coli as well as enteric viruses such as Rotavirus (RV) and Norovirus and parasites including Cryptosporidium. Other agents induce inflammatory diarrhea such as Clostridium difficile, Shigella and selected strains of pathogenic E. coli.Gastroenteritis is the result of multiple mechanisms that may mainly be summarized in enterotoxic (secretory diarrhea) or cytotoxic (osmotic diarrhea) as a consequence of ion secretion and epithelial damage, respectively. Other indirect mechanisms of infectious diarrhea include inflammation or altered regulatory processes involving hormones and neurotransmitters.The first‐line treatment of acute gastroenteritis in children is the administration of oral rehydration solution (ORS) but this neither shortens the duration of diarrhea nor reduces the frequency of stool outputs. Therefore, active therapies are now recommended in adjunct to ORS for children with gastroenteritis.The use of the specific probiotic strains, namely Lactobacillus rhamnosus GG (LGG) and Saccharomyces boulardii, is included ESPGHAN/ESPID guidelines for the management of children with AGE as an adjunct to rehydration therapy.Antidiarrheal drugs act at the luminal side of intestinal epithelium and modulate apical pathways, induce ion absorption or limit secretion, influence microbiome, modulate permeability, bind secretory moieties such as enterotoxins or bile acids. Probiotics are not drugs, but are rapidly effective in acute diarrhea reducing its duration and their effects have been linked to intestinal permeability and the modulation of intestinal microbiota and‐ indirectly‐ of inflammation. Those mechanisms are not consistent with the rapid effects of probiotics observed in children with acute diarrhea within hours since their initial administration. Evidence exists in favor of direct effects induced by probiotics on the enterocyte. Saccharomyces boulardii secreted moieties prevented RV‐induced oxidative stress and chloride secretion in human enterocytes. LGG exerted an ion proabsorptive effect through a direct antioxidant mechanisms and also promoted cell growth and differentiation acting on MAPKs. Those data indicate that the rapid and effective clinical effects by probiotics on acute diarrhea are probably the results of the direct microbe‐enterocyte rather than to the microbe‐microbiota or microbe‐immune interaction. This data provide an entirely new scenario for understanding the antidiarrheal mechanisms of probiotics in diarrhea.

Hydrogen sulfide decreases β-adrenergic agonist-stimulated lung liquid clearance by inhibiting ENaC-mediated transepithelial sodium absorption.

In pulmonary epithelia, β-adrenergic agonists regulate the membrane abundance of the epithelial sodium channel (ENaC) and, thereby, control the rate of transepithelial electrolyte absorption. This is a crucial regulatory mechanism for lung liquid clearance at birth and thereafter. This study investigated the influence of the gaseous signaling molecule hydrogen sulfide (H2S) on β-adrenergic agonist-regulated pulmonary sodium and liquid absorption. Application of the H2S-liberating molecule Na2S (50 μM) to the alveolar compartment of rat lungs in situ decreased baseline liquid absorption and abrogated the stimulation of liquid absorption by the β-adrenergic agonist terbutaline. There was no additional effect of Na2S over that of the ENaC inhibitor amiloride. In electrophysiological Ussing chamber experiments with native lung epithelia (Xenopus laevis), Na2S inhibited the stimulation of amiloride-sensitive current by terbutaline. β-adrenergic agonists generally increase ENaC abundance by cAMP formation and activation of PKA. Activation of this pathway by forskolin and 3-isobutyl-1-methylxanthine increased amiloride-sensitive currents in H441 pulmonary epithelial cells. This effect was inhibited by Na2S in a dose-dependent manner (5-50 μM). Na2S had no effect on cellular ATP concentration, cAMP formation, and activation of PKA. By contrast, Na2S prevented the cAMP-induced increase in ENaC activity in the apical membrane of H441 cells. H441 cells expressed the H2S-generating enzymes cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase, and they produced H2S amounts within the employed concentration range. These data demonstrate that H2S prevents the stimulation of ENaC by cAMP/PKA and, thereby, inhibits the proabsorptive effect of β-adrenergic agonists on lung liquid clearance.

Estrogen increases ENaC activity via PKCδ signaling in renal cortical collecting duct cells.

The most active estrogen, 17β‐estradiol (E2), has previously been shown to stimulate a female sex‐specific antisecretory response in the intestine. This effect is thought to contribute to the increase in whole body extracellular fluid (ECF) volume which occurs in high estrogen states, such as in the implantation window during estrous cycle. The increased ECF volume may be short‐circuited by a renal compensation unless estrogen exerts a proabsorptive effect in the nephron. Thus, the effect of E2 on ENaC in kidney cortical collecting duct (CCD) cells is of interest to understand estrogen regulation of ECF volume. Previous studies showed a rapid stimulatory effect of estrogen on ENaC in bronchial epithelium. In this study we examined if such a rapid effect on Na+ absorption could occur in the kidney. Experiments were carried out on murine M1‐CCD cell cultures. E2 (25 nmol/L) treatment caused a rapid‐onset (<15 min) and sustained increase in the amiloride‐sensitive Na+ current (INa) in CCD monolayers mounted in Ussing chambers (control, 1.9 ± 0.2 μA/cm2; E2, 4.7 ± 0.3 μA/cm2; n = 43, P < 0.001), without affecting the ouabain‐sensitive Na+/K+ pump current. The INa response to E2 was inhibited by PKCδ activity antagonism with rottlerin (5 μmol/L), inhibition of matrix metalloproteinases activity with GM6001 (1 μmol/L), inhibition of EGFR activity with AG1478 (10 μmol/L), inhibition of PLC activity with U‐73122 (10 μmol/L), and inhibition of estrogen receptors with the general ER antagonist ICI‐182780 (100 nmol/L). The estrogen activation of INa could be mimicked by the ERα agonist PPT (1 nmol/L). The nuclear excluded estrogen dendrimer conjugate (EDC) induced similar stimulatory effects on INa comparable to free E2. The end target for E2 stimulation of PKCδ was shown to be an increased abundance of the γ‐ENaC subunit in the apical plasma membrane of CCD cells. We have demonstrated a novel rapid “nongenomic” function of estrogen to stimulate ENaC via ERα‐EGFR transactivation in kidney CCD cells. We propose that the salt‐retaining effect of estrogen in the kidney together with its antisecretory action in the intestine are the molecular mechanisms causing the expanded ECF volume in high‐estrogen states.

Teduglutide, a novel glucagon-like peptide 2 analog, in the treatment of patients with short bowel syndrome.

Short bowel syndrome results from surgical resection, congenital defect or disease-associated loss of absorption. Parenteral support (PS) is lifesaving in patients with short bowel syndrome and intestinal failure who are unable to compensate for their malabsorption by metabolic or pharmacologic adaptation. Together, the symptoms of short bowel syndrome and the inconvenience and complications in relation to PS (e.g. catheter-related blood steam infections, central thrombosis and intestinal failure associated liver disease) may impair the quality of life of patients. The aim of treatment is to maximize intestinal absorption, minimize the inconvenience of diarrhea, and avoid, reduce or eliminate the need for PS to achieve the best possible quality of life for the patient. Conventional treatments include dietary manipulations, oral rehydration solutions, and antidiarrheal and antisecretory treatments. However, the evidence base for these interventions is limited and treatments that improve the structural and functional integrity of the remaining intestine are needed. Teduglutide, an analog of glucagon-like peptide 2, improves intestinal rehabilitation by promoting mucosal growth and possibly by restoring gastric emptying and secretion, thereby reducing intestinal losses and promoting intestinal absorption. In a 3-week, phase II balance study, teduglutide reduced diarrhea by around 700 g/day and fecal energy losses by around 0.8 MJ/day. In two randomized, placebo-controlled, 24-week, phase III studies, similar findings were obtained when evaluating the fluid composite effect, which is the sum of the beneficial effects of teduglutide - reduction in the need for PS, increase in urine production and reduction in oral fluid intake. The fluid composite effect reflects the increase in intestinal fluid absorption (and the concomitant reduction in diarrhea) and may be used in studies in which metabolic balance assessments are not performed. In studies of up to 24 weeks' duration, teduglutide appears to be safe and well tolerated. Treatment with teduglutide was associated with enhancement or restoration of the structural and functional integrity of the remaining intestine with significant intestinotrophic and proabsorptive effects, facilitating a reduction in diarrhea and an equivalent reduction in the need for PS in patients with short bowel syndrome and intestinal failure.

Local and systemic actions of loperamide on fluid transport and transmural potential difference across rat small intestine.

The ability of loperamide to influence intestinal fluid transport was assessed using a dual loop preparation. Loperamide was applied to the lumen of the oral, but not the aboral loop, yet basal and prostaglandin-stimulated fluid transport was affected in both, indicating that the drug can act systemically in addition to any local actions. Loperamide had both pro-absorptive and anti-absorptive effects, the latter only occurring when basal fluid absorption was high. The effects of loperamide were greater in the aboral loop to which it was available only via the systemic route. This difference may reflect the absence of counteracting local influences in the aboral loop or a variation in the sensitivity of different regions of the gut to loperamide.

Randomised placebo-controlled trial of teduglutide in reducing parenteral nutrition and/or intravenous fluid requirements in patients with short bowel syndrome

Background and aimsTeduglutide, a GLP-2 analogue, may restore intestinal structural and functional integrity by promoting repair and growth of the mucosa and reducing gastric emptying and secretion, thereby increasing fluid...

Impaired aldosterone responsiveness in corticosteroid binding globulin deficient mice

Corticosteroid binding globulin (CBG) is the high affinity plasma carrier protein for cortisol. It keeps the steroids inactive, prevents them from degradation and defines the amount of free hormone acting on target tissues. Previous findings have shown insufficient responsiveness of corticosterone in peripheral tissues in CBG⁻(/)⁻ mice despite elevated free plasma corticosterone. In the large intestine, glucocorticoids synergistically enhance the pro-absorptive effects of aldosterone. We therefore hypothesized that CBG⁻(/)⁻ mice have reduced responsiveness to aldosterone. We used CBG⁻(/)⁻ and CBG(+/+) mice to investigate distal colonic electrogenic Na(+) absorption. An Ussing chamber was used to quantify amiloride-sensitive Na(+) transport in distal colonic mucosa (ΔI(sc) (amil)) as a measure of the physiological effect of aldosterone. No differences were observed in ΔI(sc) (amil) or aldosterone levels in animals on control diet. When Na(+) restricted, CBG(+/+) mice responded with a marked up-regulation of ΔI(sc) (amil) (25-fold). In CBG⁻(/)⁻ mice this up-regulation was greatly attenuated as seen in a markedly reduced amiloride-sensitive short circuit current (reduced by ∼50%), a reduced ability to lower faecal Na(+) excretion and a significantly attenuated up-regulation of the ENaC channel γ-subunit. Diet-induced increases of total plasma aldosterone were similar in both genotypes, but CBG⁻(/)⁻ mice had an increased free plasma aldosterone fraction. This study defines the functional hyporesponsiveness and aldosterone resistance in distal colon of CBG⁻(/)⁻ mice. This resistance occurs despite sufficient free corticosterone plasma level. Thus, steroid actions require an intrinsic but unknown function of CBG, which allows the sufficient supply of the hormone/s to the target tissue.

Stimulation of apical Cl−/HCO3−(OH−) exchanger, SLC26A3 by neuropeptide Y is lipid raft dependent

Neuropeptide Y (NPY), an important proabsorptive hormone of the gastrointestinal tract has been shown to inhibit chloride secretion and stimulate NaCl absorption. However, mechanisms underlying the proabsorptive effects of NPY are not fully understood. The present studies were designed to examine the direct effects of NPY on apical Cl⁻/HCO₃⁻(OH⁻) exchange activity and the underlying mechanisms involved utilizing Caco2 cells. Our results showed that NPY (100 nM, 30 min) significantly increased Cl⁻/HCO₃⁻(OH⁻) exchange activity (∼2-fold). Selective NPY/Y1 or Y2 receptor agonists mimicked the effects of NPY. NPY-mediated stimulation of Cl⁻/HCO₃⁻(OH⁻) exchange activity involved the ERK1/2 MAP kinase-dependent pathway. Cell surface biotinylation studies showed that NPY does not alter DRA (apical Cl⁻/HCO₃⁻(OH⁻) exchanger) surface expression, ruling out the involvement of membrane trafficking events. Interestingly, DRA was found to be predominantly expressed in the detergent-insoluble (DI) and low-density fractions (LDF) of human colonic apical membrane vesicles (AMVs) representing lipid rafts. Depletion of membrane cholesterol by methyl-β-cyclodextrin (MβCD, 10 mM, 1 h) remarkably decreased DRA expression in the DI fractions. Similar results were obtained in Triton-X 100-treated Caco2 plasma membranes. DRA association with lipid rafts in the DI and LDF fractions of Caco2 cells was significantly enhanced (∼45%) by NPY compared with control. MβCD significantly decreased Cl⁻/HCO₃⁻(OH⁻) exchange activity in Caco2 cells as measured by DIDS- or niflumic acid-sensitive ³⁶Cl⁻ uptake (∼50%). Our results demonstrate that NPY modulates Cl⁻/HCO₃⁻(OH⁻) exchange activity by enhancing the association of DRA with lipid rafts, thereby resulting in an increase in Cl⁻/HCO₃⁻(OH⁻) exchange activity. Our findings suggest that the alteration in the association of DRA with lipid rafts may contribute to the proabsorptive effects of NPY in the human intestine.

Glucocorticoids and Tumor Necrosis Factor-α Synergize to Induce Absorption by the Epithelial Sodium Channel in the Colon

The epithelial sodium channel (ENaC) mediates electrogenic sodium absorption in distal colon. In patients with inflammatory bowel disease (IBD), ENaC induction is impaired, mainly through transcriptional suppression by proinflammatory cytokines such as tumor necrosis factor (TNF)-alpha. Glucocorticoid therapy rapidly increases sodium absorption; we investigated the molecular mechanisms underlying the interaction among TNF-alpha, glucocorticoids, and ENaC induction. ENaC-mediated sodium transport in glucocorticoid receptor (GR)-expressing HT-29/B6 cells and rat distal colon, under the influence of the synthetic glucocorticoid dexamethasone and TNF-alpha, was quantified in Ussing chambers. ENaC messenger RNA (mRNA) levels were monitored by real-time polymerase chain reaction. GR transactivation and expression were investigated by gene reporter, immunoblot, and confocal immunofluorescence microscopy analyses. The GR mRNA half-life was determined. Signaling pathways were characterized using mitogen-activated protein kinase inhibitors. Dexamethasone not only prevented TNF-alpha-mediated ENaC suppression but caused synergistic induction of ENaC-dependent sodium absorption in HT-29/B6-GR cells and rat distal colon. This synergy resulted from TNF-alpha-mediated increases in GR protein levels because of GR mRNA stabilization and subsequent GR transactivation by dexamethasone. As a consequence, transcription of the ENaC beta- and gamma-subunits was up-regulated, increasing ENaC-dependent sodium absorption. p38 Mitogen-activated protein kinase is required for this synergistic effect: p38 inhibition blocked the increase in GR protein expression and ENaC-dependent sodium absorption. TNF-alpha and dexamethasone induce ENaC, explaining the rapid and intense proabsorptive effect of glucocorticoid therapies.

Modulation of Rat Intestinal Nuclear Factor NF-κB by Gum Arabic

The objective of this study was to test the hypothesis that in an animal model of cathartic-induce intestinal dysfunction the proabsorptive effects of gum arabic (GA) could be associated with modulation of nuclear factor-kappaB (NF-kappaB) and with reduction of the inflammatory response caused by cathartics, as evidenced by intestinal mucosa cytokine production and gene expression. Juvenile male rats were given a phenolphthalein-magnesium citrate solution for 6 days, by itself or supplemented with either 10 or 20 g L(-1) GA, as a sole source of fluid. The controls given were tap water alone or with added 20 g L(-1) GA. The animals were euthanized and small-intestinal mucosa nuclear fractions and RNA were isolated. NF-kappaB p65 activity was highest after administration of cathartics, lowest in controls, and intermediate in GA-treated rats. Mucosal IL-1beta was overexpressed in tissues from cathartic-treated rats and from rats given high-GA solutions. Gene-array analysis revealed a complex pattern of gene regulation by cathartics which selectively upregulated several subfamilies of cytochrome P-450 family 2 genes. Co-administration of GA did not block this effect. These findings suggest that local anti-inflammatory effects on the small intestine could be obtained by administration of a nonabsorbable proteoglycan such as GA.

Enhancement of Absorption by Gum Arabic in a Model of Gastrointestinal Dysfunction

Objective: Diarrhea is a common and deadly threat to millions of infants and children. Similarly, malabsorption can aggravate the health status of the chronically sick and especially the elderly. Prompt recovery from intestinal dysfunction may have a substantial impact on many populations. The aim of this study was to test the hypothesis that, in an animal model of cathartic-induce diarrhea, the previously shown proabsorptive effects of gum arabic (GA) could directly reduce and ameliorate intestinal dysfunction.Methods: Young male rats were offered a standard solid feed and as a sole source of fluid a phenolphthalein-magnesium citrate solution for 3 or 6 days (PC), or the same plus either 10 (GA1) or 20 (GA2) g/L of GA. Other groups had tap water without (CTL) or with 20 g/L GA (CTL + GA), after which the animals were jejunally perfused under anesthesia to test their absorptive capacity. Similarly treated rats were killed and the small intestinal mucosa scraped and processed for nitric oxide synthase (NOS) determination.Results: In 6-day studies addition of GA to the cathartic solution led to increases in net water, sodium and glucose absorption with the higher GA2, relatively to the PC rats. For water (means ± SEM): PC = 42.4 ± 3.6; GA2 = 57.9 ± 3.9 nmol/g.min, p < 0.05. For sodium: PC = 2,139 ± 334; GA2 = 4,465 ± 444 nmol/g.min, p < 0.05. After only 3-day exposure, effects were less marked. Total NOS activity was increased in the PC, GA1 and GA2 groups (333 ± 26; 334 ± 27; 336 ± 23 nmol/h.g) compared to CTL (233 ± 27 nmol/h.g, p < 0.05), while CTL + GA showed a further reduction of activity (190 ± 18 nmol/h.g, p < 0.05 vs. CTL).Conclusions: These findings substantiate earlier physiologic and biochemical effects of GA on the gastrointestinal tract, presently conducted in a model of gastrointestinal dysfunction. The data further suggest that a natural proteoglycan such as GA can reduce secretory effects induced by cathartics and, hence, are predictive of potential effectiveness in the context of diarrhea or malabsorption by infectious or functional causes.

High-viscosity carboxymethylcellulose reduces carbachol-stimulated intestinal chloride secretion in weaned piglets fed a diet based on skimmed milk powder and maltodextrin

High-viscosity carboxymethylcellulose (CMC) promotes gastrointestinal disorders, tissue alterations and bacterial overgrowth in pigs. The impact of CMC on intestinal absorptive and secretory physiology is not known. We hypothesised that CMC consumption alters intestinal Na-dependent glucose absorption and stimulates electrogenic chloride secretion. For testing this hypothesis, twenty-four piglets were weaned at 21 d of age and pair-fed for 13 d a starter diet based on skimmed milk powder and maltodextrin containing cellulose (control) or CMC. Body weight and faecal total aerobe and coliform counts were measured kinetically. At slaughter, digesta were weighed and characterised for viscosity and pH. Gastrointestinal tissues were weighed and sampled for physiology in Ussing chambers, morphometry and enzymology. Glucose absorption tended to be higher (P = 0.08) and carbachol-stimulated chloride secretion was lower (P = 0.01) with CMC in the small intestine, without changes in the colon. Aerobes were transiently higher at day 7 (P < 0.05) but coliform counts remained unchanged (P = 0.78) and beta-haemolitic Escherichia coli were virtually absent. Stomach and small-intestinal segments were heavier, and viscosity higher with CMC (0.001 < P < 0.05). The pH in the stomach was higher, and in the caecum and proximal colon lower with CMC (0.001 < P < 0.05). Jejunal villus area was slightly reduced with CMC (P < 0.05) without effects on enzyme activities (P > 0.10). In conclusion, CMC supplementation had pro-absorptive effects on the small intestine, possibly due to the absence of pathogenic E. coli in the present study.

Effects of nitric oxide in 5-hydroxytryptamine-, cholera toxin-, enterotoxigenic Escherichia coli- and Salmonella Typhimurium-induced secretion in the porcine small intestine

The effects of nitric oxide (NO) in the secretory response to the endogenous secretagogue 5-hydroxytryptamine (5-HT), the enterotoxins heat-labile enterotoxigenic Escherichia coli (ETEC) toxin (LT) and cholera toxin (CT), and various cultures of ETEC and Salmonella serotype Typhimurium in the porcine small intestine ( Sus scrofa) were investigated. In anaesthetized pigs, jejunal tied-off loops were instilled with 5-HT, LT, CT, various cultures of ETEC or S. Typhimurium. Pigs were given intravenously isotonic saline or isotonic saline containing the NO synthase inhibitor, N ω-nitro- l-arginine methyl ester (L-NAME). L-NAME significantly induced an increased fluid accumulation in loops induced by 5-HT, ETEC and stn-mutated S. Typhimurium. Fluid accumulation in loops instilled with wild-type S. Typhimurium was increased by L-NAME, although not significantly, while there was no effect on fluid accumulation induced by an invH-mutated isogenic strain. No significant effect of L-NAME was observed on the fluid accumulation induced by the purified enterotoxins LT and CT. The results also demonstrated a relatively large difference in the ability to induce fluid accumulation between the bacteria strains. Diastolic, systolic and mean blood pressures were significantly increased and the body temperature was significantly decreased in groups of pigs treated with L-NAME. In conclusion, the results suggest that NO has a proabsorptive effect in the intact porcine jejunum and is involved in the systemic vascular tone.

Chronic diarrhea

Chronic diarrhea can be due to any of several hundred conditions. When investigation fails to uncover a specific cause that can be treated successfully, nonspecific therapy is implemented. This includes dietary alterations if specific aggravating foods can be identified, enteral or parenteral nutrition if nutritional status is compromised, and use of oral rehydration solutions if diarrhea produces volume depletion. Strategic use of dietary fiber can improve stool consistency and can be of special value when fecal incontinence is present concurrently. Medications of value include opiate antidiarrheal drugs, clonidine, octreotide, and bile acid-binding agents. Less potent opiates such as loperamide and diphenoxylate should be tried first, with more potent agents such as codeine, opium, and morphine used in refractory cases. Clonidine has both proabsorptive and motility effects that facilitate its antidiarrheal effect, but its antihypertensive action limits its utility. Octreotide is of great value in treating diarrhea due to endocrine tumors and dumping syndrome; its efficacy in other conditions or in nonspecific diarrhea is less well established. Bile acid binders such as cholestyramine or colestipol have several specific uses but have limited utility in nonspecific chronic diarrhea.

Tissue levels and post-prandial secretion of the intestinal growth factor, glucagon-like peptide-2, in controls and inflammatory bowel disease: comparison with peptide YY

Glucagon-like peptide-2 (GLP-2) and peptide YY (PYY) are produced in endocrine L-cells of the intestine and secreted in response to food intake. GLP-2 has a trophic effect on the intestinal epithelium, whereas PYY has pro-absorptive effects. It can be speculated that, in inflammatory bowel disease (IBD), the production and secretion of GLP-2 and PYY could be affected as a part of a regulatory mechanism. Therefore, tissue levels and meal-stimulated secretion of GLP-2 and PYY were studied in IBD patients and compared to controls. Outpatients with IBD and control patients were included. Mucosal biopsies were taken from the ileum and colon and the content of GLP-2 and PYY was measured. After colonoscopy the patients took a mixed meal and plasma was collected for 90 min for plasma measurements of GLP-2 and PYY. Tissue levels of GLP-2 in control patients were highest in the terminal ileum (407+/-82 pmol/g tissue, n=10), whereas PYY was highest in the rectum (919+/-249 pmol/g tissue, n=10). In IBD patients with acute inflammation, the content of GLP-2 was similar to controls, whereas PYY was decreased to 72.1+/-17.7% (P=0.03, n=13) of control values. Neither the fasting plasma levels nor the meal responses of GLP-2 and PYY differed between controls and IBD patients. The similar responses of GLP-2 and PYY in patients and controls do not support the suggestion that L-cell secretion is altered in IBD. The decreased tissue PYY concentrations may contribute to the diarrhoea of some of these patients.

Butyrate as an effective treatment of congenital chloride diarrhea

Background & Aims: Many therapeutic attempts have demonstrated to be ineffective in reducing the severity of congenital chloride diarrhea and its long-term complications. The short-chain fatty acid butyrate stimulates intestinal water and ion absorption through a variety of mechanisms, including the activation of a parallel Cl−/butyrate and Na+/H+ exchanger. In this case report, we report the therapeutic efficacy of butyrate on an 11-year-old patient affected by congenital chloride diarrhea. Methods: The efficacy of increasing doses of oral butyrate (from 50 to 100 mg/kg/day) was investigated through the daily evaluation of stool volume, bowel movements, fecal incontinence, serum, and stool electrolytes concentrations. The modifications in transepithelial intestinal ion transport elicited by butyrate were examined by rectal dialysis study. Results: A butyrate dose of 100 mg/kg/day induced a normalization of stool pattern and of serum and fecal electrolytes concentration. The rectal dialysis study demonstrated a proabsorptive effect induced by butyrate on Na+, Cl−, and K+ intestinal transport. Butyrate therapy was well tolerated during the entire 12-month observation period, and the stool pattern and fecal and serum ion concentrations remained stable within the normal ranges. No clinical adverse events or episodes of dehydration requiring hospital care were observed. Conclusions: Butyrate could be effective in treating congenital chloride diarrhea. It is easily administered, useful in preventing severe dehydration episodes, and may be a promising therapeutic approach for a long-term treatment in this rare and severe condition.

Proabsorptive effect of gum arabic in isotonic solutions orally administered to rats: effect on zinc and other solutes

We have previously shown that the addition of gum arabic (GA) to oral rehydration solution (ORS) enhances water and electrolyte absorption during jejunal perfusion in rats under anesthesia. This study investigates whether GA by oral administration could be equally effective in rats. Isotonic solutions containing 25 g/L GA (A G), or without GA (A 0) were administered via oral tube to lightly anesthetized adult female rats. Similar experiments were conducted with hypertonic solutions containing no GA (B 0), or either 10 (B 10) or 50 g/L GA (B 50). Blood concentrations of sodium, glucose, glutamate, zinc, and tritiated water were determined at 0, 15, 30, 60, 90, 120, and 180 minutes, and results between treatments were compared. Administration of the isotonic, GA-containing solution (A G) resulted in a higher blood zinc level than with the isotonic GA-free solution (A 0) from 15 minutes throughout 180 minutes. Blood zinc at 15 minutes (means ± SEM) was as follows: for A 0: 69.3 ± 2.0, for A G: 83.4 ± 3.5 nmol/L, P= 0.002. At 180 minutes, A 0: 52.6 ± 1.8; A G: 68.1 ± 4.6 nmol/L, P= 0.004. The corresponding areas under the curve (AUC) were as follows: for A 0: 10,737 ± 214; for A G: 13,919 ± 765 nmol × min/L, P< 0.001). Glucose, glutamate, sodium, and tritiated water body distribution presented no differences in blood concentrations. For sodium and tritiated water body distribution, there was a significant time effect ( P< 0.0001). In hypertonic solutions, blood zinc levels declined over time, possibly due to their osmotic, counter-absorptive action, thus obscuring possible opposite effects of GA. GA appears to be an effective enhancer of zinc absorption when orally administered in isotonic solutions to laboratory animals. This proabsorptive capacity could be attributed to some of the physicochemical and biochemical properties of GA and suggest possible applications of GA in liquid formulas and solid food preparations.