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Physiological implications of microbial digestion in the large intestine of mammals: relation to dietary factors.

The rate of digesta marker passage through the large intestine of the dog, pig, and pony correlated with the relative length and degree of sacculation of the colon. Volatile fatty acids (VFA), the end products of microbial digestion of all forms of carbohydrate, were the major anions present in large intestinal contents of all three species. Total VFA concentration was little affected by the feeding of high-versus low-fiber diets. VFA were rapidly transported across colonic mucosa of all three species. Results of comparative studies indicate that production and absorption of VFA are important to the nutrition of some mammals and to the normal secretory and absorptive functions of the large intestine of most mammals.

Animals↗

Rationale for using serotonergic agents to treat irritable bowel syndrome.

PURPOSE: The role of serotonin in gastrointestinal (GI)-tract functioning, the pharmacologic rationale for using serotonergic agents in the treatment of irritable bowel syndrome (IBS), and clinical experience with novel serotonergic agents are described. SUMMARY: IBS is a common multisymptom disorder that is associated with a high socioeconomic burden. The goal of treatment is to provide rapid and sustained global relief of the multiple symptoms of IBS with a single, effective, well-tolerated agent. Traditional treatment options target single symptoms, and many patients are dissatisfied with the level of relief achieved and adverse effects. Research has revealed that serotonin is involved in three major actions in the gut: (1) mediating intestinal motility, (2) mediating intestinal secretion in the GI tract, and (3) modulating perception in the bowels. Serotonin is also a vital link in the brain-gut axis. Alterations in key elements of serotonin signaling have been demonstrated in patients with IBS. Tegaserod, a selective serotonin type 4 (5-HT(4))-receptor partial agonist, is indicated for use in women with IBS whose primary bowel symptom is constipation. Alosetron, a 5-HT(3)-receptor antagonist, is indicated for use in women with severe diarrhea-predominant IBS in whom traditional therapies have failed. The clinical usefulness of several other serotonergic agents for IBS is being investigated. CONCLUSION: The use of serotonergic agents in patients with IBS is based on the critical role that serotonin plays in the maintenance of normal gut function and brain-gut communication. Pharmacologic therapies targeting specific serotonin receptors represent an important step in the management of IBS.

Animals↗

Compartmental analysis of the disposition of benzo[a]pyrene in rats.

We have previously reported the disposition of benzo[a]pyrene (B[a]P) and its metabolites in male Sprague-Dawley rats following intratracheal instillation of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1986) Cancer Res., 46, 5655-5661]. In some experiments, cannulas were implanted in the bile duct of the animals prior to administration of [3H]B[a]P [Weyand, E.H. and Bevan, D.R. (1987) Drug Metab. Disposition, 15, 442-448]. Based on these data, we have developed a compartmental model of the distribution of radioactivity to provide a quantitative description of the fate of B[a]P and its metabolites in rats. Modeling of the distribution of radioactivity was performed using the Simulation, Analysis and Modeling (SAAM) and conversational SAAM (CONSAM) computer programs. Compartments in the model included organs into which the largest amounts of radioactivity were distributed as well as pathways for excretion of radioactivity from the animals. Data from animals with and without cannulas implanted in the bile duct were considered simultaneously during modeling. Radioactivity was so rapidly absorbed from the lungs that an absorption phase into blood was not apparent at the earliest sampling times. Using the model of extrapolate to shorter times, it was predicted that the maximum amount of radioactivity was present in blood within 2 min after administration. In addition, considerable recycling of radioactivity back to lungs from blood was predicted by the model. Transfer of radioactivity from blood to liver and carcass (skin, muscle, bones, fat and associated blood) also was extensive. Carcass was modeled as the sum of two compartments to obtain agreement between the model and experimental data. The model accounted for enterohepatic circulation of B[a]P metabolites; data also required that intestinal secretion be included in the model. Quantitative data obtained from compartmental analysis included rate constants for transfer of radioactivity among compartments as well as statistical parameters indicating the identifiability of the rate constants. That the model is consistent with two sets of data, those obtained in animals with and without a biliary cannula, indicates its potential utility in predicting the disposition of B[a]P and its metabolites in vivo.

Animals↗

Mechanisms of disease and immunity in cholera: a review.

The adenyl cyclase-activating enterotoxin of Vibrio cholerae was shown to contain two types of subunit: six smaller units (L) that are responsible for the binding to cell membrane receptors and a larger unit (H) that mediates the toxic action. The receptor was identified as the ganglioside GM1 (galactosyl-N-acetylgalactosaminyl [sialosyl] lactosyl ceramide), and the results suggested that penetration of the toxin molecule into the membrane follows the rapid binding to GM1. The relationship of these findings to the mechanism of protective immunity, which is mediated by antibodies to the enterotoxin as well as those to the cell wall lipopolysaccharide of V. cholerae, was investigated. The antitoxic antibodies were directed mainly against the L subunit and protected by preventing binding of toxin; the antibacterial antibodies probably interfered with adhesion of V. cholerae to the intestine. The finding that the immune responses to toxin and bacteria act synergistically in protection against experimental cholera indicates that an improved cholera vaccine should contain both toxoid and lipopolysaccharide as antigens. In the rabbit, either subcutaneous or enteral immunization gave rise to intestinal synthesis of specific antibodies to V. cholerae.

Adenylyl Cyclases↗

Entamoeba histolytica: from adherence to enteropathy.

Entamoeba histolytica, a cause of invasive colitis or liver abscess, is responsible for substantial worldwide morbidity and mortality. An understanding of the biochemical basis for the parasite adherence and cytolytic activities and antiamebic host immune response mechanisms are prerequisites for vaccine development. The E. histolytica galactose (Gal) or N-acetyl-D-galactosamine (GalNAc) inhibitable adherence lectin mediates attachment of trophozoites to colonic mucins or mammalian target cells. Amebic cytolysis of target cells requires Gal/GalNAc-lectin-mediated adherence, parasite phospholipase A activity, and maintenance of an acid pH in amebic intracellular vesicles. Cytolytic activity is stimulated by phorbol esters (activators of protein kinase C) and results from an E. histolytica-mediated increase in free Ca++ within the target cell. The Gal/GalNAc adherence lectin is a highly conserved antigen that is universally recognized by human immune sera; patients cured of invasive amebiasis possess antigen-specific cell-mediated immunity effective in vitro against E. histolytica trophozoites. Promising vaccines include the purified adherence lectin, for eliciting an intestinal secretion of IgA antibody to lectin, and additional E. histolytica antigens, which elicit cell-mediated amebicidal responses.

Amebiasis↗

Effect of dietary raw soybean and soybean trypsin inhibitor on trypsin and chymotrypsin activities in the pancreas and in small intestinal juice of growing swine.

Sixty-eight growing gilts with a 12 kg average initial weight were used in seven trials to study the effect of dietary raw soybean (Harosov) and SBTI (Kunitz soybean trypsin inhibitor) on pancreatic and small intestinal trypsin and chymotrypsin activities. A solvent-extracted, heated soybean meal (SBM) was used, cause reduced growth. Both a single-meal and continuous feeding of the raw soybean diet caused a decrease in the pancreatic trypsin and chymotrypsin activities. In contrast, to the rat and the chick, the pancreas of the pigs did not enlarge subsequent to consumption of the raw soybean or SBTI diets. Raw soybean feeding also resulted in an inhibition of the intestinal trypsin and chymotrypsin activities. This inhibiting effect was greater than that of the SBTI, especially the chymotrypsin-inhibiting effect. This suggested that soybean constituents other than the SBTI, such as the Bowman-Birk inhibitor, caused inhibition. In the pig the inhibition of the intestinal proteolysis may be a major cause of reduced growth when raw soybean is fed.

Animals↗

The effects of small intestinal colonization by fecal and colonic bacteria on intestinal function in rats.

The effects of colonic and fecal bacterial proliferation on jejunal function were studied in normal rats and in low-germ rats after intraperitoneal injections of mecamylamine HCl. Jejunal bacteriology, bile salts, ultrastructure, and transport capacity were assessed. Normal rats given mecamylamine for 3 days had increased anaerobic bacteria in the intestinal fluid, and had high concentrations of deconjugated bile salts in the intraluminal contents. Jejunal bacteria were lodged between microvilli without penetrating the cell cytoplasm. However, there was focal cellular damage, including fused microvilli, dilated endoplasmic reticulum, and secondary lysosomes. In the mecamylamine treated normal rats intestinal glucose transport was reduced with an alteration compatible with noncompetitive inhibition. The absorption rates of galactose, fructose, 3-0-methyl-D-glucose, tyrosine, Na, and K were also decreased. In contrast, low-germ mecamylamine-treated rats showed no evidence of either increased anaerobic bacterial proliferation or deconjugation of bile salts, and had none of the fine structural alterations seen in regularly raised rats. Also, the transport of carbohydrates was unaltered. The findings suggest that non-invasive enteric proliferation of colonic and fecal bacterial anaerobes in rats may be associated with deconjugation of bile salts, ultrastructural alterations of the intestinal epithelial cells, and a diminished jejunal transport capacity of carbohydrates and other solutes.

Anaerobiosis↗

Oxalic acid metabolism in the rat.

Feeding experiments indicated that approximately 15% of dietary oxalate is adsorbed in the rat intestine and that dietary oxalate accounts for about one third of the oxalic acid normally excreted in rat urine. Oxalate excretion increased by about 40% when a low calcium diet was fed, decreased by 65% when a low protein diet was fed and increased by 100% when a high protein diet was fed. Fasting for 24 hours resulted in a fall in calcium excretion but phosphate and creatinine excretion increased. Oxalate excretion also tended to increase. Between 60% and 70% of activity was recovered in the urine, faeces and body tissues after 14C-oxalic acid had been administered intraperitoneally. Recoveries of 14C-labeled compounds as urinary 14C-oxalic acid decreased in the following order: glyoxylic acid greater than ascorbic acid greater than citric acid greater than glycollic acid greater than tryptophan greater than hydroxyproline greater than glycine. It is suggested that conversion of citrate to oxalate in the rat may occur via the "glyoxylate cycle." It is concluded that a higher proportion of dietary oxalate is absorbed in the rat intestine compared with man, and that dietary oxalate accounts for a higher proportion of urinary oxalate in the rat than in man. Intestinal secretion and bacterial degradation of oxalate also appear to be proportionately greater in the rat than in man.

Animals↗

The permissive effect of zinc deficiency on uroguanylin and inducible nitric oxide synthase gene upregulation in rat intestine induced by interleukin 1alpha is rapidly reversed by zinc repletion.

Deficient intake of zinc from the diet upregulates both uroguanylin (UG) and inducible nitric oxide synthase (iNOS) expression in rats. Because these changes influence intestinal fluid secretion and intestinal cell pathophysiology, they relate to the incidence of diarrheal disease and its reversal by zinc as well as intestinal inflammation in general. A model of moderate zinc deficiency in rats, which changes molecular indices of zinc deficiency, was used to further explore the effects of the proinflammatory cytokine interleukin (IL)-1alpha and zinc repletion on these changes. IL-1alpha has been shown to have a role in the intestinal inflammation that occurs with bacterial infection. Our results showed a permissive effect of zinc deficiency on both UG and iNOS expression. Specifically, UG expression was responsive to zinc deficiency and IL-1alpha challenge, which were additive when combined, whereas iNOS expression was upregulated by IL-1alpha only during the deficiency. Immunohistochemistry showed that the increase in UG was limited to enterocytes of the upper villus but, in contrast, the increase in iNOS was principally in cells of the lamina propria of IL-1alpha-treated rats. Cells exhibiting UG upregulation did not co-express serotonin. Repletion with zinc reversed upregulation of the iNOS gene within 1 d, whereas UG upregulation required 3-4 d to return to normal. This differential response to repletion suggests that mechanisms of UG and iNOS dysregulation are different. Dysregulation of both genes may contribute to the severity of zinc-responsive diarrheal disease and intestinal inflammatory disease.

Animals↗