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Deficient UDP-glucuronosyltransferase detoxification enzyme activity in the small intestinal mucosa of patients with coeliac disease.

BACKGROUND: Small intestinal malignancies in humans are rare; however, patients with coeliac disease have a relatively high risk for such tumours. Intestinal UDP-glucuronosyltransferases are phase II drug metabolism enzymes also involved in the detoxification of ingested toxins and carcinogens. As many toxins and carcinogens are ingested via food, the human gastrointestinal tract not only has an important role in the uptake of essential nutrients, but also acts as a first barrier against such harmful constituents of the food. Therefore, the gastrointestinal mucosa contains high levels of detoxification enzymes such as cytochromes-P450, glutathione S-transferases and UDP-glucuronosyltransferases. AIM: To compare the UDP-glucuronosyltransferase detoxification capacity in small intestinal mucosa of patients with coeliac disease vs. that in normal controls. METHODS: We assessed UDP-glucuronosyltransferase enzyme activities towards 4-methylumbelliferone in small intestinal biopsies of patients with coeliac disease (n = 22) and age- and sex-matched controls (n = 27). RESULTS: Small intestinal UDP-glucuronosyltransferase enzyme activity in controls was significantly higher than in patients with coeliac disease: 0.55 +/- 0.27 vs. 0.35 +/- 0.16 nmol/min mg protein, respectively (mean +/- s.d., P = 0.005). DISCUSSION: The low small intestinal UDP-glucuronosyltransferase detoxification activity in patients with coeliac disease may result in a deficient detoxification of potential carcinogens, and thus could explain in part the relatively high small intestinal cancer risk in these patients.

Carcinogens↗

Experimental diabetes induces an early change in the level of the G-protein subunit, alpha i2, in rat intestinal mucosa.

This study was undertaken to investigate the consequences of diabetes on Gi-protein expression and alpha 2-adrenergic receptivity in rat intestinal mucosa. Experimental diabetes was induced by treatment with streptozotocin. Quantification of alpha i-subunits by immunoblotting demonstrated that the level of the G alpha i2 but not the G alpha i3 subunit was markedly decreased in jejunum and colon membranes from diabetic rats as compared to controls. Parallel assessment of sympathetic innervation was performed by determination of norepinephrine content, measurement of tyrosine hydroxylase and monoamine oxidase activities, and quantification of alpha 2-adrenergic receptors in the different segments. At this stage of diabetes (6 weeks after streptozotocin injection), none of these parameters was significantly modified. Consequently, the decrease in G alpha i2 amount appears to be independent of the neuropathy describe in later stages of diabetes.

Animals↗

Decreased brush border hydrolase activities without gross morphologic changes in human intestinal mucosa after prolonged total parenteral nutrition of adults.

Animal experimentation with total parenteral nutrition (TPN) has revealed the occurrence of atrophy of the intestinal mucosa and decreased enzyme activities of the brush border, notably the disaccharidases. These findings have heretofore not been confirmed in human investigation. We performed endoscopic biopsies in the third part of the duodenum in 7 adults before TPN, after 21 days of TPN, and after a progressive oral refeeding. We noted a clear-cut decrease of major enzyme activities during TPN (sucrase, maltase, lactase, glucoamylase, acid aminopeptidase, dipeptidyl peptidase) without any morphologic modifications as observed with standard histology. Electron microscopy showed a slight but significant decrease in the height of microvilli. The decreased enzyme activities were rapidly restored after oral refeeding. Thus, the functional consequences of the modifications observed during medium-term TPN in adults are probably limited.

Adult↗

The immune response of the intestinal mucosa to foreign proteins.

In order to prevent the penetration of intraluminal material such as micro-organisms, food antigens, toxins etc. across the intestinal mucosa, a complex defence mechanism has been developed. This mechanism consists of non-immunological defence with enzymatic detoxification as well as an immunological one. The nature of the immunological defence has been thoroughly elucidated during the past 10-15 years. This mechanism is in man based on a special local immunological resistance, where production of secretory IgA plays the main role. Immunoglobulin producing plasma cells appear relatively late after birth in the lamina propria of the gut mucosa. Therefore a physiological immaturity of the immunological defence during first weeks of life can be anticipated. The role of the immunological defence system in the control of dietary antigen penetration across gut epithelium has been much discussed. Circulating antibodies to cow's milk proteins in small infants after milk ingestion and the almost constant finding of such antibodies in high titre in patients with selective IgA deficiency even without intestinal disease indicate a highly significant function of this local immunity in antigen handling. It has been suggested that the apparently high incidence of food allergy in infancy is due to immaturity of this system. Cow's milk protein induced enteropathy is also strictly bound to this age group.

Antibody Formation↗

Ion transport across the isolated intestinal mucosa of the winter flounder, Pseudopleuronectes americanus. I. Functional and structural properties of cellular and paracellular pathways for Na and Cl.

The isolated intestinal mucosa of the flounder, Pseudopleuronectes americanus, when bathed in a 20 mM HCO3-Ringer's solution bubbled with 1% CO2 in O2, generated a serosa-negative PD and, when short-circuited, absorbed Cl at almost 3 times the rate of Na. Reducing HCO3 to 5 mM decreased the net Cl flux by more than 60%. The following results suggest that, despite the PD, Na and Cl transport processes are nonelectrically coupled: replacing all Na with choline abolished both the PD and net Cl flux; replacing all Cl with SO4 and mannitol abolished the PD and the net Na flux; and adding ouabain (to 0.5 mM) abolished the PD and the net Cl flux. Nearly all of the unidirectional serosa-to-mucosa Cl flux (JClsm) seemed to be paracellular since it varied with PD and Cl concentration in a manner consistent with simple diffusion. JClsm was only about one-fourth of JNasm, suggesting that the paracellular pathway is highly cation-selective. The data can be explained by the following model: (i) Na and Cl uptake across the brush border are coupled 1 : 1; Na is pumped into the lateral space and Cl follows passively, elevating the salt concentration there; (ii) the tight junction is permeable to Na but relatively impermeable to Cl; and (iii) resistance to Na diffusion is greater in the lateral space (considered in its entirety) than in the tight junction. If these assumptions are correct, the serosa-negative transmural PD is due mainly to a salt diffusion potential across the tight junction and, under short-circuit condition, most of the Na pumped into the lateral space diffuses back into the luminal solution, whereas most of the Cl enters the serosal solution. Morphological features of the epithelium support this interpretation: the cells are unusually long (60 micrometer); there is little distension of the apical 12 micrometer of the lateral space during active fluid absorption; and distension distal to this region is intermittently constricted by desmosomes.

Animals↗

The binding of a glycopeptide component of wheat gluten to intestinal mucosa of normal and coeliac human subjects.

A carbohydrate-containing component of wheat gluten (glyc-gli) has been prepared which is toxic to coeliac intestinal mucosa. Its amino acid composition is uniquely different from that of the parent gluten and from alpha-gliadin. This glyc-gli material has been shown to bind to membrane components of the coeliac intestinal cell but to bind only poorly to normal intestinal cell membranes. Furthermore this binding can be interfered with by exogenous free carbohydrate suggesting that the toxic moiety of gluten acts in an analagous way to plant lectins. These data suggest that the underlying defect in coeliac disease is related to the composition of the surface membrane of the enterocyte.

Amino Acids↗

Inactivation of corticosteroids in intestinal mucosa by 11 beta-hydroxysteroid: NADP oxidoreductase (EC 1.1.1.146).

Activity of the enzyme 11 beta-hydroxysteroid:NADP oxidoreductase (EC 1.1.1.146) in human intestinal mucosa was determined by incubating scraped mucosa with 3H-cortisone and 14C-cortisol; these steroids were then extracted, separated chromatographically, and the radioactivity assayed to determine simultaneously both reductase and dehydrogenase activities. This was the only significant metabolic alteration which the substrate underwent. Only two cases had slight (5 and 13%) reductase activity. In 35 patients, 16 male and 19 female, including seven cases of Crohn's disease, three ulcerative colitis, five diverticulitis, two undergoing surgery for repair of injuries and 18 for carcinoma of colon or rectum, cortisol was converted to cortisone in 15 min with a wide range of values distributed uniformly up to 85% dehydrogenation, with a mean of 42%. When tissue homogenates were fortified with coenzymes, excess NADPH lowered dehydrogenase activity 81%; excess NADP increased dehydrogenase activity 2-fold in three cases. It is possible that a value is characteristic of an individual but perhaps more likely enzyme activity varies with metabolic events involving changes in the coenzyme levels in mucosa, and a random sampling might be expected to yield such a distribution of values. In any event, where activity is high most of the cortisol is inactivated within minutes. It is suggested that synthetic corticoids which escape such metabolic alteration might, except during pregnancy, prove superior in the treatment of conditions such as inflammatory bowel disease.

11-beta-Hydroxysteroid Dehydrogenases↗

Functional and morphologic characterization of eosinophils in the lower intestinal mucosa of patients with food allergy.

OBJECTIVE: The aim of this study was to characterize the functional and morphologic features of eosinophils in the intestinal mucosa of patients with food allergy. METHODS: Eighteen patients with food allergy and 11 controls took part in this study. In every patient, corresponding biopsy samples obtained during colonoscopy were quantitatively assessed by immunohistochemical methods (EPO-I) and subjected to mucosa oxygenation using eosinophilic cationic protein (ECP). Initial basal release, spontaneous and anti-IgE-dependent release, and the total ECP content of mucosal biopsies were studied. RESULTS: Morphologically, mucosal eosinophils in patients with food allergy have distinct features, occur in larger amounts, and show a distinct distribution pattern (i.e., intraepithelial, lamina propria, and submucosa). Their initial basal release is similar to that of controls, but stimulation of the IgE receptor with anti-IgE results in 40-fold activation (p < 0.001). In food allergy patients, the density of eosinophils, the presence of intraepithelial eosinophils, and the rate of degranulation showed a highly significant correlation to the initial basal release of ECP by mucosal tissue (Kendall tau = 0.619, 0.381, and 0.609, respectively; p < 0.05 for all) but not to their capability to be stimulated with anti-IgE. CONCLUSIONS: Eosinophils of the lower intestine of patients with food allergy show characteristic features with regard to morphology, distribution, and functional behavior to IgE receptor stimulation. Immunostaining of eosinophil peroxidase (EPO) detects important characteristic features that are missed with conventional hematoxylin-eosin staining.

Adult↗

Histological development of the small intestinal mucosa in the ovine fetus.

Histological changes in the small intestine of 85 ovine fetuses were studied, with particular reference to the mucosa. In 24-day-old fetuses the endoderm of the intestine consisted of a single layer of epithelium. By the 26th day the epithelium was flattened and stratified. The first evidence of rudimentary villus formation was noted in 39-day-old fetuses. Intestinal glands were first observed at 56 days. Other mucosal structures were present by 101 days. At birth the intestinal mucosa was fully mature.

Animals↗

Intestinal absorption of several beta-lactam antibiotics. IV. Binding to the various components in the intestinal mucosa of rat and role in absorption process.

The binding characteristics of zwitterionic and monobasic beta-lactam antibiotics to the components in the intestinal mucosa of rat was investigated. From the binding experiments using the brush border membrane preparation and the insoluble cellular fractions, there was no correlation between the binding behavior and the absorption characteristics. However, there was a highly significant correlation between the affinity to the soluble F1 fraction and the absorption characteristics of these antibiotics. It was also found that the binding of these antibiotics to the other soluble protein fractions were significantly smaller than that to F1 fraction. It was postulated that the binding properties of these antibiotics to soluble F1 fraction play an important role in the absorption process.

Animals↗

Regeneration of small intestinal mucosa after acute ischemia-reperfusion injury.

To determine whether c-Fos and c-Jun are involved in the repair of small intestinal mucosa after ischemia-reperfusion (I/R), we investigated the mechanism of regeneration following acute I/R injury in rats by evaluating changes in DNA synthesis, fractional synthesis rate (FSR) of proteins, and alkaline phosphatase (ALP) activity. Furthermore, we examined the sequential expression of c-Fos and c-Jun using western blot analysis and immunohistochemical staining. Proliferating cell nuclear antigen (PCNA) labeling index (LI) demonstrated that the LI of the I/R group at 2 and 6 hr after reperfusion was significantly higher than that of the controls. Statistically significant differences were found between the FSRs of the I/R group and the corresponding conventional group at 2, 6, and 12 hr. The expression of c-Fos and c-Jun proteins increased markedly after I/R and these proteins decreased with time. The levels of ALP in the I/R group were significantly decreased at 2 and 6 hr after reperfusion compared to controls. These results indicate that c-Fos and c-Jun play a central role in the repair process that results in complete restoration of intestinal mucosal function after I/R.

Animals↗

Enzyme histochemistry of the small intestinal mucosa in experimental infections of calves with rotavirus and enterotoxigenic Escherichia coli.

The effect of rotavirus and enterotoxigenic Escherichia coli, administered in different sequences, on alkaline and acid phosphatase, leucinaminopeptidase, beta-galactosidase, and succinicdehydrogenase of the intestinal mucosa of cesarian-derived, colostrum-deprived calves was investigated. Decrease in enzyme activity was most prominent in dual infections; it also occurred in parts of the small intestine in monoinfected animals. Increases in enzyme activity involved totally either one or all tissue compartments (crypt, basal villus area, villus tips). Increased activity was present in enteric mucosae that were either not affected or were only slightly affected by rotavirus or enterotoxigenic E. coli. We interpret the increase in enzyme activity as an adaptation of the enteric mucosa to maintain the absorptive function.

Acid Phosphatase↗

[Lymphoid cells of the intestinal mucosa with double kappa and lambda specificity in normal man].

The presence of lymphoid cells possessing both kappa and lambda specificities has been observed in the intestinal mucosa of normal subjects. The variability in the number of such cells in different sections of the same sample and in different subjects seems to be a characteristic of this cell population and may reflect the high activity of the immune system in the small intestine.

Fluorescent Antibody Technique↗

Photochemical ablation of intestinal mucosa for bladder augmentation.

Complications associated with enterocystoplasty include mucus production, electrolyte abnormalities, infections, stones and cancer at the vesicoenteric anastomosis. Removal of the intestinal mucosa with subsequent urothelialization may obviate these problems. We describe a unique approach whereby photodynamic therapy is used to de-epithelialize an ileal segment before augmentation. Enterocystoplasty was performed in 32 female Fischer 344 rats using a 1.5 cm. patch of terminal ileum. Of the 32 rats 24 survived at least 6 weeks before euthanasia. The experimental group (10 rats) received hematoporphyrin derivative intravenously 24 hours before surgery. The ileal patch was treated with red light for 20 minutes and then used for augmentation. There were 3 control groups, including 1 group of 5 rats that underwent augmentation alone, while the other 2 groups were augmented but received either light treatment (4 rats) or hematoporphyrin derivative (5 rats). Histological analysis revealed urothelialization of the augments treated with hematoporphyrin derivative and light, which did not occur in the controls. The preoperative and postoperative bladder capacities increased substantially in all groups. Mucus production and bacterial colonization were reduced while stone formation increased in the treated animals.

Animals↗