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Gastric, intestinal and colonic absorption of metoprolol in the rat.

The absorption of metoprolol from the stomach, small intestine and colon of anaesthetized rats has been evaluated using an in situ technique. Absorption rates were measured in terms of the rate of disappearance of metoprolol fumarate from the lumen between 5 and 30 min after dosing. Adsorption was estimated from the initial rapid fall in luminal content within the first 5 min after drug administration. The rate of drug absorption from the stomach was low or negligible. In the small intestine, the absorption rate constants, ka, at pH 6.2 and 7.5 were 0.66 and 0.81 h-1, respectively. In the colon, the rate of drug absorption at pH 7.5 was faster (ka = 1.21 h-1) than in other segments of the gut. Drug adsorption in the stomach amounted to 11% of the administered dose. In the small intestine adsorption was greater (16-22%), presumably because of the larger surface area in this segment of the gut, but in the colon adsorption was negligible.

Animals↗

Precancerous significance of colonic type intestinal metaplasia.

Numerous epidemiologic, morphologic and experimental studies have demonstrated the precancerous significance of intestinal metaplasia. We report here the results of a histochemical study of intestinal metaplasia in which 2 types were observed: one with sialomucin-secreting cells typical of the small intestine, and the other with sulphomucin-secreting cells typical of colonic mucosa. The correlation between colonic type intestinal metaplasia and gastric cancer is explored, since a significant precancerous value for this type of intestinal metaplasia is suggested.

Adult↗

[Intestinal parasitic colonization and protein-caloric malnutrition].

Intestinal parasitic infection was determined by fecal examination for parasites with several complementary methods in 380 young Gabonese infants aged 6 to 24 months (190 with normal weights and 190 with malnutrition, matched for age). Trichuris trichiura, Ascaris lombricoides, Giardia intestinalis, Entamoeba histolytica and Strongyloides stercoralis were the most prevalent parasites, without any difference between well-fed infants and patients with malnutrition. The higher prevalence of Strongyloides stercoralis in protein energy malnutrition might be related to a methodologic problem. However, more than 20% of diarrheas in infants with severe malnutrition were dramatically improved by specific treatment of S. stercoralis or Giardia with thiabendazole or metronidazole.

Diarrhea, Infantile↗

The role of NO synthases in arginine-dependent small intestinal and colonic carcinogenesis.

Arginine is catabolized by NOS2 and other nitric oxide synthases to form nitric oxide. We evaluated the roles of dietary arginine and Nos2 in Apc-dependent intestinal tumorigenesis in Min mice with and without a functional Nos2 gene. NOS2 protein was expressed only in intestinal tissues of Apc(Min/+) Nos2+/+ mice. NOS3 expression was higher in intestinal tissues of mice lacking Nos2, mainly in the small intestine. When diet was supplemented with arginine (0.2% and 2% in drinking water), lack of Nos2 results in decreased tumorigenesis in both small intestine and colon. In Nos2 knockout mice, supplemental arginine (up to 2%) caused a decrease in small intestinal tumor number and size. The arginine-dependent decrease was associated with an increase in nitrotyrosine formation and apoptosis in the region of intestinal stem cells. Mice expressing Nos2 did not show these changes. These mice did, however, show an arginine-dependent increase in colon tumor number and incidence, while no effect on apoptosis was seen. These changes were associated with increased nitrotyrosine formation in epithelial cells. Mice lacking Nos2 did not show changes in tumorigenesis or nitrotyrosine formation, while demonstrating an arginine-dependent increase in apoptosis. These data suggest that Nos2 and dietary arginine have significant effects on intestinal and colonic tumorigenesis in Min mice. In both tissues, loss of Nos2 is associated with decreased tumorigenesis when mice are supplemented with dietary arginine. In the small intestine, Nos2 prevents the arginine-induced decrease in tumor number and size, which is associated with NOS3 expression and increased apoptosis. In the colon, Nos2 is required for the arginine-induced increase in tumor number and incidence.

Adenomatous Polyposis Coli Protein↗

The rheology of pig small intestinal and colonic mucus: weakening of gel structure by non-mucin components.

Mechanical spectroscopy has been used to study the structure and properties of pig small intestinal and colonic adherent mucus gel. Both mucus secretions had properties of viscoelastic gels, but that from the small intestine was substantially weaker in quality. Small intestinal mucus gel was disrupted by acid (pH 1), detergents (bile) and protein denaturants while that from the colon remained stable following these treatments. Concentration of purified colonic mucin produced a gel with the same rheological properties as the native secretion. Purified small intestinal mucin when concentrated produced a stronger gel than the native secretion and, in contrast to the latter, one which was not disrupted by acid or denaturants. The instability of native small intestinal mucus was shown not to be a function of the mucin components (which alone could account for the gel-forming properties), but to arise from the presence of insoluble material largely from sloughed mucosal cells. These studies show (1) that mucus gels from the colon and small intestine have similar mechanical behaviour and properties to those from the stomach and duodenum, and (2) emphasise the caution that should be exercised when interpreting the rheological properties of mucus preparations, particularly with respect to their content of mucosal cellular material.

Animals↗

Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.

Whereas the adult gastrointestinal epithelium undergoes tremendous self-renewal through active proliferation in crypt stem cell compartments, the responsible growth factors regulating this continuous proliferation have not been defined. The exploration of physiologic functions of Wnt proteins in adult organisms has been hampered by functional redundancy and the necessity for conditional inactivation strategies. Dickkopf-1 (Dkk1) is a potent secreted Wnt antagonist that interacts with Wnt coreceptors of the LRP family. To address the contribution of Wnt signaling to gastrointestinal epithelial proliferation, adenoviral expression of Dkk1 was used to achieve stringent, conditional, and reversible Wnt inhibition in adult animals. Adenovirus Dkk1 (Ad Dkk1) treatment of adult mice repressed expression of the Wnt target genes CD44 and EphB2 within 2 days in both small intestine and colon, indicating an extremely broad role for Wnt signaling in the maintenance of adult gastrointestinal gene expression. In parallel, Ad Dkk1 markedly inhibited proliferation in small intestine and colon, accompanied by progressive architectural degeneration with the loss of crypts, villi, and glandular structure by 7 days. Whereas decreased Dkk1 expression at later time points (>10 days) was followed by crypt and villus regeneration, which was consistent with a reversible process, substantial mortality ensued from colitis and systemic infection. These results indicate the efficacy of systemic expression of secreted Wnt antagonists as a general strategy for conditional inactivation of Wnt signaling in adult organisms and illustrate a striking reliance on a single growth factor pathway for the maintenance of the architecture of the adult small intestine and colon.

Adenoviridae↗

Malignant fibrous histiocytoma metastases to the small intestine and colon presenting as an intussusception.

A case of malignant fibrous histiocytoma metastases to the small intestine and colon presenting as an intussusception is described. Although malignant fibrous histiocytoma is the most common soft tissue sarcoma in late adult life, GI involvement has rarely been reported. The review of both our case and eight cases in the English-language literature suggests that GI involvement from malignant fibrous histiocytoma occurs most frequently in the small intestine (six of nine) and that two major clinical manifestations of GI involvement are GI bleeding (five of nine) from ulcerated tumors and intussusception (two of nine) led by polypoid tumors.

Colonic Neoplasms↗

Small intestinal and colonic changes induced by a chemically defined diet.

Three groups of rats were fed, respectively, a chemically defined diet intragastrically (IG), an equivalent diet intravenously (IV) and solid food orally (CH) for 8 days, and their small intestines and colons compared. All received equal calories. The small intestine was divided into equal proximal (A), middle (B), and distal (C) segments for measurements. Mucosal weight per cm in segments A and B of IG were, respectively, 65 and 38% higher than in IV (P less than 0.01), but 27 and 33% lower than in CH (P less than 0.01). However, in the distal segment, C, mucosal weight in IG was similar to IV and CH was 79% higher (P less than 0.01). DNA and protein followed the same pattern. Segment A sucrase activities were similar in CH and IG and were much higher than in IV (P less than 0.01). Sucrase in IG dropped very rapidly distally so that it became much lower than in CH (P less than 0.05) and similar to IV. Mucosal weight, DNA, and protein in the colon were not significantly different in IG and IV, which were both significantly lower than in CH (P less than 0.01). The results indicate that a chemically defined diet maintains intestinal mass well in the proximal small intestine, but the effect diminishes rapidly in a distal direction so that distal small intestine and colon become atrophied and similar to those in intravenous feeding.

Animals↗

Changes of colonic vasoactive intestinal peptide and cholinergic activity in rats with chemical colitis.

The vasoactive intestinal peptide concentration was examined in the colonic wall and portal venous plasma of rats with chemical colitis by radioimmunoassay, and the colonic localization was determined with immunocytochemistry. Colonic acetylcholine esterase activity was also measured, and the response of vasoactive intestinal peptide to acetylcholine administration was determined. Colitis was induced by administration of dextran sulfate for three months. The chemical colitis was histologically similar to active human ulcerative colitis. We observed a significant increase of immunostained neurons and nerve fibers and a significant rise in the colonic wall vasoactive intestinal peptide content in chemical colitis rats, while plasma concentrations of the peptide did not change significantly. Colonic acetylcholine esterase activity was significantly elevated in colitis rats compared with control rats. Systemic administration of acetylcholine significantly increased the colonic and plasma vasoactive intestinal peptide concentrations in colitis rats. These findings demonstrated a positive association between colitis activity and an increase of vasoactive intestinal peptide and suggested that increased vagal tone promoted the peptide's release.

Acetylcholine↗

Evaluation of the Intelisite capsule to deliver theophylline and frusemide tablets to the small intestine and colon.

The objective of the research was to establish the capability of the Intelisite capsule to deliver the probe drugs, theophylline and frusemide, in the form of split immediate release (IR) tablets, to the small intestine and colon. The two probe drugs were administered together in an open, random, three-way crossover study in eight healthy volunteers, comparing absorption following Intelisite delivery in the small bowel and colon to conventional IR dosing. Gamma scintigraphy was employed to monitor the gastrointestinal transit and activation of the Intelisite capsule. Standard pharmacokinetic parameters, and the percentage remaining in the capsules post defecation were determined. The Intelisite capsule was well tolerated in human volunteers and successfully activated on 15/16 occasions. Pharmacoscintigraphy showed internal marker release from the Intelisite capsule to be approximately 10-fold faster in the small intestine than in the colon. Theophylline and frusemide were both well absorbed following Intelisite activation in the small intestine, whereas complete colonic absorption was only observed in 1/7 subjects for theophylline, and 0/7 subjects for frusemide. The probe drugs were successfully delivered in particulate form from the Intelisite capsule in the small intestine and produced expected pharmacokinetic profiles. However drug release in the colon was incomplete and variable possibly due to: low water content, poor mixing, and a high loading dose.

Adult↗

Anti-diarrhoeal effects of seirogan in the rat small intestine and colon examined in vitro.

BACKGROUND: Seirogan is a beechwood extract composed of guaiacol, creosol and other related phenolic compounds which is widely used as an anti-diarrhoeal agent in Asia. Abnormalities in water and electrolyte transport are often the cause of diarrhoea, but the mechanism of action of seirogan on small intestinal and colonic mucosal ion transport is unknown. AIM: To examine the effect of seirogan on electrogenic ion transport in vitro. METHODS: Sheets of rat jejunum and colon were mounted in Ussing chambers, and transmural potential difference (PD) was used as an electrical marker of changes in mucosal ion transport. Hypersecretory conditions were induced by acetylcholine (ACh). RESULTS: Serosal or mucosal application of seirogan (0.1-100 microg/mL) decreased basal jejunal transmural PD. Pre-treatment of the tissue with the neurotoxin, tetrodotoxin, did not inhibit the seirogan-induced changes in basal electrical activity. Seirogan had no effect on basal transmural PD in the ileum and colon. Under ACh-induced hypersecretory conditions in the small intestine and colon, addition of serosal or mucosal seirogan produced antisecretory effects determined indirectly by measurement of transmural PD. CONCLUSION: The ability of seirogan to decrease basal transmural PD in the jejunum, and inhibit the ACh-induced electrical responses, may contribute to its anti-diarrhoeal action.

Animals↗

Inducible gene knockouts in the small intestinal and colonic epithelium.

We have developed two systems for performing Cre-mediated recombination of target genes in the rapidly self-renewing mouse small intestinal and colonic epithelium. When expression of Cre recombinase is placed directly under the control of transcriptional regulatory elements from a fatty acid-binding protein gene (Fabp), deletion of loxP flanked (floxed) DNA sequences is initiated as early as embryonic day 13.5, well before completion of intestinal morphogenesis. By embryonic day 16.5, Fabp-Cre also directs recombination in all cell layers of the transitional epithelium that lines the renal calyces and pelvis, ureters, and bladder. Fabp-Cre expression and recombination are maintained in both epithelia throughout adulthood. The second system allows recombination to be induced only in the gut and at any period during adulthood. This system uses Fabp regulatory elements to direct expression of a reverse tetracycline-regulated transactivator (rtTA). Another transgene encodes Cre under the control of tet operator sequences and a minimal promoter from human cytomegalovirus (tetO-P(hCMV)-Cre). In the absence of a doxycycline inducer, no basal recombination is detectable in the gut of adult tri-transgenic mice containing Fabp-rtTA, tetO-P(hCMV)-Cre, plus a floxed reporter gene. After 4 days of oral administration of doxycycline, recombination of the reporter is apparent in the small intestinal, cecal, and colonic epithelium. After doxycycline is withdrawn, the recombined locus persists for at least 60 days, indicating that recombination has occurred in epithelial cell progenitors that have long residency times in the proliferative units of the intestine (crypts of Lieberkühn). This inducible system should have a number of applications for examining gene function at selected times in postnatal life, under selected physiologic or pathophysiologic conditions.

Animals↗

Contribution of plasmid-encoded fimbriae and intimin to capacity of rabbit-specific enteropathogenic Escherichia coli to attach to and colonize rabbit intestine.

Attachment to the intestinal mucosa is an essential step in the pathogenesis of diarrhea caused by enteropathogenic Escherichia coli (EPEC). Fimbriae and intimin, the outer membrane protein product of the chromosomal eae gene, contribute to this process, but their relative roles and the nature of their interaction are not known. The aim of this study was to determine the relative contribution of plasmid-encoded fimbriae, termed Ral, and intimin to the capacity of rabbit-specific EPEC (REPEC) to attach to the intestinal mucosa of rabbits. To achieve this, we constructed a series of mutants in REPEC strain 83/39 (O15:H-), in which the ralE and eae genes were insertionally inactivated. These strains were then inoculated into ligated loops of rabbit ileum, which were resected 18 h later and examined by light and electron microscopy. The results showed that intimin, but not Ral, is essential for the elicitation of attaching-effacing lesions by REPEC. Nevertheless, a delta eae Ral-bearing mutant adhered to the intestinal epithelium to the same extent as its eae-positive parent and far more extensively than an eae(+) delta ral strain. To examine the contribution of Ral and intimin to colonization of rabbit intestine, we fed these strains to weanling rabbits, which were killed 4 days later, so that the number of bacteria in various regions of the intestine could be determined. The results indicated that strain 83/39 requires both Ral and intimin to colonize the intestine successfully and that a delta eae delta ralE double mutant was incapable of colonizing the intestine. Taken together, these findings indicate that Ral and intimin act independently as adhesion factors of REPEC strain 83/39 and that this strain carries no other significant colonization factor. When both Ral and intimin are present, they appear to act cooperatively, with Ral-mediated adhesion preceding that mediated by intimin.

Adhesins, Bacterial↗

Ultrastructural modifications of intestinal and colonic mucosa induced by free or bound bile acids.

There is substantial evidence that bile acids may enhance the colon tumorigenesis induced by chemical carcinogens and that agents stimulating increased bile acid excretion may show similar promoting or enhancing activity. To test the premise that these agents might modify topographical ultrastructure of the small intestine and colon in the absence of carcinogens, rats were fed for 6 weeks on chemically defined diets containing 2% levels of three commercial bile acid sequestrants or 15% levels of wheat brain, cellulose, pectin, or alfalfa. Major qualitative and quantitative deviations from normal morphology were observed with each of the three sequestrants. Similar but less dramatic modifications occurred with diets containing alfalfa or pectin, both of which either "bind" bile acids in vitro or result in increased bile acid excretion. Bran and cellulose which neither "bind" bile acids nor increase their fecal excretion, were without significant effects on intestinal or colonic morphology. The morphological deviations observed with bile acid sequestrants were shown to be a direct response to free or bound bile acids by comparing the morphological modifications resulting from daily intracolonic infusions of free bile acids, sequestrant-bound bile acids, or the sequestrant alone.

Animals↗

On the difference between colonic and small intestinal alkaline phosphatase.

Colonic and small intestinal alkaline phosphatase extracts were studied biochemically and electrophoretically to elucidate the source of a reported difference in cellulose acetate electrophoretic mobility. Both preparations were inactivated with 0.5 mmol/L L-phenylalanine but retained full activity in the presence of 1.0 mmol/L tetramisole. Treatment with neuraminidase changed a minor fraction of the small intestinal but the major portion of the colonic alkaline phosphatase to a cathodically migrating form. The most likely explanation for our findings is that the colon and small intestinal alkaline phosphatase are mixtures of the same multiple forms but in different proportions.

Alkaline Phosphatase↗

Invasive amebiasis as an emerging parasitic disease in patients with human immunodeficiency virus type 1 infection in Taiwan.

BACKGROUND: Whether risk of invasive amebiasis due to Entamoeba histolytica is higher among human immunodeficiency virus (HIV)-infected persons than uninfected persons remains unclear, although intestinal colonization by Entamoeba dispar is common among men who have sex with men. Our objective was to determine the prevalence of invasive amebiasis and intestinal colonization by E histolytica and E dispar in HIV-infected persons and uninfected controls. METHODS: We assessed the prevalence of invasive amebiasis by case review of 951 HIV-infected persons and by serologic studies of 634 of the 951 HIV-infected persons, 429 uninfected controls with gastrointestinal symptoms, and 178 uninfected healthy controls using indirect hemagglutination antibody assay. We assessed the rate of intestinal colonization by E histolytica and E dispar by fecal antigen and polymerase chain reaction tests in 332 asymptomatic HIV-infected persons and 144 of the 178 uninfected healthy controls. RESULTS: Forty-nine (5.2%) of 951 HIV-infected persons had 51 episodes of invasive amebiasis. A high indirect hemagglutination antibody titer was detected in 39 (6.2%) of 634 HIV-infected persons compared with 10 (2.3%) of 429 uninfected controls with gastrointestinal symptoms and 0 of 178 uninfected healthy controls (P<.001). Stool specimens from 40 (12.1%) of 332 HIV-infected persons and 2 (1.4%) of 144 uninfected healthy controls were positive for E histolytica or E dispar antigen (P<.001). Ten (25.0%) of the 40 antigen-positive stool specimens from HIV-infected persons contained E histolytica. CONCLUSION: Persons infected with HIV in Taiwan are at increased risk for invasive amebiasis and exhibit a relatively high frequency of elevated antibody titers and intestinal colonization with E histolytica.

AIDS-Related Opportunistic Infections↗

Tissue-specific gene expression results from a purine- and pyrimidine-free diet and 6-mercaptopurine in the rat small intestine and colon.

Dietary purines and pyrimidines are not considered to have a nutritional role, much less a direct effect on the functioning of the gastrointestinal tract. We found that a dramatic decrease in adult rat small intestinal and colonic total ribonucleic acid (RNA) results from the removal of dietary purines and pyrimidines or the administration of 6-mercaptopurine. Ribonucleic acid hybridization analysis indicated specific decrease of the messenger ribonucleic acid (mRNA) for the purine salvage enzymes hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase in the small intestine and proximal colon but not in the liver of animals fed a diet lacking purines and pyrimidines. Levels of intestinal and hepatic beta-actin mRNA transcripts were generally not depressed by either diet or by the administration of 6-mercaptopurine. Liver hypoxanthine-guanine phosphoribosyl transferase and adenine phosphoribosyl transferase mRNAs were unaffected by the change in diet but were lowered by the administration of 6-mercaptopurine. These data indicate that nutrition and 6-mercaptopurine affect both total RNA, and individual mRNA concentrations at specific sites in the gastrointestinal tract. These findings are of potentially great significance because the regulation of intestinal total RNA levels and purine salvage mRNAs by both 6-mercaptopurine and a purine- and pyrimidine-free diet suggests a potential mechanism by which dietary components differentially control specific proteins synthesized in the body. These findings may be related to the efficacy of 6-mercaptopurine as well as so-called elemental diets as therapeutic agents in chronic inflammatory bowel disease (i.e., Crohn's disease).

Adenine Phosphoribosyltransferase↗