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PubMed2000

Blood group antigen expression in the rat colon I. age-dependent and region-related changes.

The blood group antigens H, A, B, and Le(b) are oncofetal antigens of the human distal colon. Although these antigens are present in the digestive mucosa of the rat, little is known about their ontogenic expression in the developing rat colon. The present study was undertaken to assess age-dependent and region-related changes of blood group antigens during colonic development and maturation with the aim of determining their fetal phenotype. Antigen expression was assessed by immunohistochemistry using H-, A-, B-, Le(a)-, and Le(b)-specific monoclonal antibodies and formalin-fixed, paraffin-embedded colon sections from fetal, suckling, weanling, and adult rats. Staining of antigen was analyzed with respect to its locations in colonic goblet cells, brush borders, and columnar cells. H, B, and Le(b) antigens were expressed by goblet cells of the distal colon, beginning at 20 days of gestation, but expression was lost from the colon during the first postnatal week, thus exhibiting a fetal phenotype. H and Le(b), but not B, were also expressed by goblet cells of the fetal proximal colon; however, unlike that of the distal colon, their expression increased progressively during postnatal development until adulthood. Fetal phenotypic expression was observed in the brush border of the proximal and distal colon for H antigen, whereas it was observed in that of the distal colon for B antigen. No fetal phenotypic expression of H, B, and Le(b) by columnar cells of the colon was observed. Antigen A was expressed by goblet cells, brush border, and columnar cells of the entire colon at all ages, in concert with the development and maturation of the colon. Therefore, its expression in the rat colon was not fetal in nature. Le(a) was not detected in the colon at any age, except for some sporadic staining in the Golgi zone of columnar cells of the postnatal proximal colon. In conclusion, these data indicate significant age- and region-related changes of blood group antigen expression in the rat colon. Because the fetal phenotypic expression of H, B, and Le(b) by goblet cells of the distal colon mimics that in the human distal colon, the adult rat colon is a potentially useful model for assessing the effects of cocarcinogenic dietary factors, including ethanol, that may induce reexpression of these so-called oncofetal tumor-associated antigens of the colon.

ABO Blood-Group System↗

PubMed2000

Enterochromaffin and serotonin cells are abnormal for patients with colonic inertia.

PURPOSE: In recent studies, serotonin and several gut peptides have been shown to serve as regulators of colonic transit. Thus, the distribution, density, and intensity of cells secreting serotonin or certain gut peptides could be abnormal in patients with colonic inertia. The aim of this study was to evaluate the distribution, density, and staining intensity of enterochromaffin and serotonin cells in the colonic mucosa of patients with colonic inertia compared with a control group. METHODS: Between 1993 and 1998 tissue blocks from the right and left side of the colon were obtained in 19 consecutive patients (18 females; mean age, 43.7 +/- 11.5 years) who underwent subtotal colectomy for colonic inertia. The control group consisted of colonoscopic biopsies from the right and left colon of 15 patients (all females; mean age, 52.7 +/- 16.5 years) for indications other then constipation, inflammatory bowel diseases, or carcinoma. Immunocytochemical staining of enterochromaffin and serotonin cells were performed on 4 microm tissue sections with the primary rabbit antibody against chromogranin A or serotonin, and the biotinylated secondary antibody and enzyme-labeled-streptavidin. The average cell number per microscopic field (x200) was calculated and the proportion of cells with various staining distribution was expressed as the percentage of the entire positive cell population as low, moderate, and high intensity. Student's t-test and chi-squared test were used for statistical analysis, with significance level set at P < 0.05. RESULTS: The quantity of both enterochromaffin cells (16.8 +/- 10.2) and serotonin cells (12.1 +/- 6.4) in the mucosa of the left colon in patients with colonic inertia was significantly higher when compared with the right side of the colon (enterochromaffin cells, 9.4 +/- 6.0; serotonin cells, 7.8 +/- 3.6; P < 0.01). The percentage of both types of cells with low staining intensity was increased, whereas the cells with high and moderate staining intensity were decreased (P < 0.01) in the left colon as compared with the right. The number of enterochromaffin cells in left-sided colonic mucosa was significantly higher in the colonic inertia group than in the control group (16.8 +/- 10.1 vs. 10.4 +/- 6.0; P < 0.05). Moreover, the numbers of serotonin cells in both the right and left colon was also significantly higher in the colonic inertia group than in the control group (right, 7.8 +/- 3.6 vs. 4.1 +/- 2.4; left, 12.1 +/- 6.4 vs. 5.8 +/- 3.7; P < 0.01). In both sides of the colon, the percentage of enterochromaffin and serotonin cells with low staining was significantly higher, whereas percentage of those cells with high or moderate staining was significantly lower in the colonic inertia group than in the control group. In the colonic inertia group there was a significantly positive correlation between numbers of enterochromaffin and serotonin cells (right side, P < 0.01; left side, P < 0.05). CONCLUSION: In patients with colonic inertia, the number of both enterochromaffin and serotonin cells are significantly increased in the colonic mucosa, especially in the left colon. As indicated by staining distribution, enterochromaffin and serotonin cells contain significantly less hormone than do the same cells in the control group.

Adult↗

PubMed1995

Effect of beta-carotene supplementation on indices of colonic cell proliferation.

BACKGROUND: Epidemiologic studies have shown that consuming foods containing beta-carotene is associated with a decreased incidence of colon cancer. The validity of this association has recently been questioned. It is not known if the rate of colonic cell proliferation differs among individuals with or without a history of colonic polyps or cancer and if proliferation changes in response to beta-carotene. PURPOSE: This study was intended to (a) determine whether differences exist in colonic cell proliferation in individuals with and without prior colonic polyps or tumors, (b) demonstrate that beta-carotene accumulates in colonic mucosa following dietary supplementation, and (c) determine whether mucosal beta-carotene accumulation influences colonic cell proliferation. METHODS: Subjects were enrolled in the phase I study from June 1991 until February 1994. The participants included 20 individuals (11 males and nine females, aged 62.3 +/- 8.9 years [means +/- SD]) with normal colons (as judged by recent colonoscopy), 40 (24 males and 16 females, aged 59.6 +/- 10.1 years) with a history of colonic polyp(s), and 41 (30 males and 11 females, aged 67.2 +/- 9.7 years) with prior colon cancer. The subjects in the last two groups consumed either 30 mg of beta-carotene or placebo each morning for 3 months. This dose of beta-carotene has no known toxic effects, but it can increase the serum level by approximately 10-fold. beta-carotene concentration in serum and colonic tissue was quantitated by high-pressure liquid chromatography in samples collected before and after supplementation with beta-carotene or placebo. Cellular proliferation was assessed on the basis of tissue ornithine decarboxylase activity, urinary polyamine excretion, and proliferating cell nuclear antigen expression. The differences in colonic cell proliferation parameters due to beta-carotene supplementation, within and among different groups, were evaluated by the Wilcoxon matched-pairs signed ranked test and the Mann-Whitney test, respectively. All statistical tests were two-sided. RESULTS: Colonic cell proliferation did not differ in samples obtained from individuals with and without prior colonic polyp(s) or cancer. beta-carotene concentrations in serum and colonic tissue were significantly increased in groups receiving beta-carotene (P < .001). However, cell proliferation did not differ, as judged by any of the three measures, among samples from all experimental groups collected before and after supplementation with beta-carotene. CONCLUSIONS: Dietary supplementation with beta-carotene for a period of 3 months does not alter colonic cell proliferation in individuals with a history of colonic polyps or cancer. IMPLICATIONS: The mechanism by which beta-carotene might reduce colon cancer incidence does not appear to involve or result in a change in cell proliferation in the normal colonic mucosa as studied in individuals with a history of colonic polyps or cancer.

Adult↗

PubMed1990

Retention of in vivo antipyrimidine effects of Brequinar sodium (DUP-785; NSC 368390) in murine liver, bone marrow and colon cancer.

Brequinar sodium (DUP-785) is a potent inhibitor of the pyrimidine de novo enzyme, dihydroorotic acid dehydrogenase (DHO-DH). In order to determine whether in vitro data could be extrapolated to the in vivo situation we investigated antipyrimidine effects of DUP-785 in mice bearing colon cancer. Two tumor models were used, Colon 26 and Colon 38, resistant and moderately sensitive to DUP-785, respectively. DUP-785 at 50 mg/kg caused a depletion of plasma uridine in mice, and depleted tissue uridine levels in Colon 38 down to 10%, which was retained for several days; in Colon 26 the decrease was less and tissue uridine levels recovered rapidly. In livers of these mice no significant effect on uridine was observed. DUP-785 depleted UTP in bone marrow cells within 2 hr to 25% of control levels, after 4 days normal levels were found. In livers of both Balb-c mice (bearing Colon 26) and C57Bl/6 mice (bearing Colon 38) a small decrease of uridine nucleotide pools was found. In Colon 26 DUP-785 increased uridine nucleotide pools to 170% after 2 hr, at 1 day normal levels were observed, but after 2 days again an increase was found. In Colon 38 DUP-785 decreased the uridine nucleotide pool by 50% after 1 and 2 days. DUP-785 did not affect cytidine nucleotide pools of livers and of Colon 26 and Colon 38. The ratio between uridine nucleotides and cytidine nucleotides decreased from 2.2 to 0.90 in Colon 38, in the other tissues the decrease was less. DHO-DH was measured in bone marrow cells and Colon 26 and 38 before and after treatment. Basal levels of DHO-DH were 3 times higher in Colon 26 than in Colon 38. In treated tumors DHO-DH was initially inhibited by more than 90%, after 7 days enzyme activity in Colon 26 was 50% and in Colon 38 about 200% of basal levels. In bone marrow cells DHO-DH was also rapidly inhibited but recovered within 4 days. It is concluded that the retention of antipyrimidine effects of DUP-785 in Colon 38 were more pronounced than in Colon 26, which is in agreement with the better antitumor effect of DUP-785 in Colon 38.

Animals↗

PubMed2005

Determination of optical properties of normal and adenomatous human colon tissues in vitro using integrating sphere techniques.

AIM: The purpose of the present study is to compare the optical properties of normal human colon mucosa/submucosa and muscle layer/chorion, and adenomatous human colon mucosa/submucosa and muscle layer/chorion in vitro at 476.5, 488, 496.5, 514.5 and 532 nm. We believe these differences in optical properties should help differential diagnosis of human colon tissues by using optical methods. METHODS: In vitro optical properties were investigated for four kinds of tissues: normal human colon mucosa/submucosa and muscle layer/chorion, and adenomatous human colon mucosa/submucosa and muscle layer/chorion. Tissue samples were taken from 13 human colons (13 adenomatous, 13 normal). From the normal human colons a total of 26 tissue samples, with a mean thickness of 0.40 mm, were used (13 from mucosa/submucosa and 13 from muscle layer/chorion), and from the adenomatous human bladders a total of 26 tissue samples, with a mean thickness of 0.40 mm, were used (13 from mucosa/submucosa and 13 from muscle layer/chorion). The measurements were performed using a double-integrating-sphere setup and the optical properties were assessed from these measurements using the adding-doubling method that was considered reliable. RESULTS: The results of measurement showed that there were significant differences in the absorption coefficients and scattering coefficients between normal and adenomatous human colon mucosa/submucosa at the same wavelength, and there were also significant differences in the two optical parameters between both colon muscle layer/chorion at the same wavelength. And there were large differences in the anisotropy factors between both colon mucosa/submucosa at the same wavelength, there were also large differences in the anisotropy factors between both colon muscle layer/chorion at the same wavelength. There were large differences in the value ranges of the absorption coefficients, scattering coefficients and anisotropy factors between both colon mucosa/submucosa, and there were also large differences in these value ranges between both colon muscle layer/chorion. There are the same orders of magnitude in the absorption coefficients for four kinds of colon tissues. The scattering coefficients of these tissues exceed the absorption coefficients by at least two orders of magnitude. CONCLUSION: There were large differences in the three optical parameters between normal and adenomatous human colon mucosa/submucosa at the same laser wavelength, and there were also large differences in these parameters between both colon muscle layer/chorion at the same laser wavelength. Large differences in optical parameters indicate that there were large differences in compositions and structures between both colon mucosa/submucosa, and between both colon muscle layer/chorion. Optical parameters for four kinds of colon tissues are wavelength dependent, and these differences would be useful and helpful in clinical applications of laser and tumors photodynamic therapy (PDT).

Adenomatous Polyposis Coli↗

PubMed1985

16,16-Dimethyl prostaglandin E2 suppresses the increases in the proliferative activity of rat colonic epithelium induced by indomethacin and aspirin.

Treatment of rats with indomethacin rapidly increased ornithine decarboxylase (4 h) of colonic mucosa and [3H]thymidine incorporation into colonic mucosal deoxyribonucleic acid (DNA) (1 or 5 days) when this parameter was examined in vivo and ex vivo. The changes in colonic mucosal ornithine decarboxylase and DNA synthesis induced by indomethacin were correlated temporally with suppression of colonic prostaglandin synthesis, as assessed from ex vivo colonic production of prostaglandin E, the dominant prostaglandin product of colon. Autoradiographic studies indicated that the enhancement of proliferative activity of colonic epithelium after treatment with indomethacin for 1 day was confined to the lower third of the colonic crypt (normal proliferative zone). After 5 days of indomethacin treatment, however, there was an extension of the proliferative zone to the upper third of the colonic crypts. Concurrent treatment of rats with the stable prostaglandin E2 analogue, 16,16-dimethyl prostaglandin E2, suppressed indomethacin-induced increases in colonic mucosal ornithine decarboxylase and DNA synthesis. Concurrent administration of 16,16-dimethyl prostaglandin E2 also prevented the extension of the proliferative zone of colonic epithelium induced by 5 days of indomethacin administration. 16,16-Dimethyl prostaglandin E2 alone for 1-5 days had no detectable effects on colonic mucosal ornithine decarboxylase and DNA synthesis compared with corresponding control values. Increases in colonic mucosal DNA synthesis were also induced by treatment of rats for 5 days with aspirin (ASA). The stimulation of colonic mucosal DNA synthesis induced by ASA was significantly suppressed by concurrent administration of 16,16-dimethyl prostaglandin E2 and was also correlated with the inhibition of colonic prostaglandin synthesis by ASA. The colons of rats treated with indomethacin for 1 day or ASA for 5 days appeared normal by light microscopy. However, treatment of rats for 5 days with indomethacin resulted in mild to moderate inflammation of the lamina propria and some goblet cell depletion at the mucosal surface, but no loss of surface epithelium. The ultrastructure of the surface epithelium of the colons of rats treated with indomethacin or ASA was normal as assessed by electron microscopy. The results thus demonstrate that inhibition of local colonic prostaglandin synthesis is associated with increases in the proliferative activity of colonic epithelium, and that these increases are suppressed by administration of 16,16-dimethyl prostaglandin E2.(ABSTRACT TRUNCATED AT 400 WORDS)

16,16-Dimethylprostaglandin E2↗

PubMed2003

[CT-colonography with the 16-slice CT for the diagnostic evaluation of colorectal neoplasms and inflammatory colon diseases].

PURPOSE: Comparison of the performance of virtual and conventional colonoscopy for the detection of colorectal polyps and inflammatory colon diseases using a 16-slice spiral CT scanner. Furthermore, presentation of the first experiences with a new three-dimensional reconstruction mode ("colon-dissection") that dissects the colonic wall like a pathologic-anatomic preparation to increase the sensitivity. MATERIALS AND METHODS: Forty patients were studied using a 16-slice spiral CT (Lightspeed 16, General Electric Medical Systems, Milwaukee, Wisconsin 53201, USA). The examination was performed after standard oral preparation for colonoscopy. The colonic distension was achieved with room air and intravenous butylscopolamine. Images were obtained in supine and prone position using a detector configuration of 16 x 0.625 mm, pitch 1.7, rotation time 0.5 s, 160 mAs and 120 kV. Axial reconstruction with a slice thickness of 0.625 mm. The CT data were assessed by two radiologists on an Advantage Workstation (Volume Analysis 2, USA) using a software with the capabilities of axial, multiplanar and volume rendering, virtual endoscopy, and colon dissection. Conventional colonoscopy was used to determine the sensitivity. RESULTS: A total of 30 polyps were found in 8 patients and a carcinoma was detected in two patients. Colonography identified 4 polyps with a diameter of 10 mm or more, 6 polyps with a diameter of 5 mm to 9.9 mm, 11 polyps with a diameter of 3 to 4.9 mm and 9 polyps with a diameter of 3.0 mm or less. There were two false negative findings (one polyp of 3 mm and one of 4 mm had been overseen) and two false positive findings for polyps (polyps of 4 mm and 6 mm). The sensitivity and specificity for the detection of colonic polyps were 93% and 94% with the "colonic-dissection" mode, 87 % and 94 % with the "virtual-endoscopy" mode and 63 % and 97 % with multi-planar reconstruction, respectively. Depending on the diameter of the colonic polyps, the "colon-dissection" mode ("virtual-coloscopy") had a sensitivity and specificity of 100 % and 100 % for polyps with a diameter over 5.0 mm, 91 % and 82 % for polyps with a diameter from 3.0 to 4.9 mm and 89 % and 78 % for polyps with a diameter under 3.0 mm, respectively. Inflammatory colon diseases presented as thickening of the colon wall over 5 mm. CONCLUSIONS: Virtual colonoscopy with 16-slice spiral CT allows accurate detection of colonic polyps, including small polyps below a diameter of 3 mm. In comparison with the 2D- and 3D-"virtual-endoscopic" reconstruction, the 3D-reconstruction software "colon-dissection" achieves the highest sensitivity for the detection of colonic masses. Therefore, the combination of a 16-slice spiral CT and the "colon-dissection" reconstruction software provides a high resolution in the z-axis for detecting colonic masses and polyps down to a diameter of less than 2 mm, with a sensitivity of about 90 %. This sensitivity is much higher than the sensitivity achievable with 4-slice spiral CT and without "colon-dissection" mode. A thickened colon wall over 5 mm indicates inflammatory colon disease.

Colonic Polyps↗

PubMed1994

Family history of cancer and colon cancer risk: the Utah Population Database.

BACKGROUND: Family history of colon cancer has been shown to be related to the risk of developing colon cancer. The impact that a comprehensive family history of colon or other cancers has on the risk of colon cancer has not been thoroughly studied. PURPOSE: The purpose of this study was to assess the risk of developing colon cancer associated with having a family history of colon, rectal, breast, ovarian, endometrial, or prostate cancer. METHODS: A case-control study was conducted using data from the Utah Population Database. Case patients had first primary colon cancers (n = 2543). Three control subjects per case were individually matched to case patients on year of birth, place of birth, marital status, and sex. RESULTS: Those case patients with the highest familial standardized incidence ratio were at an increased risk of developing colon cancer (for men, odds ratio [OR] = 2.51 and 95% confidence interval [CI] = 1.88-3.29; for women, OR = 2.90 and 95% CI = 2.17-3.82). A second- or third-degree relative with colon cancer increased risk from 25% to 52%. Risk associated with family history was greater in those patients diagnosed before age 50 (for men, OR = 3.61 and for women, OR = 7.18) than in those diagnosed at 50 or more years of age (for men, OR = 2.44 and for women, OR = 2.73). The risk associated with a family history of colon cancer was greatest for the distal segment of the colon. Women were at an increased risk of colon cancer if they had a first-degree relative with breast (OR = 1.59; 95% CI = 1.25-2.03), uterine (OR = 1.50; 95% CI = 0.99-2.26), ovarian (OR = 1.63; 95% CI = 1.41-1.89), or prostate (OR = 1.49; 95% CI = 1.21-1.82) cancer; men were at increased risk of colon cancer if they had a first-degree relative with breast (OR = 1.30; 95% CI = 1.02-1.66), uterine (OR = 1.96; 95% CI = 1.34-2.87), or ovarian (OR = 1.59; 95% CI = 0.90-2.81) cancer. CONCLUSIONS: These findings support previous observations that people with a family history of colon cancer are at increased risk of colon cancer. Those with a second- or third-degree relative with colon cancer or a first-degree relative with breast, ovarian, uterine, or prostate cancer also have an increased risk of developing colon cancer. IMPLICATIONS: These data support the recommendations that individuals who have a first-degree, and possibly a second- or third-degree, relative with colon cancer should have regular screening for colon cancer.

Adult↗

PubMed1983

Neurohumoral control of colonic motility in the rabbit.

Colonic motility was examined in the proximal (taeniated) and distal (nontaeniated) colon of New Zealand White rabbits. Colonic myoelectric and contractile activities were recorded by bipolar electrodes and extraluminal strain gauges sewn on the antimesenteric serosal surface of the proximal and distal colon. Slow-wave frequency consistently was slower in the proximal colon (13.2 +/- 0.9) compared with the distal colon (15.8 +/- 1.2) (P less than 0.05). During the control period 81.8 +/- 5.2% of slow waves have superimposed spike potentials in the proximal colon. The distal colon had similar amounts of spike activity. The distal colon had increased base-line contractility (P less than 0.02). Atropine inhibited spike and contractile activity on both sides of the colon, but the distal colon still had more contractile activity than the proximal colon (P less than 0.02). The alpha-adrenergic agonist phenylephrine and antagonist phentolamine had no effect on colonic motility. Isoproterenol inhibited colonic smooth muscle spike and contractile activity. This effect was blocked by propranolol. Administration of trimethaphan camsylate caused an increase in spike and contractile activity only in the distal colon. The effect of trimethaphan on the distal colon was inhibited by atropine. These studies show that 1) tonic cholinergic stimulation exists both in the proximal and in the distal colon, 2) circulating catecholamines have minimal effect on base-line colonic motility, and 3) tonic nonadrenergic inhibition of the distal colon modulates the tonic cholinergic stimulation.

Animals↗

PubMed1996

The microvascular structure of the normal colon in rats and humans.

The colonic microcirculation may be expected to have a central role in the absorptive, secretory, and protective functions of the colon. To characterize the microvascular structure of the colon in rats and humans, microvascular casts were prepared and examined by scanning electron microscopy. Quantitative measures of the microvasculature were obtained from histological sections. The overall organization of microvessels was found to be similar in the rat and human colon. Capillaries in the colonic mucosa formed a honeycomb-like network around each of the mucosal glands. This capillary plexus was supplied by arterioles which divide into their capillary branches at the level of the submucosa. Mucosal capillaries drain into venules at the luminal surface of the mucosa. Venules then pass to submucosal veins without receiving further capillary branches. Examination of vascular casts also showed that in both the rat and the human colon, there was an increased density of subluminal capillaries in the cecum and proximal colon compared to that of the rest of the colon. This was supported by quantitative measures which indicated a significantly greater microvascular surface area in the rat cecum (24.1 mm2/mm3) compared to that of the midcolon (19.8 mm2/mm3) (P = 0.04) and the distal colon (19.1 mm2/mm3) (P = 0.03). Similarly in the human colon there was a significantly greater total microvascular volume in the proximal colon (13.4%) compared to that of the distal colon (7.7%) (P < 0.0005) and there was a significantly greater total microvascular surface area in the proximal colon (22.4 mm2/mm3) compared to that of the distal colon (17.5 mm2/mm3)(P=0.032). This study details quantitative vascular data for the colon in rats and humans which has not previously been documented, despite its important role in the absorptive function of the colon and in many disease processes affecting the colon. These data provide the normal values with which pathological conditions of the colon which affect the vasculature can be compared.

Animals↗

PubMed2001

Nonfixation of an atretic colon predicts Hirschsprung's disease.

PURPOSE: After noting the colon to be nonfixed and coiled in the pelvis of a patient with colonic atresia and total colonic Hirschsprung's disease, the authors sought to determine whether this colonic position might be predictive of aganglionosis in the atretic colon. METHODS: The authors reviewed all cases of colonic atresia treated in their institution over the past 2 decades with regard to colonic orientation and the presence of aganglionosis. RESULTS: We identified 9 patients with colonic atresia. Two of these patients, as well as one patient with ileal atresia, also had long-segment Hirschsprung's disease. All 3 of these patients had foreshortened nonfixed colons located predominantly in the pelvis. None of the other 6 patients with colonic atresia had this configuration. Reviewing 12 reported cases from other institutions of total colonic aganglionosis associated with atresia, 7 appear to have had a pelvic nonfixed colon; colonic orientation could not be determined from the remaining reports. The diagnosis of Hirschsprung's disease was not established in any case before repair of the atresia, and each patient required a secondary enterostomy. CONCLUSIONS: An early gestational atresia, occurring before secondary retroperitoneal fixation of the colon at approximately 11 weeks may result in interruption of caudal migration of enteric nerves manifesting as Hirschsprung's disease distal to the atresia. Moreover, the aganglionosis may be predicted by a foreshortened, nonfixed colon coiled in the pelvis. Thus, biopsy of the colon should be performed at initial exploration in all cases of atresia in which the colon is not properly fixated to avoid immediate or delayed anastomosis to an aganglionic colon.

Colon↗

PubMed2004

Colonization of the neonatal rat intestinal tract from environmental exposure to the anaerobic bacterium Oxalobacter formigenes.

Oxalobacter formigenes, an anaerobic bacterium that inhabits the mammalian gastrointestinal tract, has an important symbiotic relationship with its vertebrate hosts by regulating oxalic acid homeostasis. Epidemiological studies of O. formigenes colonization in man have shown that colonization occurs in young children, that every child can become colonized naturally, that >20% lose colonization during adolescence or as adults and that stable colonization can be disrupted by antibiotic use or changes in diet, greatly affecting subsequent health. As O. formigenes is a fastidious anaerobe that seldom re-colonizes adults, the question arises as to how initial colonization occurs. To investigate this question, non-colonized female laboratory rats were placed on diets high in oxalate and were colonized by oesophageal gavage with O. formigenes either before or after being impregnated. Faecal specimens from their offspring were tested for the presence of O. formigenes. Although the bacterium was first detected in a few neonates as early as 7 days post-partum, colonization of all the offspring did not occur until after weaning. In each case, the offspring were colonized with the bacterial strain carried by their mothers. To determine whether O. formigenes colonization occurs vertically or horizontally, newborn rats were placed with foster mothers that were either non-colonized or colonized with an O. formigenes strain different from that of their natural mothers. Colonization occurred temporally in a manner similar to natural colonization but all offspring became colonized only with the O. formigenes strain of the foster mothers. These data indicate that intestinal colonization occurs horizontally, but does not answer the question of how O. formigenes survives the aerobic environment in order to be transmitted.

Animals↗

PubMed2005

Cytolethal distending toxin is essential for Helicobacter hepaticus colonization in outbred Swiss Webster mice.

Helicobacter hepaticus, which induces chronic hepatitis and typhlocolitis in susceptible mouse strains, produces a cytolethal distending toxin (CDT) consisting of CdtA, CdtB, and CdtC. A cdtB-deficient H. hepaticus isogenic mutant (HhcdtBm7) was generated and characterized for colonization parameters in four intestinal regions (jejunum, ileum, cecum, and colon) of outbred Swiss Webster (SW) mice. Inactivation of the cdtB gene abolished the ability of HhcdtBm7 to colonize female mice at both 8 and 16 weeks postinfection (wpi), whereas HhcdtBm7 colonized all of four intestinal regions of three of five males at 8 wpi and then was eliminated by 16 wpi. Wild-type (WT) H. hepaticus was detected in the corresponding intestinal regions of both male and female mice at 8 and 16 wpi; however, colonization levels of WT H. hepaticus in the cecum and colon of male mice were approximately 1,000-fold higher than in females (P < 0.0079) at 16 wpi. Infection with WT H. hepaticus, but not HhcdtBm7, at 8 wpi was associated with significantly increased mRNA level of ileal and cecal gamma interferon (IFN-gamma) in females (P < 0.016 and 0.031 between WT H. hepaticus-infected and sham-dosed females, respectively). In contrast, the mRNA levels of IFN-gamma were significantly higher in the colon (P < 0.0079) and trended to be higher in the cecum (P < 0.15) in the HhcdtBm7-colonized male mice versus the sham-dosed controls at 8 wpi. In addition, mRNA levels of ileal IFN-gamma were significantly higher in the control females than males at 8 wpi (P < 0.016). There were significantly higher Th1-associated immunoglobulin G2a (IgG2a), Th2-associated IgG1 and mucosal IgA (P < 0.002, 0.002, 0.002, respectively) responses in the mice infected with WT H. hepaticus when compared to HhcdtBm7 at 16 wpi. Colonic interleukin-10 (IL-10) expressions at 16 wpi were significantly lower in both female and male mice colonized by WT H. hepaticus or in males transiently colonized through 8 wpi by HhcdtBm7 versus control mice (P < 0.0159). These lines of evidence indicate that (i) H. hepaticus CDT plays a crucial role in the persistent colonization of H. hepaticus in SW mice; (ii) SW female mice are more resistant to H. hepaticus colonization than male mice; (iii) there was persistent colonization of WT H. hepaticus in cecum, colon, and jejunum but only transient colonization of H. hepaticus in the ileum of female mice; (iv) H. hepaticus colonization was associated with down-regulation of colonic IL-10 production.

Animals↗

PubMed1999

Novel oral colon-specific drug delivery systems for pharmacotherapy of peptide and nonpeptide drugs.

The increasing number of peptide and protein drugs being investigated demands the development of dosage forms which exhibit site-specific release. Delivery of drugs into systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that are poorly absorbed from the upper gastrointestinal (GI) tract. Oral colon-specific drug delivery systems offer obvious advantages over parenteral administration. Colon targeting is naturally of value for the topical treatment of diseases of the colon such as Crohn's disease, ulcerative colitis and colorectal cancer. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Peptides, proteins, oligonucleotides and vaccines are the potential candidates of interest for colon-specific drug delivery. Sulfasalazine, ipsalazide and olsalazine have been developed as colon-specific delivery systems for the treatment of inflammatory bowel disease (IBD). The vast microflora and distinct enzymes present in the colon are being increasingly exploited to release drugs in the colon. Although the large intestine is a potential site for absorption of drugs, some difficulties are involved in the effective local delivery of drugs to the colon bypassing the stomach and small intestine. Furthermore, differential pH conditions and long transit time during the passage of drug formulations from mouth to colon create numerous technical difficulties in the safe delivery of drugs to the colon. However, recent developments in pharmaceutical technology, including coating drugs with pH-sensitive and bacterial degradable polymers, embedding in bacterial degradable matrices and designing into prodrugs, have provided renewed hope to effectively target drugs to the colon. The use of pH changes is analogous to the more common enteric coating and consists of employing a polymer with an appropriate pH solubility profile. The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the GI tract. Polysaccharide and azopolymer coating, which is refractory in the stomach and small intestine yet degraded by the colonic bacteria, have been used as carriers for colon-specific targeting. Finally, the availability of optimal preclinical models and clinical methods fueled the rapid development and evaluation of colon-specific drug delivery systems for clinical use. Future studies may hopefully lead to further refinements in the technology of colon-specific drug delivery systems and improve the pharmacotherapy of peptide drugs.

Journal Article↗

PubMed1991

Physiology and pathophysiology of colonic motor activity (2).

The basic motor function of the colon is to mix and knead its contents, propel them slowly in the caudad direction, hold them in the distal colon until defecation, and provide a strong propulsive force during defecation. Infrequently, it also produces mass movements in the proximal colon. These motor functions are achieved in most species by three different types of contractions: the individual phasic contractions that include the short- and long-duration contractions, organized groups of contractions that include the migrating and nonmigrating motor complexes, and special propulsive contractions (giant migrating contractions). The spatial and temporal patterns of all of these contractions are controlled by myogenic, neural, and chemical control mechanisms. The individual phasic contractions are highly disorganized in time and space in the colon. For this reason, they are effective in mixing and kneading and slow distal propulsion. The underlying cause of the disorganization of short duration contractions is the irregularity in the frequency and waveshape of colonic electrical control activity and its phase unlocking throughout the colon. The individual contractions in many species occur in cyclic bursts called contractile states. At least in some species, these contractile states exhibit mostly caudad and sometimes orad migration. However, there are also nonmigrating or randomly migrating contractile states in the colon. These two patterns of contractile states are called colonic migrating motor complexes and colonic nonmigrating motor complexes, respectively. The giant migrating contractions provide the strong propulsive force for defecation and mass movements. The neural control of colonic contractions is organized at three levels--enteric, autonomic, and central. The enteric nervous system contains cholinergic and peptidergic neurons and plays a major role in the control of colonic contractions. The autonomic nerves, the vagi, pelvic, lumbar colonic, hypogastric, and splanchnic nerves, seem to continuously monitor the state of the colon and provide a modulatory input when necessary. These nerves play a major role in the reflexive control of colonic motor function. The voluntary input from the central nervous system coordinates the motor activity of the colon, rectum, anal canal and sphincters for orderly evacuation of feces during defecation. The role of acetylcholine, nonadrenaline, and the yet to be completely identified nonadrenergic, noncholinergic neurotransmitter, possibly VIP, in the control of contractions is fairly well established. Besides these, there are several other peptides and chemicals that are localized in the colonic wall; their physiological roles remain unknown. Colonic motor activity has been studied in several disease states. The findings have not always been consistent.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗

PubMed1995

Increased N-myristoyltransferase activity observed in rat and human colonic tumors.

BACKGROUND: Colorectal cancer is one of the leading causes of cancer death in North America. Since treatment of colonic cancer remains difficult because of the lack of effective chemotherapeutic agents, it is important to continue to search for cellular functions that can be disrupted by chemotherapeutic drugs and inhibit the development or progression of this disease. Modification of proteins by myristoylation has been recognized as important in the function of various viral, oncogenic, and signal-transduction proteins and thus has been proposed as a target for chemotherapeutic drug design. However, the activity of the enzyme that catalyzes this modification, N-myristoyltransferase, has not been investigated in cancer relative to normal tissue. PURPOSE: The purpose of this study was twofold: 1) to investigate the activity of N-myristoyltransferase in azoxymethane-induced rat colonic cancer tissue compared with normal and normal-appearing rat colonic tissue and 2) to determine if similar differences would be observed in a small sample of human colonic tumors. METHODS: N-Myristoyltransferase activity was determined in 45 colonic tissue specimens from Sprague-Dawley rats--10 given injections of the colon carcinogen, azoxymethane, and three untreated. Tissue specimens included 35 colonic tumors of varying pathologic stages, seven specimens of normal-appearing adjacent mucosa, and three specimens of normal colonic mucosa. Colectomy specimens from five patients were assayed for N-myristoyltransferase activity. Subcellular distribution of N-myristoyltransferase activity was determined. Synthetic peptides of known myristoylated proteins--pp60src and cyclic adenosine monophosphate-dependent protein kinase--were used in kinetic analyses of N-myristoyltransferase in colonic cancer and normal-appearing colonic tissue. All P values are two-tailed. RESULTS: N-Myristoyltransferase activity was increased in rat colonic tumors compared with normal-appearing adjacent mucosa and normal mucosa (P = .0002). Elevation of N-myristoyltransferase activity was present in all tumors, including colonic polyps. Increased N-myristoyltransferase activity was also observed in human colonic tumors and was predominantly cytosolic. N-Myristoyltransferase of colonic cancer tissues had a similar Michaelis constant but an approximate twofold higher maximum velocity for both the pp60src- and cyclic adenosine monophosphate-dependent protein kinase-derived peptides compared with N-myristoyltransferase of normal-appearing tissue. CONCLUSIONS: This study demonstrates for the first time that N-myristoyltransferase activity is higher in colonic epithelial neoplasms than in normal-appearing colonic tissue and that an increase in N-myristoyltransferase activity appears at an early stage in colonic carcinogenesis.

Acyltransferases↗

PubMed2004

Downregulation of prostaglandin E receptor subtype EP3 during colon cancer development.

BACKGROUND AND AIMS: Involvement of prostaglandin E(2) (PGE(2)) receptors EP(1), EP(2), and EP(4) in the formation of aberrant crypt foci (ACF) and/or intestinal polyps has been suggested. In contrast, EP(3) appears to have no influence on the early stages of colon carcinogenesis. In the present study, we examined expression of PGE(2) receptor subtypes EP(1), EP(2), EP(3), and EP(4) in normal colon mucosa and colon cancers, and assessed the contribution of EP(3) to colon cancer development. METHODS: mRNA expression of PGE(2) receptor subtypes EP(1), EP(2), EP(3), and EP(4) in normal colon mucosa and colon cancers in azoxymethane (AOM) treated mice and rats, and in humans, were examined by reverse transcription-polymerase chain reaction (RT-PCR), quantitative real time RT-PCR, and immunohistochemical analyses. Evaluation of the role of EP(3) was performed by intraperitoneal injection of AOM, using EP(3) receptor knockout mice. Effects of EP(3) receptor activation on cell growth of human colon cancer cell lines were examined using ONO-AE-248, an EP(3) selective agonist. Moreover, EP(3) expression in colon cancer cell lines was analysed with or without 5-aza-2'-deoxycytidine (5-aza-dC) treatment. RESULTS: Expression levels of EP(1) and EP(2) mRNA were increased in cancer tissues. EP(4) mRNA was constantly expressed in normal mucosa and cancers. In contrast, expression of EP(3) mRNA was markedly decreased in colon cancer tissues, being 5% in mice, 9% in rats, and 28% in humans compared with normal colon mucosa, analysed by quantitative real time RT-PCR. Immunohistochemical staining demonstrated the rat EP(3) receptor protein to be expressed in epithelial cells of normal mucosa and some parts of small carcinomas but hardly detectable in large carcinomas of the colon. Colon cancer development induced by AOM in EP(3) receptor knockout mice was enhanced compared with wild-type mice, with a higher incidence of colon tumours (78% v 57%) and mean number of tumours per mouse (2.17 (0.51) v 0.75 (0.15); p<0.05). Expression of EP(3) mRNA was detected in only one of 11 human colon cancer cell lines tested. Treatment with 5 microM of an EP(3) selective agonist, ONO-AE-248, resulted in a 30% decrease in viable cell numbers in the HCA-7 human colon cancer cell line in which EP(3) was expressed. Treatment with 5-aza-dC restored EP(3) expression in CACO-2, CW-2, and DLD-1 cells but not in WiDr cells, suggesting involvement of hypermethylation in the downregulation of EP(3) to some extent. CONCLUSION: The PGE(2) receptor subtype EP(3) plays an important role in suppression of cell growth and its downregulation enhances colon carcinogenesis at a later stage. Hypermethylation of the EP(3) receptor gene could occur and may contribute towards downregulating EP(3) expression to some extent in colon cancers.

Animals↗

PubMed1999

Colonic wall thickening in patients with cirrhosis: CT findings and clinical implications.

OBJECTIVE: The purpose of this study was to determine the prevalence and spectrum of colonic wall changes in patients with cirrhosis and to determine the association between these colonic wall changes and portal hypertension. MATERIALS AND METHODS: Abdominal CT examinations of 57 patients with cirrhosis were evaluated for colonic abnormalities including bowel wall thickening and pneumatosis. The degree and extent of colonic involvement, other CT features of cirrhosis including ascites and portal hypertension, and clinical symptoms were recorded. A correlation was made with available colonoscopy, exploratory laparotomy, and pathologic results. RESULTS: Colonic wall abnormalities were seen in 37% (21/57) of the patients with cirrhosis, 25% (14/57) of whom had isolated or predominantly right-sided colonic changes. Abnormal bowel wall thickening (ranging from 6 mm to 3 cm in thickness) was present in 35% of the patients. Pneumatosis was found in 4% of the patients. Of the 18 liver transplant recipients who had CT examinations before and after liver transplantation, colonic changes were seen in 44% preoperatively but in only 6% postoperatively. Isolated right-sided colonic changes and diffuse colonic changes were associated with varices in 93% and 100% of the patients, respectively; with ascites in 93% and 100%, respectively; and with splenomegaly in 83% and 86%, respectively. Specific or focal bowel symptoms were present in only 29% of the patients with colonic changes, whether the changes were diffuse or isolated to the right side. CONCLUSION: Thirty-five percent of the patients with severe cirrhosis who underwent CT were shown to have colonic wall thickening; two thirds of these patients had thickening limited predominantly to the right colon. We postulated that predominantly right-sided colonic wall thickening may be related to changes in blood flow and hydrostatic pressures caused by portal hypertension. Many patients with isolated or predominately right-sided colonic wall thickening did not have specific or focal bowel symptoms, and in most patients, the colonic wall thickening resolved after successful liver transplantation, requiring no further testing. On the other hand, we found that pneumatosis or severe diffuse colonic wall thickening may indicate a more serious colonic problem such as ischemia or infection with Clostridium difficile and should prompt further investigation.

Adult↗