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The mucus-associated intestinal M3 antigen, normally restricted to intestinal goblet cells, was found in 35 out of 100 gastric adenocarcinomas belonging to intestinal (19/64) as well as diffuse (16/36) types according to Laurén's classification. often accompanying the other mucus-associated gastric M1 and M2 antigens. This M3 antigen was predominant over the gastric M antigens in 25 of these 35 tumors; 18 of these belonged to the histological intestinal type. According to the WHO classification, the M3 antigen was found to predominate in all mucinous adenocarcinomas (7/7), was never present in the undifferentiated carcinomas (0/8), but was also found in some tubulo-papillar (16/57) and signet-ring cell (12/27) adenocarcinomas. This antigen could be used as a new criterion and incorporated into a point system containing morphological and tumor cell behavioral considerations; then it would appear to be a good marker for intestinal-type differentiation. Indeed, 22 of these 25 gastric adenocarcinomas which produced predominantly M3 antigen showed such an intestinal-like differentiation. The M antigen pattern of gastric carcinoma suggested a duodenal rather than colonic-type differentiation.
Intestinal metaplasia (IM) is a preneoplastic lesion of the stomach in which there is transdifferentiation of the gastric mucosa to an intestinal phenotype. The caudal-related homeobox gene CDX2 encodes an intestine-specific transcription factor crucial for the regulation of proliferation and differentiation of intestinal cells. In addition, CDX2 is involved in the induction of IM in the stomach. The aim of this study was to access the putative involvement of OCT-1 in the induction of CDX2 expression de novo in gastric mucosa leading to the onset of IM. OCT-1 protein expression was evaluated by immunohistochemistry in 31 biopsies with chronic gastritis, 15 biopsies with foci of IM and adjacent gastric mucosa and 42 gastric carcinomas. Furthermore, we evaluated OCT-1 binding by electrophoretic mobility shift assay and activation of the CDX2 promoter by co-transfecting a CDX2 promoter/reporter construct with an OCT-1 expression vector in two gastric carcinoma cell lines, GP220 and MKN45. Our results show that OCT-1 is expressed in chronic gastritis, particularly when it is adjacent to IM and is expressed in 87% of IM foci. Furthermore, 74% of the gastric carcinomas were positive for OCT-1 and a strong association was observed between OCT-1 expression and intestinal-type carcinoma. We identified that OCT-1 binds to the CDX2 promoter, although we could not see a transactivation effect in gastric carcinoma cell lines. In conclusion, we observed increased OCT-1 expression in IM and in intestinal gastric carcinomas and identified the capacity of OCT-1 to bind to the CDX2 promoter, although we could not demonstrate a direct effect of OCT-1 in the transactivation of CDX2.
We experienced two cases with disseminated HP and IND occurring with normal bowel in between (disseminated mixed intestinal dysmotility--DMID) and postulate whether it could be classified as a new intestinal motility disorder. Our cases, both boys, died at 3 and 7 months, respectively. Both had irregular stool passage, and abdominal distention with bilious vomiting since birth. On barium enema, both had rigid distal ileum and colon with narrow lumens, with dilated and atonic proximal ileum and jejunum. An ileostomy was created on days 3 and 2 of life, respectively, however, they did not function and jejunostomies were created, which also did not function well. Both boys died after repeated episodes of severe enterocolitis. In each case, three 10 cm specimens were obtained randomly from the jejunum and ileum, and two 5 cm specimens were obtained randomly from each of the ascending colon, transverse colon, descending colon, and rectum and treated with hematoxylin and eosin (H & E) staining, acetylcholine esterase (AchE) histochemistry, and protein gene product 9.5 (PGP9.5) and neural cell adhesion molecule (NCAM) immunohistochemistry for histopathologic assessment. All specimens showed a mixture of disseminated IND and HP, with normal intestine in between. There was abnormal expression of NCAM activity in the intestinal smooth muscle layers in small and large intestine. This is the first report about disseminated IND and HP occurring with normal bowel in between (DMID) and we suggest it should be classified as a new intestinal motility disorder. The present findings demonstrate that patients with DMID have a complicated abnormality of NMJ that may directly influence bowel motility and prognosis according to the severity of the abnormality.
The intensive cytotoxic treatment given in connection with bone marrow transplantations induces severe injury to the gut consistent with an increase in intestinal permeability. Currently, extent of the gut injury is assessed by inspecting the mouth and recording symptoms deriving from the gastro-intestinal tract. The aims of this study were to evaluate whether changes in permeability correlate with clinical assessment of gut toxicity, according to the WHO criteria, and also to examine the duration of intestinal permeability after high-dose chemotherapy. In 18 consecutive patients undergoing bone marrow transplantation, gastrointestinal permeability was assessed by a 51Cr-EDTA absorption test before the start of cytotoxic treatment, and 4, 7, 10 and 14 days after stem-cell infusion. In another seven patients, permeability was assessed 2 days after the start of cytotoxic treatment, and 1, 7 and 14 days after stem cell infusion. During the same period, oral- and non-oral clinical toxicity according to the WHO criteria were recorded. Permeability increased significantly 2 days after the start of cytotoxic treatment (P < 0.05), on day 1 (P < 0.05), on day 4 (P < 0.0005), on day 7 (P < 0.0005) and on day 10 (P < 0.005) after stem cell infusion, compared with pre-treatment permeability. Despite significant barrier dysfunction, clinical toxicity was very moderate in the early transplantation course. Gastro-intestinal, but not oral clinical toxicity requiring therapy, was consistent with a significant increase in permeability compared with no clinical toxicity or toxicity not requiring therapy. Similarly, cumulative gastro-intestinal, but not oral toxicity correlated positively with the increase in permeability. The permeability test was unable to predict the severity of the clinical gastro-intestinal toxicity.
Metabolic and functional properties of probiotic lactic acid bacteria (LAB) in the human gastro-intestinal ecosystem may be related to certain beneficial health effects. In this study, lactobacilli of either intestinal or fermented food origin were compared in their capability to survive low pH and bile, in their metabolic activity in the presence of bile salts and mucins, as well as in their potential to attach to enterocyte-like CaCO-2 cells. Food fermenting bacteria especially strains of the species Lactobacillus plantarum showed high tolerance to the consecutive exposure to hydrochloric acid (pH 1.5-2.5) and cholic acid (10 mM). Growth in and deconjugation of glycocholic (5 mM) and taurocholic acids (5 mM), as demonstrated for all lactobacilli of intestinal origin, was detected for food fermenting strains of the species L. plantarum, but not L. paracasei and L. sakei. Degradation of mucins was not observed for lactobacilli. Adhesion to the intestinal epithelial cell line CaCO-2 was demonstrated for several food fermenting bacterial strains in vitro. Soluble factors in the spent culture supernatants from intestinal and fermented food lactobacilli but not staphylococci cross reacted and synergized with cell wall components to promote adhesion to CaCO-2 cells. A competitive role of fecal bacteria on the adhesion of lactobacilli to CaCO-2 cells was demonstrated. In conclusion we have shown that metabolic and functional properties of intestinal lactobacilli are also found in certain bacteria of fermented food origin.
AIM: To determine the long-term risk of intestinal and extra-intestinal malignancies in Crohn's disease patients in Copenhagen County, Denmark. METHODS: In Copenhagen County, a strictly population-based cohort of 374 patients with Crohn's disease diagnosed between 1962 and 1987 was followed until 1997 in order to determine the long-term risk of intestinal and extra-intestinal malignancies. Information on cancer occurrence was provided by the Danish National Cancer Registry and confirmed by the examination of hospital files. The observed number of cases was compared with the expected number, calculated from individually computed person-years at risk and 1995 cancer incidence rates for the background population. RESULTS: The risk of small bowel adenocarcinoma was significantly increased, independent of age and gender (standardized morbidity ratio, 66.7; 95% confidence interval, 18.1-170.7). The risk of colorectal cancer was not increased, either in the total group of patients or in patients with colonic Crohn's disease exclusively (standardized morbidity ratio, 1.64; 95% confidence interval, 0.20-5.92). Extra-intestinal cancer did not occur more frequently than expected. CONCLUSIONS: This population-based study of patients with Crohn's disease revealed no increase in colorectal cancer risk, possibly due to maintenance treatment with 5-aminosalicylic acid preparations and surgery in treatment failure. In contrast, the risk of small bowel cancer was increased more than 60-fold, but the numbers were small. The risk of extra-intestinal cancer was not increased and no lymphomas were observed.
Minute lesions of intestinal metaplasia composed of a few metaplastic tubules were observed in the gastric mucosa during routine histological examination of gastrectomy specimens. The histological findings indicated that these lesions might be an initial stage of more advanced intestinal metaplasia. Accordingly, more than 18,000 serial sections in 10 stomachs with chronic ulcers were examined to clarify the histopathogenesis of the intestinal metaplasia. It was concluded from the three dimensional reconstruction of minute intestinal metaplasia lesions that these lesions originated during the regenerative process of healing of gastric erosions. The lesions were roughly globoid with a depression on the surface. It is thought that with continuous formation and healing of gastric erosions, more extensive intestinal metaplasia lesions would be formed by an increase in size and confluence of these focal minute intestinal metaplasia lesions.
BACKGROUND/AIMS: A descending gradient of alkaline phosphatase (AP) activity is well known to exist in the rat intestine. To understand the physiological role(s) of intestinal AP (IAP), we examined in detail the distribution of IAP subtypes along the longitudinal axis of the rat intestine. METHODS: The consecutive 2-cm segments of the upper intestine were analyzed by sodium dodecylsulfate polyacrylamide gel electrophoresis (SDS-PAGE) followed by staining for IAP activity. The reverse transcription-polymerase chain reaction was conducted to assess the relative levels of tissue mRNA for the 2 distinct genes of rat IAP, rIAP-I and rIAP-II. RESULTS: A descending gradient of IAP activity was found along the upper small intestine, where 3 bands of the activity, termed types 1, 2 and 3 from the anode were located on SDS-PAGE gels. Along the longitudinal axis, types 1 and 3 showed ascending and descending gradients, respectively; whereas type 2 had a broad uniform distribution. The mRNA level for rIAP-I showed an ascending distribution, and that of rIAP-II, a descending one. Type 3 IAP was drastically diminished in duodenum of cysteamine-ulcer rats, but type 1 remained constant. CONCLUSION: These distinctive gradients of IAP subtypes may provide a clue to scrutinize the physiological significance of AP in the rat intestine, which is a flow system with polarity.
Intestinal trefoil factor (ITF), a small peptide secreted by intestinal goblet cells, maintains mucosal integrity and promotes epithelial wound healing. Although ITF has been cloned, the detailed mechanism by which ITF interacts with intestinal epithelium remains elusive. In the present study, we expressed mature rat ITF (rITF) with pXa (a prokaryotic expression vector) in Escherichia coli to generate a biotinylated rITF fusion protein (bTag-ITF). By using bTag-ITF probe, we identified ITF binding cells in the crypts of the small intestine and mucous cells of the region of gastric glands. Using a ligand blotting technique, we further characterized a 50 kDa glycosylated protein from the membrane fraction of the small intestine, which bound to bTag-ITF. Our data suggest that this 50 kDa membrane glycoprotein is a putative receptor for ITF in the gastrointestinal tract.
To clarify the pathognomonic changes of intestinal lesions of Behçet's disease and to determine effective therapeutic measures, we recruited 13 patients with the intestinal form of this disease for study. We performed pathology studies on the resected specimens of 7 patients and treated 5 of the other 6 patients with a low-residue diet. Pathology examination revealed that 6 of 7 had inflammatory ulcerations in the ileocecal region. The ileal ulcers were mainly on the antimesenteric side. We observed remnants of Peyer's patches at the margins of the major ulcerative lesions in 2 of 2 patients examined. There were aggregations of lymphocytes resembling destroyed lymph follicles in the superficial layer at the mouths of small fissuring lesions, and ulcer scars were also noted in Peyer's patches in 4 of 5 other patients. X-ray and endoscopic examinations revealed the disappearance of intestinal lesions in 5 patients within 1 month during, or following the low-residue diet treatment. We found the intestinal lesions of Behçet's disease at sites coinciding with intramucosal lymphoid tissue. The "rest cure" for the affected bowel was effective, i.e., there was significant alleviation of gastrointestinal symptoms and the intestinal lesions disappeared. We speculated that acute exudative inflammation, abscess formation, and consequent ulceration may occur in these tissues by the same mechanisms as those that operate in the positive needle-prick reactions seen in patients with Behçet's disease.
The effect of interleukin-4 (IL-4) on the induction of intestinal mast cells and cytokine profiles during Strongyloides ratti infection was studied using IL-4 knockout (IL-4 KO) mice. The antigen-specific proliferative response of mesenteric lymph node cells was not impaired in IL-4 KO mice. The number of intestinal mast cells induced in IL-4 KO mice during S. ratti infection was 2- to 3-fold lower than that observed in WT mice. Intestinal mastocytosis had disappeared in IL-4 KO mice by day 21 postinfection, when significant mastocytosis continued to be observed in WT mice. In mesenteric lymphnode of IL-4 KO, IL-3 production decreased and mice IFN-gamma production significantly increased as compared with those of WT mice. The numbers of eggs excreted per gram of feces (EPG) by IL-4 KO mice were greater than those excreted by WT mice on day 6 postinfection, but no difference was observed in the subsequent period. In conclusion, intestinal mast cells are induced during S. ratti infection in the absence of IL-4, and IL-4 is not essential for protection against intestinal adult worms of S. ratti.
The uptake of beta-lactam antibiotics into small intestinal enterocytes occurs by the transport system for small peptides. The role of membrane-bound peptidases in the brush border membrane of enterocytes from rabbit and pig small intestine for the uptake of small peptides and beta-lactam antibiotics was investigated using brush border membrane vesicles. The enzymatic activity of aminopeptidase N was inhibited by beta-lactam antibiotics in a non-competitive manner whereas dipeptidylpeptidase IV was not affected. The peptidase inhibitor bestatin led to a strong competitive inhibition of aminopeptidase N whereas the uptake of cephalexin into brush border membrane vesicles was only slightly inhibited at high bestatin concentrations (greater than 1 mM). Modification of brush border membrane vesicles with the histidine-modifying reagent diethyl pyrocarbonate led to a strong irreversible inhibition of cephalexin uptake whereas the activity of aminopeptidase N remained unchanged. A modification of serine residues with diisopropyl fluorophosphate completely inactivated dipeptidylpeptidase IV whereas the transport activity for cephalexin and the enzymatic activity of aminopeptidase N were not influenced. With polyclonal antibodies raised against aminopeptidase N from pig renal microsomes the aminopeptidase N from solubilized brush border membranes from pig small intestine could be completely precipitated; the binding protein for beta-lactam antibiotics and oligopeptides of apparent Mr 127,000 identified by direct photoaffinity labeling with [3H]benzylpenicillin showed no crossreactivity with the aminopeptidase N anti serum and was not precipitated by the anti serum. These results clearly demonstrate that peptidases of the brush border membrane like aminopeptidase N and dipeptidylpeptidase IV are not directly involved in the intestinal uptake process for small peptides and beta-lactam antibiotics and are not a constituent of this transport system. This suggests that a membrane protein of Mr 127,000 is (a part of) the uptake system for beta-lactam antibiotics and small peptides in the brush border membrane of small intestinal enterocytes.
The effect of widely different doses of Trichinella spiralis muscle larvae on time to rejection of intestinal adults and on host survival was assessed in mice of the three rejection phenotypes; strong, intermediate, and weak. Rejection is weak with doses of less than 50 larvae per mouse. At these doses all mice rejected worms at a similar rate and no phenotypic variation was evident among strains. In contrast, rejection time was shortest for all strains and phenotypic variation among strains was evident in the range 50-100 muscle larvae/mouse. Above this dose the time taken to rejection increases monotonically with dose for all mouse strains examined. Despite this, the relative strength of rejection (i.e., phenotype) of a given strain of mouse was not changed at higher doses. Based on an end point of 98% rejection of the infective dose, time to rejection was predictable to +/- 1 day for all mouse strains and doses tested over the range 100-1000 worms administered. The principal reason for the increased time to complete rejection with larger worm doses was a delay in the initiation of intestinal rejection. This delay was evident above a dose of 50-100 larvae per mouse and occurred in all strains. Once begun, rejection was faster and eliminated more worms in unit time at higher doses (400-800 more) than at lower doses of worms. This appeared to be due to a stronger immune response of the host at higher doses. However, the increase in the rate of rejection was still not as great as the increase in the dose. We postulate that the delay in rejection with increased dose is due to a requirement for a "critical mass" of effectors/worm required to cause rejection. As dose increases, more time is required to reach the level at which worm rejection commences. Deaths due to higher doses of worms also occurred in a strain-specific manner and were temporally biphasic. The intestinal phase of infection produced mortality from 1 to 5 days after infection and the strongest rejection phenotype (NFS) was also the most resistant to intestinal deaths. Deaths occurring after Day 5 were due to the parenterally migrating newborn larvae. The weakest rejection phenotype, that of the B10 congenics, was also the least resistant to intestinal deaths. An experimental formula describing 98% worm rejection time with different doses was derived from the data.(ABSTRACT TRUNCATED AT 400 WORDS)
Intestinal resection stimulates proliferative activity in the intestinal remnant. The aim of this study was to determine the influence of intestinal resection on the growth of intestinal neomucosa. Forty-eight New Zealand white rabbits had 2 x 5-cm ileal defects patched with adjacent cecal serosal surface. Group I (n = 24) served as controls. Group II (n = 24) underwent simultaneous 50% enterectomy. Neomucosal coverage was significantly greater in Group II at 1 week (36 +/- 11% vs 67 +/- 9%, P less than 0.05) and 2 weeks (94 +/- 2% vs 99 +/- 1%, P less than 0.05), but was similar at 3 and 4 weeks. There was significantly more neomucosa at 1 week in the animals that underwent resection (134 +/- 55 mm2 vs 199 +/- 54 mm2, P less than 0.05). Degree of patch contraction, glucose uptake, and disaccharidase activities were similar in each group. Ornithine decarboxylase activity and crypt cell production rate were significantly greater at 1 week in the animals that underwent resection. Intestinal resection results in an early increase in neomucosal growth and increased proliferative activity. Since contraction of the patches occurs to a similar extent in both groups, the total amount of neomucosa was not increased. Thus, performing patching at the time of resection is not necessary for optimal growth.