Villus Cells Research Articles

Inhibition of rotavirus ECwt infection in ICR suckling mice by N-acetylcysteine, peroxisome proliferator-activated receptor gamma agonists and cyclooxygenase-2 inhibitors

Live attenuated vaccines have recently been introduced for preventing rotavirus disease in children. However, alternative strategies for prevention and treatment of rotavirus infection are needed mainly in developing countries where low vaccine coverage occurs. In the present work, N-acetylcysteine (NAC), ascorbic acid (AA), some nonsteroidal anti-inflammatory drugs (NSAIDs) and peroxisome proliferator-activated receptor gamma (PPARγ) agonists were tested for their ability to interfere with rotavirus ECwt infectivity as detected by the percentage of viral antigen-positive cells of small intestinal villi isolated from ECwt-infected ICR mice. Administration of 6 mg NAC/kg every 8 h for three days following the first diarrhoeal episode reduced viral infectivity by about 90%. Administration of AA, ibuprofen, diclofenac, pioglitazone or rosiglitazone decreased viral infectivity by about 55%, 90%, 35%, 32% and 25%, respectively. ECwt infection of mice increased expression of cyclooxygenase-2, ERp57, Hsc70, NF-κB, Hsp70, protein disulphide isomerase (PDI) and PPARγ in intestinal villus cells. NAC treatment of ECwt-infected mice reduced Hsc70 and PDI expression to levels similar to those observed in villi from uninfected control mice. The present results suggest that the drugs tested in the present work could be assayed in preventing or treating rotaviral diarrhoea in children and young animals.

Sa1997 Osteopontin Splice Variant As a Potential Prognostic Marker for Pancreatic Adenocarcinoma

both the crypt-villus and cephalo-caudal intestinal axes. In normal mice fed AIN76A, pS6 staining was sporadic and focal along the cephalo-caudal axis in both villus and crypt epithelial cells. When fed NWD1, staining was more localized to villus cells and more homogeneous along the cephalo-caudal axis. A similar pattern was seen at 3 months in AIN76A fed mice when Notch signaling was inactivated. However, at 9 months staining became less intense and diffuse from villus to crypt. The combination of Notch inactivation and feeding NWD1 produced staining in both villus and crypt cells which was continuous along the cephalo-caudal axis, regardless of age. Conclusion: mTOR activation in the intestine is influenced by both dietary and genetic factors, and is heterogeneous among intestinal epithelial cells. Feeding of NWD1 long-term causes sporadic tumors and elevated mTOR signaling. Although inhibition of Notch signaling may decrease the probability of cell autonomous tumor development, long term effects include secretory cell hyperplasia, copious mucin secretion and inflammation, leading to dysplasia and tumor development, especially in mice fed purified diets. Thus, the increase in mTOR signaling with both higher risk diet and inhibition of Notch signaling, may link this pathway to tumorigenesis regardless of etiology.

Lactoferrin ameliorates Prostaglandin E2 (PGE2)‐mediated inhibition of Na‐glucose cotransport in enterocytes

Enhanced cyclooxygenase pathway metabolite, PGE2, inhibits SGLT1 mediated glucose absorption in chronically inflamed intestinal villus cells. Lactoferrin (Lf), a multifunctional glycoprotein is absorbed by receptor‐mediated transcytosis has been shown to exert anti‐inflammatory effects. This study was designed to investigate whether Lf would prevent PGE2 inhibition of SGLT1 mediated glucose absorption in enterocytes. [3H]O‐Methyl‐Glucose uptake was measured in 10 days postconfluent rat intestinalepithelial cells (IEC‐6) grown on transwell plates. The cells used were treated with phlorizin, PGE2, AH6809, and Lf. Na‐dependent glucose uptake, phlorizin, and immunoblotting studies established the activity and apical membrane localization of SGLT1. PGE2 inhibited SGLT1 in both concentration and time dependent manner with an inhibitory constant Ki of 50.03 nM and antagonized by prostanoid receptor inhibitor. PGE2 did not alter Na+/K+‐ATPase activity. In contrast, qRT‐PCR and western blot analyses revealed that SGLT1 specific transcripts and protein expression level were decreased 3‐fold by PGE2 treatment. Kinetic studies demonstrated that PGE2 inhibited SGLT1 by reducing the cotransporter expression which is reversed by treatment with Lf. We speculate that Lf ameliorates PGE2 inhibition of SGLT1 mediated glucose absorption by interfering with the signal transduction pathway in IEC‐6 cells.

The Effect of Dietary Prebiotics and Probiotics on Body Weight, Large Intestine Indices, and Fecal Bile Acid Profile in Wild Type and IL10−/− Mice

Previous studies have suggested roles of probiotics and prebiotics on body weight management and intestinal function. Here, the effects of a dietary prebiotic, inulin (50 mg/g diet), and probiotic, Bfidobacterium animalis subsp. lactis (Bb12) (final dose verified at 105 colony forming unit (cfu)/g diet, comparable to human consumption), were determined separately and in combination in mice using cellulose-based AIN-93G diets under conditions allowed for the growth of commensal bacteria. Continuous consumption of Bb12 and/or inulin did not affect food intake or body, liver, and spleen weights of young and adult mice. Fecal bile acid profiles were determined by nanoESI-MS/MS tandem mass spectrometry. In the presence of inulin, more bacterial deconjugation of taurine from primary bile acids was observed along with an increased cecal weight. Consumption of inulin in the absence or presence of Bb12 also increased the villus cell height in the proximal colon along with a trend of higher bile acid sulfation by intestinal cells. Feeding Bb12 alone at the physiological dose did not affect bile acid deconjugation and had little effect on other intestinal indices. Although interleukin (IL)10-null mice are susceptible to enterocolitis, they maintained the same body weight as the wild type mice under our specific pathogen-free housing condition and showed no signs of inflammation. Nevertheless, they had smaller cecum suggesting a mildly compromised intestinal development even before the disease manifestation. Our results are consistent with the notion that dietary factors such as prebiotics play important roles in the growth of intestinal microbiota and may impact on the intestinal health. In addition, fecal bile acid profiling could potentially be a non-invasive tool in monitoring the intestinal environment.

Human Primary Intestinal Epithelial Cells as an Improved In Vitro Model for Cryptosporidium parvum Infection

The study of human intestinal pathogens has been limited by the lack of methods for the long-term culture of primary human intestinal epithelial cells (PECs). The development of infection models with PECs would allow a better understanding of host-parasite interactions. The objective of this study was to develop a novel method for prolonged in vitro cultivation of PECs that can be used to study Cryptosporidium infection. We isolated intact crypts from human intestines removed during weight loss surgery. The fragments of intestinal layers were cultivated with culture medium supplemented with growth factors and antiapoptotic molecules. After 7 days, the PECs formed self-regenerating cell clusters, forming villi that resemble intestinal epithelium. The PECs proliferated and remained viable for at least 60 days. The cells expressed markers for intestinal stem cells, epithelial cells, and mature enterocytes. The PECs were infected with Cryptosporidium. In contrast to older models in which parasite numbers decay, the burden of parasites increased for >120 h. In summary, we describe here a novel method for the cultivation of self-regenerating human epithelial cells from small intestinal crypts, which contain both intestinal stem cells and mature villus cells. We present data that suggest these cells support Cryptosporidium better than existing cell lines. PECs should provide an improved tool for studying host-parasite interactions involving Cryptosporidium and other intestinal pathogens.

Prostaglandins, not the leukotrienes, regulate Cl−/HCO3− exchange (DRA, SLC26A3) in villus cells in the chronically inflamed rabbit ileum

Previously studies have demonstrated that Cl−/HCO3− exchange was inhibited during chronic intestinal inflammation secondary to decrease in the affinity of the exchanger for Cl− rather than the number of transporters. Arachidonic acid metabolites (AAM) are elevated in the mucosa of the chronically inflamed small intestine. However, their role in the alteration of Cl−/HCO3− during chronic enteritis was unknown. Inhibition of AAM formation with arachidonyl trifluoro methylketone (ATMK) in chronically inflamed rabbit intestine reversed the diminished Cl−/HCO3− exchange activity. Kinetics studies showed that the reversal was secondary to restoration of the altered affinity of transporter. Downstream regulation of Cl−/HCO3− inhibition by AAM was determined to be by the cyclooxygenase pathway since only inhibition of cyclooxygenase with piroxicam treatment reversed the inhibited Cl−/HCO3− exchange. Further, DRA was shown to be the primary Cl−/HCO3− exchanger in villus cells. Kinetics and molecular studies indicated that the mechanism of inhibition of Cl−/HCO3− exchange by cyclooxygenase pathway metabolites was secondary to diminished affinity of the transporter for Cl− without a change in DRA BBM expression. Thus our data indicated that cyclooxygenase pathway metabolites mediate the inhibition of DRA during chronic intestinal inflammation.

Therapeutic effects of smecta on multiorgans injury induced by paraquat in rats

Objective To evaluate therapeutic effect and the possible mechanism of smecta on paraqual plasma concentrations and multiorgans injury induced by paraquat intoxication in rats. Methods A total of 76 healthy adult SD rats were randomly ( random number) divided into group A (control group n =6),group B ( poisoned group n =30 ),group C (smecta-treated group n=30).Rats in groups B and C were treated intragastrically with PQ at 50 mg/kg,the rats in the group C were given with smecta at 50 mg/kg,while the rats in the other two groups were only intragastrically adminstered with saline.Live rats in groups B and C were sacrificed at 2,6,24,48,72 h after administration of PQ for the determination of paraquat plasma concentrations and for HE staining of lung,stomach and jejunum.The rats were executed at the end of trial by the same way in group A.All measurement data were expressed as means + standard deviation ((x) ±s).The data of pathological score were compared with Independent-samples T test and the data of PQ concentration compared with analysis of variance (ANOVA) followed by LSD-t multiple comparison test.P-values of less than 0.05 were considered statistically significant.Results The paraquat plasma concentration ( ng/ml ) was 440.314 ± 49.776 to 4320.6150 ± 413.947.There were different pathological changes of lung,stomach and jejunum in group B. Lung injuries gradually deteriorated,congestion,edema,leukocyte infiltration,incrassated septa and lung consolidation were observed.The pathological changes were obvious such as abruption of mucosa,hyperemic gastric mucosa and leukocyte infiltration in stomach.Haemorrhage of jejunum mucosa,abruption of villus,gland damage and inflammatory cell infiltration were found. Compared with group B,all the pathological changes mentioned above were obviously alleviated in group C ( P ＜ 0.05 ),and the concentrations reduced ( P ＜ 0.01 ).Conclusions Smecta reduced paraquat plasma concentrations and alleviated pathologic injury of rats with PQ poisoning. Key words: Smecta; Paraquat; Plasma concentration; Pathological change; Therapeutic effect

Crypt Base Columnar Stem Cells in Small Intestines of Mice Are Radioresistant

Adult stem cells have been proposed to be quiescent and radiation resistant, repairing DNA double-strand breaks by nonhomologous end joining. However, the population of putative small intestinal stem cells (ISCs) at position +4 from the crypt base contradicts this model, in that they are highly radiosensitive. Cycling crypt base columnar cells (CBCs) at crypt positions +1-3 recently were defined as an alternative population of ISCs. Little is known about the sensitivity of this stem cell population to radiation. Radiation-induced lethality of CBCs was quantified kinetically in Lgr5-lacZ transgenic mice. γ-H2AX, BRCA1, RAD51, and DNA-PKcs foci were used as DNA repair surrogates to investigate the inherent ability of CBCs to recognize and repair double-strand breaks. 5-ethynyl-2'-deoxyuridine and 5-bromo-2'-deoxyuridine incorporation assays were used to study patterns of CBC growth arrest and re-initiation of cell cycling. Apoptosis was evaluated by caspase-3 staining. CBCs are relatively radioresistant, repairing DNA by homologous recombination significantly more efficiently than transit amplifying progenitors or villus cells. CBCs undergo apoptosis less than 24 hours after irradiation (32% ± 2% of total lethality) or mitotic death at 24-48 hours. Survival of CBCs at 2 days predicts crypt regeneration at 3.5 days and lethality from gastrointestinal syndrome. Crypt repopulation originates from CBCs that survive irradiation. Adult ISCs in mice can cycle rapidly yet still be radioresistant. Importantly, homologous recombination can protect adult stem cell populations from genotoxic stress. These findings broaden and refine concepts of the phenotype of adult stem cells.

The protective effects of inhibition of c-Jun N-terminal kinase signal pathway on the intestinal barrier in rats with endotoxemia

To examine the protective effects of inhibition of c-jun N-terminal kinase (JNK) stress signal pathway on the injured barrier in endotoxemic rats. Twenty-four male Sprague Dwaley (SD) rats were randomly divided into control group, endotoxemia model group and JNK inhibitor group (n=8 each) to receive administration of: 1 normal saline 2 ml/kg + PPCES 2.5 ml/kg [vehicle of JNK inhibitor (SP600125), control group]; 2 lipopolysaccharide (LPS) 10 mg/kg + PPCES 2.5 ml/kg (endotoxemia model group); 3 LPS 10 mg/kg + JNK inhibitor (SP600125) 10 mg/kg (JNK inhibitor group). The activity and survival rate of the rats were recorded. Ileum tissue samples were collected 12 hours after drug administration for pathological examination. Blood samples were collected at the same time for determination of concentration of D-lactate by enzyme linked immunosorbent assay (ELISA). Rats in control group were active normally, and there was no death. Pathological examination showed there was edema of ileal mucosa, and shortening of villus and inflammatory cell infiltration in model group as compared with control group. JNK inhibitor greatly ameliorated the lesions compared with model group. The concentration of D-lactate (µg/L) in model group was significantly higher than that in control group. (943.8 ± 439.6 vs 227.9 ± 130.0, P<.05). JNK inhibitor could decrease the plasma D-lactate concentration (637.4 ± 114.4 vs 943.8 ± 439.6, P<.05). Inhibition of the JNK stress signal pathway could attenuate the intestinal barrier injury in endotoxemic rats.

In Vitro Expansion and Transplantation of Intestinal Crypt Stem Cells

Adult tissue stem cells hold great promise for regenerative medicine strategies. Major hurdles in their clinical application persist and include the identification of such stem cells, their isolation and in vitro expansion, and—finally—their transplantation. These hurdles have recently been overcome for stem cells of the intestinal tract. Thus, exciting avenues are now opening up to apply these stem cells for a variety of therapeutic strategies. Herein, we highlight recent developments in intestinal stem cell biology and discuss this progress from the perspective of clinical application. Adult tissue maintenance and repair involves cell production by somatic stem cells and their transit-amplifying (TA) progenitor cells, followed by lineage commitment and terminal differentiation. The intestinal epithelium is the most vigorously regenerating tissue and is renewed every 3‐5 days. This rapid cell renewal, in combination with its modular architecture of crypts and villi, makes it an ideal model to study stem cell biology. The intestinal stem cells reside at the bottoms of crypts in the small intestine and colon. Their TA daughters occupy the remainder of the crypts. Differentiated cells reside on the villi in the small intestine and in crypt tops and in the flat surface epithelium of the colon. The differentiated cell types of the small intestine include the absorptive enterocytes and multiple secretory lineages (Paneth cells, goblet cells, enteroendocrine cells, and tuft cells), as well as the M cells of the Peyer’s patches. 1 Intestinal homeostasis is tightly controlled by wellcharacterized signaling pathways. In particular, the Wnt-, Bmp-, epidermal growth factor (EGF), and Notch pathways have been shown to be major players in this regulation. Wnt signaling constitutes the key pathway to maintain the stem cells and drive proliferation at crypt bottoms. Mice lacking Tcf7l2/Tcf4, a key transcription factor in this pathway, lose all proliferation in crypts. 2 Conversely, colon cancer is caused by loss of the Apc gene, which encodes a key negative regulator of the Wnt pathway. In addition to Wnt signals, Notch signaling is required to maintain crypt cells in the undifferentiated state. 3 EGF signals maintain the proliferative state of the crypt cells. Bmp and Tgf- signaling are activated in villus cells and are believed to regulate differentiation. Bmp ligands are expressed in villi, whereas Bmp antagonists such as noggin and gremlins are expressed at crypt mesenchyme to block Bmp signals from the crypts.4 All these pathways cross-talk with each other, forming complex molecular networks to govern tissue homeostasis.

Mo1818 Cyclooxygenase Pathway Selectively Reverses Altered Na-Glutamine Co-Transport in Villus and Crypt Cells During Chronic Enteritis in Rabbit Small Intestine

Mo1818 Cyclooxygenase Pathway Selectively Reverses Altered Na-Glutamine Co-Transport in Villus and Crypt Cells During Chronic Enteritis in Rabbit Small Intestine

Regulation of sodium-glutamine cotransport in villus and crypt cells by glucocorticoids during chronic enteritis

Assimilation of the preferred nutrient of enterocytes is mediated primarily by sodium (Na)-dependent cotransport (NGct) in the intestine. The predominant NGcT in villus cells, B0AT1, is inhibited secondary to a decrease in cotransporter numbers during chronic intestinal inflammation. In contrast, NGcT mediated by SN2 in crypt cells is stimulated secondary to increased affinity of the cotransporter for glutamine during chronic ileitis. Glucocorticoid is a mainstay of treatment for inflammatory bowel disease. However, its effect on NGcT is not known. The inhibition of B0AT1 in villus cells during chronic intestinal inflammation was reversed back to normal by methylprednisolone (MP). This was secondary to the restoration of the cotransporter numbers in the brush border membrane rather than an alteration in the affinity. The stimulation of NGcT in crypt cells during chronic ileitis was also restored back to its normal levels by MP treatment. This reversal was secondary to the restoration of the altered affinity of the cotransporter SN2 for glutamine. Kinetic studies and western blot analysis were consistent with functional studies for both cotransporters. Thus, glucocorticoids restore two uniquely altered Na-glutamine cotransporters, B0AT1 in villus and SN2 in crypt cells during chronic enteritis. These data indicate that glucocorticoids function as an upstream broad spectrum immune modulator in the chronically inflamed intestine.

Effects of fermented plant product on growth performance, some blood variables, carcase characteristics, and intestinal histology in broilers

1. Fermented plant product (FPP) is a natural fermented food which is produced from a mixture of fermented fruit and vegetables, and rice bran (1:9). 2. To investigate the effects of FPP on growth performance, some blood variables, carcase characteristics and intestinal histology were determined in 192 broilers. They were divided into 4 groups, with 4 replicates of 12 chicks each; the chicks were provided ad libitum access to a diet consisting of 0, 0·5, 2·0 and 4·0% dietary FPP. 3. The crude protein and metabolisable energy concentrations of these diets were adjusted to 230 g CP/kg and 13·40 MJ ME/kg for the 7 to 21 d old chicks, and 200 g CP/kg and 13·40 MJ ME/kg for the 22 to 49 d old chicks, respectively. 4. At 49 d of age, feed intake, body weight gain and feed efficiency tended to increase with increase in FPP concentrations. Feed intake increased in the 4·0% dietary FPP group, BW gain increased in the 2·0% and 4·0% dietary FPP groups and feed efficiency increased in all experimental groups. 5. There were no differences among diets in the blood variables and carcase characteristics, except for total visceral organ weight, increased in all experimental groups. 6. Most of the intestinal villus heights, villus areas, epithelial cell areas and cell mitosis tended to increase with increase in FPP concentrations; duodenal villus height and cell mitosis in the 2·0 and 4·0% dietary FPP groups, and jejunal cell mitosis in all experimental groups were significantly increased. Compared with flat cells on the villus apical surface in the 0% FPP group, all experimental groups had protuberant cells in all intestinal parts. 7. In conclusion, hypertrophy of the villi and epithelial cells was observed in the present study, indicating improved growth performance, especially in the 4·0% dietary FPP group. Furthermore, increased total visceral organ weights suggested that FPP has no harmful effects on broilers.

Plasma Diamine Oxidase Activity Is a Useful Biomarker for Evaluating Gastrointestinal Tract Toxicities during Chemotherapy with Oral Fluorouracil Anti-Cancer Drugs in Patients with Gastric Cancer

Objectives: Diamine oxidase (DAO) is an enzyme that catalyzes oxidation and is highly active in the mature upper villus cells of the intestinal mucosa. This study sought to evaluate plasma DAO activities during adjuvant chemotherapy in patients with gastric cancer. Methods: We investigated 20 patients with gastric cancer who were treated with oral fluorouracil anti-cancer drugs as adjuvant chemotherapy. Plasma DAO activity was measured in all patients before chemotherapy and at 2, 4 and 6 weeks after the start of chemotherapy, and quality of life was evaluated simultaneously. Results: The median DAO activity after 4 weeks of chemotherapy was significantly decreased compared to the pre-chemotherapy levels (6.6 vs. 7.5 U/l; p = 0.038). The changes in the rate of DAO activity at 2 and 6 weeks following the start of chemotherapy in patients with gastrointestinal tract toxicity were significantly lower than in those without toxicity (p =0.021 and 0.047, respectively). The patient cohort showed a slightly positive correlation between DAO activity and global health status and a negative correlation between DAO activity and appetite loss. Conclusions: Plasma DAO activities may be useful for monitoring and evaluating gastrointestinal tract toxicities induced by adjuvant chemotherapy with oral fluorouracil in patients with gastric cancer.

Effects of hydrolysed Saccharomyces cerevisiae yeast and yeast cell wall components on live performance, intestinal histo-morphology and humoral immune response of broilers

1. The effects of enzymatically hydrolysed whole Saccharomyces cerevisiae yeast (HY) and the pellets of yeast cell wall (YCW) on production traits, the microbiology and histo-morphology of the small intestine, and humoral immune responses against Newcastle disease virus (NDV), of Ross 308 broilers were investigated. 2. The control group received a maize-soyabean meal based basal diet for 42 days. In the treated groups the basal diet was supplemented with 1 g/kg of HY and YCW. There were 8 replicate pens per group (n = 12 birds/pen). 3. HY and YCW supplementation improved live weight (P = 0·006) and FCR (P = 0·003) at 42-d as compared with the control group. 4. In the small intestine, Salmonella spp and Escherichia coli numbers were higher (P = 0·01) in the mucosa and lower (P = 0·01) in the digesta of the HY and the YCW fed groups at 25 d of age. Lactobacillus in the duodenal and jejunal digesta was higher (P < 0·05) in the HY and the YCW fed groups as compared with the control. 5. Following oral challenge with Salmonella pullorum, Escherichia coli and Lactobacillus increased (P < 0·05) in the mucosa and decreased in the digesta (P < 0·05) of the HY and YCW supplemented groups, relative to the control. 6. Supplementation of HY and YCW increased villus height in the jejunum (P = 0·02), width of villus in the ileum (P = 0·034) and number of goblet cells in villi of the jejunum (P = 0·006) and ileum (P = 0·01). 7. YCW increased antibody level against NDV at 21 and 42 d of age compared with the control and the HY supplemented diets (P < 0·05). 8. It was concluded that HY and YCW improved growth and feed efficiency in broilers, and considering the improvements in production traits and humoral immune responses, yeast cell wall may be a better dietary tool than the hydrolysed whole yeast cell as a performance enhancer for broilers.

Na-glutamine co-transporters B0AT1 in villus and SN2 in crypts are differentially altered in chronically inflamed rabbit intestine

Glutamine is a major nutrient utilized by the intestinal epithelium and is primarily assimilated via Na-glutamine co-transport (NGcT) on the brush border membrane (BBM) of enterocytes. Recently we reported that B0AT1 (SLC6A19) mediates glutamine absorption in villus while SN2 (SLC38A5) does the same in crypt cells. However, how B0AT1 and SN2 are affected during intestinal inflammation is unknown. In the present study it was shown that during chronic enteritis NGcT was inhibited in villus cells, however, it was stimulated in crypt cells. Our studies also demonstrated that the mechanism of inhibition of NGcT during chronic enteritis was secondary to a reduction in the number of B0AT1 co-transporters in the villus cell BBM without a change in the affinity of the co-transporter. In contrast, stimulation of NGcT in crypt cells was secondary to an increase in the affinity of SN2 for glutamine without an alteration in the number of co-transporters. Thus, glutamine assimilation which occurs via distinct transporters in crypt and villus cells is altered in the chronically inflamed intestine.

Intestinal involvement during 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced chronic liver injury in a mouse model

Purpose Although a physiologic relationship between intestinal mucosal integrity and hepatic function has been previously described, the effect of primary liver disease on intestinal mucosal homeostasis has not been previously well documented. In the current study, we studied the effects of chronic liver injury as a primary injury on enterocyte turnover (proliferation and apoptosis) in a mouse model. Methods The liver toxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-enriched diet was used to induce chronic cholestatic liver injury in mice. Livers and intestine were harvested after 3 weeks of dietary treatment of histologic analysis and a determination of cell proliferation (immunohistochemistry for Ki67), or apoptosis (immunohistochemistry for caspase-3), as well as a determination of Wnt/ β-catenin signaling activity. Results All DDC-fed animals exhibited histologic evidence of liver damage that was associated with the expansion of atypical ductal proliferation near the periportal areas and increased oxidative stress. In the intestine, DDC-induced liver damage was associated with decreased villus height, decreased enterocyte proliferation, and increased cell apoptosis compared with control animals. There was also evidence for decreased β-catenin expression by immunostaining in crypt and villus cells of DDC-fed mice compared with control animals. Conclusion Primary liver injury and cholestasis is associated with intestinal mucosal hypoplasia. Decreased cell proliferation and increased cell apoptosis may be responsible for decreased intestinal epithelial cell mass. The observed decrease in cell turnover is accompanied by an alteration in Wnt/ β-catenin signaling.

Paneth cell marker expression in intestinal villi and colon crypts characterizes dietary induced risk for mouse sporadic intestinal cancer

Nutritional and genetic risk factors for intestinal tumors are additive on mouse tumor phenotype, establishing that diet and genetic factors impact risk by distinct combinatorial mechanisms. In a mouse model of dietary-induced sporadic small and large intestinal cancer in WT mice in which tumor etiology, lag, incidence, and frequency reflect >90% of intestinal cancer in Western societies, dietary-induced risk altered gene expression profiles predominantly in villus cells of the histologically normal mucosa, in contrast to targeting of crypt cells by inheritance of an Apc(1638N) allele or homozygous inactivation of p21(Waf1/cip1), and profiles induced by each risk factor were distinct at the gene or functional group level. The dietary-induced changes in villus cells encompassed ectopic expression of Paneth cell markers (a lineage normally confined to the bottom of small intestinal crypts), elevated expression of the Wnt receptor Fzd5 and of EphB2 (genes necessary for Paneth cell differentiation and localization to the crypt bottom), and increased Wnt signaling in villus cells. Ectopic elevation of these markers was also present in the colon crypts, which are also sites of sporadic tumors in the nutritional model. Elevating dietary vitamin D(3) and calcium, which prevents tumor development, abrogated these changes in the villus and colon cells. Thus, common intestinal cancer driven by diet involves mechanisms of tumor development distinct from those mechanisms that cause tumors induced by the rare inheritance of a mutant adenomatous polyposis coli (Apc) allele. This is fundamental for understanding how common sporadic tumors arise and in evaluating relative risk in the population.

Evaluation of small-intestinal abnormalities in adult patients with Henoch–Schönlein purpura using video capsule

temic vasculitis mediated by IgA and characterized by the clinical manifestations of nonthrombocytopenic palpable purpura, abdominal pain, arthritis, and renal disorder [1,2]. Gastrointestinal symptoms occur in up to 85% of patients with HSP and abnormalities may be observed throughout the gastrointestinal tract, especially in the small bowel [3]. The characteristics of the small-intestinal lesions in five adult patients with HSP were retrospectively evaluated using video capsule endoscopy (VCE). None of the patients experienced any adverse events. In three of the five examinations, the battery of the VCE became exhausted before the device reached the cecum. It did however detect small-intestinal lesions in all cases. In contrast, for two of the patients computed tomography (CT) was able to detect only smallintestinal edema. VCE findings were classified as petechiae/redness, or erosions/ ulcers. Petechiae/redness, which was referred to as “intestinal purpura”, was observed throughout the small intestine in all cases (● Fig. 1). Erosions/ulcers were observed in four patients (● Fig. 2). A biopsy sample obtained by balloon enteroscopy from a petechial area showed extravasation of red blood cells in villi with mild inflammation (● Fig. 3). VCE is useful for comprehensive evaluation of small-intestinal HSP lesions that may not be detected by CT.

Mechanism of Regulation of Villus Cell Na/H Exchange (NHE3) by CNO in the Rabbit Ileum

Mechanism of Regulation of Villus Cell Na/H Exchange (NHE3) by CNO in the Rabbit Ileum