Dextran sulfate enhances the level of an oxidative DNA damage biomarker, 8-oxo-7,8-dihydro-2 0-deoxyguanosine, in rat colonic mucosa

Dextran sodium sulfate (DSS) given in drinking water can induce colonic Inflammation and produce colorectal tumors in rodents, although it is not directly genotoxic. The hypothesis that DSS can produce free radicals and induce oxidative DNA damage in colonic mucosa has been tested. In rats fed for 2 days with water containing 3% and 6% DSS, colonic Inflammation manifestations were recorded and 8-oxo-7,8-dihydro-2 0-deoxyguanosine (8-oxodGuo), a major biomarker of oxidative DNA damage, was assayed in colonic mucosa. As compared with control rats given pure water, inflammatory manifestations were seen in rats given DSS. At the same time, 8-oxodGuo levels in colonic mucosa were doubled (P , 0:001). These results suggest that formation of oxidative DNA damage in colonic mucosa depends on inflammation and maybe on the production of reactive oxygen species. This study shows that DSS can induce oxidative DNA damage within only 2 days, which could explain in part its carcinogenic properties

Increased colonic propionate reduces anticipatory reward responses in the human striatum to high-energy foods

Background: Short-chain fatty acids (SCFAs), metabolites produced through the microbial fermentation of nondigestible dietary components, have key roles in energy homeostasis. Animal research suggests that colon-derived SCFAs modulate feeding behavior via central mechanisms. In humans, increased colonic production of the SCFA propionate acutely reduces energy intake. However, evidence of an effect of colonic propionate on the human brain or reward-based eating behavior is currently unavailable. Objectives: We investigated the effect of increased colonic propionate production on brain anticipatory reward responses during food picture evaluation. We hypothesized that elevated colonic propionate would reduce both reward responses and ad libitum energy intake via stimulation of anorexigenic gut hormone secretion. Design: In a randomized crossover design, 20 healthy nonobese men completed a functional magnetic resonance imaging (fMRI) food picture evaluation task after consumption of control inulin or inulin-propionate ester, a unique dietary compound that selectively augments colonic propionate production. The blood oxygen level–dependent (BOLD) signal was measured in a priori brain regions involved in reward processing, including the caudate, nucleus accumbens, amygdala, anterior insula, and orbitofrontal cortex (n = 18 had analyzable fMRI data). Results: Increasing colonic propionate production reduced BOLD signal during food picture evaluation in the caudate and nucleus accumbens. In the caudate, the reduction in BOLD signal was driven specifically by a lowering of the response to high-energy food. These central effects were partnered with a decrease in subjective appeal of high-energy food pictures and reduced energy intake during an ad libitum meal. These observations were not related to changes in blood peptide YY (PYY), glucagon-like peptide 1 (GLP-1), glucose, or insulin concentrations. Conclusion: Our results suggest that colonic propionate production may play an important role in attenuating reward-based eating behavior via striatal pathways, independent of changes in plasma PYY and GLP-1. This trial was registered at clinicaltrials.gov as NCT00750438

Nonobstructing Colonic Dilatation and Colon Perforations Following Renal Transplantation

Nonobstructing colonic dilatation has not been commonly reported following renal transplantation, and colon perforations carry a high morbidity and mortality in this population. During a 7-year period, nonobstructing colonic dilatation developed in 13 adults 1 to 13 days after renal transplantation. Twelve (92%) of the 13 had poorly functioning allografts. Five (83%) of the 6 with and 2 (29%) of the 7 without colonoscopy had resolution of nonobstructing colonic dilatation. Of the seven right-sided colon perforations during this period, six were associated with nonobstructing colonic dilatation. An additional 4 patients had diverticular perforations in the left colon. Of a total of 11 patients with colon perforation, 7 had surgery within 24 hours of the perforation and 6 (86%) of these survived. Only 1 (25%) of the 4 having surgery more than 24 hours later survived. Six of the survivors retained functioning allografts. Nonobstructing colonic dilatation seems to be a potential complication of poor graft function after renal transplantation, and colonoscopy is effective in its treatment. In patients with colon perforations, early surgery and reduced immunosuppression are essential in decreasing mortality. © 1990, American Medical Association. All rights reserved

Alteration of colonic excitatory tachykininergic motility and enteric inflammation following dopaminergic nigrostriatal neurodegeneration

Background: Parkinson's disease (PD) is frequently associated with gastrointestinal (GI) symptoms, including constipation and defecatory dysfunctions. The mechanisms underlying such disorders are still largely unknown, although the occurrence of a bowel inflammatory condition has been hypothesized. This study examined the impact of central dopaminergic degeneration, induced by intranigral injection of 6-hydroxydopamine (6-OHDA), on distal colonic excitatory tachykininergic motility in rats. Methods: Animals were euthanized 4 and 8 weeks after 6-OHDA injection. Tachykininergic contractions, elicited by electrical stimulation or exogenous substance P (SP), were recorded in vitro from longitudinal muscle colonic preparations. SP, tachykininergic NK1 receptor, and glial fibrillary acidic protein (GFAP) expression, as well as the density of eosinophils and mast cells in the colonic wall, were examined by immunohistochemical analysis. Malondialdehyde (MDA, colorimetric assay), TNF, and IL-1 beta (ELISA assay) levels were also examined. The polarization of peritoneal macrophages was evaluated by real-time PCR. Results: In colonic preparations, electrically and SP-evoked tachykininergic contractions were increased in 6-OHDA rats. Immunohistochemistry displayed an increase in SP and GFAP levels in the myenteric plexus, as well as NK1 receptor expression in the colonic muscle layer of 6-OHDA rats. MDA, TNF, and IL-1 beta levels were increased also in colonic tissues from 6-OHDA rats. In 6-OHDA rats, the number of eosinophils and mast cells was increased as compared with control animals, and peritoneal macrophages polarized towards a pro-inflammatory phenotype. Conclusions: The results indicate that the induction of central nigrostriatal dopaminergic degeneration is followed by bowel inflammation associated with increased oxidative stress, increase in pro-inflammatory cytokine levels, activation of enteric glia and inflammatory cells, and enhancement of colonic excitatory tachykininergic motility

The anti-cancer effect of retinoic acid signaling in CRC occurs via decreased growth of ALDH+ colon cancer stem cells and increased differentiation of stem cells

Background: Tumorigenesis is driven by stem cell (SC) overpopulation. BecauseALDH is both a marker for SCs in many tissues and a key enzyme in retinoid acid (RA)signaling, we studied RA signaling in normal and malignant colonic SCs.Hypothesis: RA signaling regulates growth and differentiation of ALDH+ colonicSCs dysregulation of RA signaling contributes to SC overpopulation and colorectalcancer (CRC) development.Methods: We analyzed normal and malignant colonic tissues and CRC cell linesto see if retinoid receptors (RXR &RAR) are exclusively expressed in ALDH+ SCs,and if RA signaling changes during CRC development. We determined whether RAsignaling regulates cancer SC (CSC) proliferation, differentiation, sphere formation,and population size.Results: RXR &RAR were expressed in ALDH+ colonic SCs, but not in MCM2+proliferative cells. Western blotting/immunostaining of CRCs revealed that RAsignaling components become overexpressed in parallel with ALDH overexpression,which coincides with the known overpopulation of ALDH+ SCs that occurs during,and drives, CRC development. Treatment of SCs with all-trans retinoic acid (ATRA)decreased proliferation, sphere formation and ALDH+ SC population size, and induceddifferentiation along the neuroendocrine cell (NEC) lineage.Conclusions: Retinoid signaling, by regulating ALDH+ colonic CSCs, decreases SCproliferation, sphere formation, and population size, and increases SC differentiation toNECs. Dysregulation of RA signaling in colonic SCs likely contributes to overpopulationof ALDH+ SCs and CRC growth.Implications: That retinoid receptors RXR and RAR are selectively expressed inALDH+ SCs indicates RA signaling mainly occurs via ALDH+ SCs, which provides amechanism to selectively target CSCs. © 2018 Impact Journals LLC. All rights reserved

Dimethyl Fumarate Alleviates Dextran Sulfate Sodium-Induced Colitis, through the Activation of Nrf2-Mediated Antioxidant and Anti-inflammatory Pathways.

Oxidative stress and chronic inflammation play critical roles in the pathogenesis of ulcerative colitis (UC) and inflammatory bowel diseases (IBD). A previous study has demonstrated that dimethyl fumarate (DMF) protects mice from dextran sulfate sodium (DSS)-induced colitis via its potential antioxidant capacity, and by inhibiting the activation of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. This study aims to clarify the nuclear factor erythroid 2-related factor 2/antioxidant responsive element (Nrf2/ARE) pathway pharmacological activation and anti-inflammatory effect by DMF, through focusing on other crucial antioxidant enzymes and inflammatory mediator, including glutamate-cysteine ligase catalytic subunit (GCLC), glutathione peroxidase (GPX) and cyclooxygenase-2 (COX-2), in a DSS-induced colitis mouse model. The oral administration of DMF attenuated the shortening of colons and alleviated colonic inflammation. Furthermore, the expression of key antioxidant enzymes, including GCLC and GPX, in the colonic tissue were significantly increased by DMF administration. In addition, protein expression of the inflammatory mediator, COX-2, was reduced by DMF administration. Our results suggest that DMF alleviates DSS-induced colonic inflammatory damage, likely via up-regulating GCLC and GPX and down-regulating COX-2 protein expression in colonic tissue

Flagellin induces β-defensin 2 in human colonic ex vivo infection with enterohemorrhagic Escherichia coli

Enterohemorrhagic E. coli (EHEC) is an important foodborne pathogen in the developed world and can cause life-threatening disease particularly in children. EHEC persists in the human gut by adhering intimately to colonic epithelium and forming characteristic attaching/effacing lesions. In this study, we investigated the innate immune response to EHEC infection with particular focus on antimicrobial peptide and protein expression by colonic epithelium. Using a novel human colonic biopsy model and polarized T84 colon carcinoma cells, we found that EHEC infection induced expression of human β-defensin 2 (hBD2), whereas hBD1, hBD3, LL-37 and lysozyme remained unchanged. Infection with specific EHEC deletion mutants demonstrated that this was dependent on flagellin, and apical exposure to purified flagellin was sufficient to stimulate hBD2 and also interleukin (IL)-8 expression ex vivo and in vitro. Flagellin-mediated hBD2 induction was significantly reduced by inhibitors of NF-κB, MAP kinase p38 and JNK but not ERK1/2. Interestingly, IL-8 secretion by polarized T84 cells was vectorial depending on the side of stimulation, and apical exposure to EHEC or flagellin resulted in apical IL-8 release. Our results demonstrate that EHEC only induces a modest immune response in human colonic epithelium characterized by flagellin-dependent induction of hBD2 and low levels of IL-8

K-ras and p53 mutations in colonic lavage fluid of patients with colorectal neoplasias

Background: The adenoma-carcinoma sequence has its molecular basis in several gene mutations of which K-ras and p53 are of paramount importance. The aims of this study were to evaluate whether these genetic alterations can be detected in colonic lavage fluid from patients with colorectal adenomas and carcinomas. Methods: In 45 patients with adenomas, 20 patients with colorectal carcinomas and 38 patients with non-neoplastic and noninflammatory diseases of the colon p53 and K-ras mutations were evaluated in colonic lavage fluid employing single-strand confirmation polymorphism analysis and dot-blot hybridization, respectively. Results: Mutations of the K-ras and the p53 gene were found in 15.6% (p = 0.065) of patients with adenomas, in 25.0% (p = 0.016) of patients with carcinomas and in 2.6% in the control group. Conclusion: Genetic alterations in the colonic lavage fluid could be an additional diagnostic tool for the surveillance of patients with colorectal neoplasias. Copyright (C) 2001 S. Karger AG, Basel

Enterohemorrhagic Escherichia coli infection inhibits colonic thiamin pyrophosphate uptake via transcriptional mechanism.

Colonocytes possess a specific carrier-mediated uptake process for the microbiota-generated thiamin (vitamin B1) pyrophosphate (TPP) that involves the TPP transporter (TPPT; product of the SLC44A4 gene). Little is known about the effect of exogenous factors (including enteric pathogens) on the colonic TPP uptake process. Our aim in this study was to investigate the effect of Enterohemorrhagic Escherichia coli (EHEC) infection on colonic uptake of TPP. We used human-derived colonic epithelial NCM460 cells and mice in our investigation. The results showed that infecting NCM460 cells with live EHEC (but not with heat-killed EHEC, EHEC culture supernatant, or with non-pathogenic E. Coli) to lead to a significant inhibition in carrier-mediated TPP uptake, as well as in level of expression of the TPPT protein and mRNA. Similarly, infecting mice with EHEC led to a significant inhibition in colonic TPP uptake and in level of expression of TPPT protein and mRNA. The inhibitory effect of EHEC on TPP uptake by NCM460 was found to be associated with reduction in the rate of transcription of the SLC44A4 gene as indicated by the significant reduction in the activity of the SLC44A4 promoter transfected into EHEC infected cells. The latter was also associated with a marked reduction in the level of expression of the transcription factors CREB-1 and ELF3, which are known to drive the activity of the SLC44A4 promoter. Finally, blocking the ERK1/2 and NF-kB signaling pathways in NCM460 cells significantly reversed the level of EHEC inhibition in TPP uptake and TPPT expression. Collectively, these findings show, for the first time, that EHEC infection significantly inhibit colonic uptake of TPP, and that this effect appears to be exerted at the level of SLC44A4 transcription and involves the ERK1/2 and NF-kB signaling pathways