The effect of red meat consumption on the formation of N-nitroso compounds, a group of compounds which may be harmful to humans, in relation to colorectal cancer
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ABSTRACT:
DISEASE(S): Inflammatory Bowel Disease,Colorectal Cancer Risk
PROVIDER: 2415737 | ecrin-mdr-crc |
REPOSITORIES: ECRIN MDR
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Project description:It has been proposed that endogenously formed N-nitroso compounds (NOCs) are partly responsible for the link between red meat consumption and colorectal cancer (CRC) risk. As nitrite has been indicated as one of the critical factors in the formation of endogenous NOCs, it is of high importance to replace or reduce the nitrite levels in meat. Therefore, the PHYTOME project was initiated (Phytochemicals to reduce nitrite in meat products; www.phytome.eu), an EU funded research project aiming to develop innovative meat products in which the food additive sodium nitrite (E251) has been replaced by natural compounds originating from fruits and vegetables. A human dietary intervention study was conducted in which healthy subjects consumed 300 grams of meat for two weeks, in subsequent order: normal processed red meat, white meat, and red processed meat with standard or reduced levels of nitrite and added phytochemicals. Consumption of standard-nitrite PHYTOME meat products leads to a significant reduction in Apparent Total N-nitroso Compounds (ATNC) levels in faecal water, a surrogate marker of endogenously formed NOCs, as compared to the consumption of conventional processed red meat products. A reduction of nitrite in the PHYTOME meat lowered these levels even further. In addition, DNA strand breaks induced in ex-vivo faecal water exposed Caco-2 cells and O6-methyl-guanine adducts levels in colonic DNA were significantly higher after consumption of normal processed red meat as compared to white meat intake. PHYTOME meat intake resulted in reduced levels of these genotoxic markers, however, these were not statistically significant. Whole genome gene expression analyses in colonic tissue identified differentially expressed genes and genes associated with ATNC, which are related to molecular pathways which may explain cancer risk initiation after intake of processed red meat and cancer risk prevention after intake of the PHYTOME meat. Together these results indicate that addition of natural extracts to conventional processed red meat products results in reduced endogenous formation of NOCs, and may therefore contribute to a reduced risk of CRC, which is mechanistically supported by gene expression analyses.
2021-08-17 | GSE147996 | GEO
Project description:Study 1: Transcriptomic profiles in colon tissue from inflammatory bowel diseases patients in relation to N-nitroso compound exposure and colorectal cancer risk Study 1: N-nitroso compounds (NOC) have been suggested to play a role in human cancer development but definitive evidence is still lacking. In this study we investigated gene expression modifications induced in human colon tissue in relation to NOC exposure to gain insight in the relevance of these compounds in human colorectal cancer (CRC) development. Since there are indications that inflammation stimulates endogenous NOC formation, the study population consisted of patients with inflammatory bowel disease (IBD) and irritable bowel syndrome patients as controls without inflammation. Strong transcriptomic differences were identified in colonic biopsies from IBD patients and compared to controls that enhance the understanding of IBD pathophysiology. However, fecal NOC levels were not increased in IBD patients, suggesting that inflammation did not stimulate NOC formation. By relating gene expression changes of all subjects to fecal NOC levels, we did, however, identify a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending the molecular basis of NOC-induced carcinogenesis. We conclude that NOC exposure is associated with gene expression modifications in the colon that may increase CRC risk in humans. Study 2: Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon Study 2: Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat intake on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to transcriptomic changes induced in colonic tissue. In order to evaluate the potential effect of an inflamed colon on endogenous nitrosation, the study population consisted of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) control subjects without inflammation. The intervention had no effect on fecal NOC formation but fecal water genotoxicity significantly increased in response to red meat intake. Since IBD patients showed no difference in fecal NOC formation or fecal water genotoxicity levels as compared to IBS controls, for transcriptomic analyses, all subjects were grouped together. Genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated that are known to play a part in the carcinogenic process in the human colon. These results are in line with a possible oxidative effect of dietary heme. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a possible risk of CRC development in humans. The study investigated transcription levels in human colon biopsies obtained during a colonoscopic exam in 32 subjects suffering from either inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS). IBS patients served as control patients for comparison with IBD patients (see Study 1). 12 of these patients (6 IBD and 6 IBS) also followed a 7-day diet high in red meat (300 grams/day) after which a second colonscopic exam was performed to obtain colon biopsies to investigate the effect of the red meat intervention (Study 2). For each subject, cRNA copies of mRNA isolated from the colon biopsies were labeled with one dye (Cy3) and each sample was hybridized on a separate array. One replicate per subject or before/after red meat intervention (so 44 arrays in total, i.e. 20 before patients and 12 before and after patients).
2011-02-01 | E-GEOD-25220 | biostudies-arrayexpress
Project description:Study 1: Transcriptomic profiles in colon tissue from inflammatory bowel diseases patients in relation to N-nitroso compound exposure and colorectal cancer risk Study 1: N-nitroso compounds (NOC) have been suggested to play a role in human cancer development but definitive evidence is still lacking. In this study we investigated gene expression modifications induced in human colon tissue in relation to NOC exposure to gain insight in the relevance of these compounds in human colorectal cancer (CRC) development. Since there are indications that inflammation stimulates endogenous NOC formation, the study population consisted of patients with inflammatory bowel disease (IBD) and irritable bowel syndrome patients as controls without inflammation. Strong transcriptomic differences were identified in colonic biopsies from IBD patients and compared to controls that enhance the understanding of IBD pathophysiology. However, fecal NOC levels were not increased in IBD patients, suggesting that inflammation did not stimulate NOC formation. By relating gene expression changes of all subjects to fecal NOC levels, we did, however, identify a NOC exposure-associated transcriptomic response that suggests that physiological NOC concentrations may induce genotoxic responses and chromatin modifications in human colon tissue, both of which are linked to carcinogenicity. In a network analysis, chromatin modifications were linked to 11 significantly modulated histone genes, pointing towards a possible epigenetic mechanism that may be relevant in comprehending the molecular basis of NOC-induced carcinogenesis. We conclude that NOC exposure is associated with gene expression modifications in the colon that may increase CRC risk in humans. Study 2: Red meat intake-induced increases in fecal water genotoxicity correlate with pro-carcinogenic gene expression changes in the human colon Study 2: Red meat consumption is associated with an increased colorectal cancer (CRC) risk, which may be due to an increased endogenous formation of genotoxic N-nitroso compounds (NOCs). To assess the impact of red meat intake on potential risk factors of CRC, we investigated the effect of a 7-day dietary red meat intervention in human subjects on endogenous NOC formation and fecal water genotoxicity in relation to transcriptomic changes induced in colonic tissue. In order to evaluate the potential effect of an inflamed colon on endogenous nitrosation, the study population consisted of inflammatory bowel disease (IBD) and irritable bowel syndrome (IBS) control subjects without inflammation. The intervention had no effect on fecal NOC formation but fecal water genotoxicity significantly increased in response to red meat intake. Since IBD patients showed no difference in fecal NOC formation or fecal water genotoxicity levels as compared to IBS controls, for transcriptomic analyses, all subjects were grouped together. Genes significantly correlating with the increase in fecal water genotoxicity were involved in biological pathways indicative of genotoxic effects, including modifications in DNA damage, cell cycle, and apoptosis pathways. Moreover, WNT signaling and nucleosome remodeling pathways were modulated that are known to play a part in the carcinogenic process in the human colon. These results are in line with a possible oxidative effect of dietary heme. We conclude that the gene expression changes identified in this study corroborate the genotoxic potential of diets high in red meat and point towards a possible risk of CRC development in humans.
2011-02-01 | GSE25220 | GEO
Project description:Colorectal cancer (CRC) is strongly affected by diet, with red and processed meat increasing risk. To understand the role of microbiome in this phenomenon and to identify specific microbiome/metabolomics profiles associated with CRC risk, will be studied: 1) healthy volunteers fed for 3 months with: a high-CRC risk diet (meat-based MBD), a normalized CRC risk diet (MBD plus alpha-tocopherol, MBD-T), a low-CRC risk diet (pesco-vegetarian, PVD). At the beginning and at the end of the intervention, gut microbiome profiles (metagenomics and metabolomics), and CRC biomarkers (genotoxicity, cytotoxicity, peroxidation in faecal water; lipid/glycemic indexes, inflammatory cytokines, oxidative stress), 2) Colon carcinogenesis: the same diets will be fed (3 months) to carcinogen-induced rats or to Pirc rats, mutated in Apc, the key gene in CRC; faecal microbiome profiles, will be correlated to carcinogenesis measuring preneoplastic lesions, colon tumours, and faecal and blood CRC biomarkers as in humans; 3) To further elucidate the mechanisms underlying the effect of different microbiomes in determining CRC risk, faeces from rats fed the experimental diets will be transplanted into carcinogen-induced germ-free rats, measuring how microbiome changes correlate with metabolome and disease outcomes. The results will provide fundamental insight in the role of microbiome in determining the effect of the diet, in particular red/processed meat intake, on CRC risk
| 2264615 | ecrin-mdr-crc
Project description:RNAseq and LC/MS metabolomics analysis of C. difficile strain 630 grown in BHIS media with 50% (vol/vol) faecal water added, compared with control BHIS containing only the additional PBS used for prep of Faecal water. Cells grown in biological triplicates to late log phase (T=6h) prior to harvest. Goal was to determine changes in gene expression caused by exposure to Faecal water, and changes in the metabolite profile of faecal water containing medium when incubated with actively growing C. difficile cells
2018-11-12 | GSE112422 | GEO
Project description:Colon cancer is a major cause of cancer deaths in Western countries and is associated with diets high in red meat. Heme, the iron-porphyrin pigment of red meat, induces cytotoxicity of gut contents which injures surface cells leading to compensatory hyperproliferation of crypt cells. This hyperproliferation results in epithelial hyperplasia which increases the risk of colon cancer. In humans, a high red-meat diet increases Bacteroides spp in feces. Therefore, we simultaneously investigated the effects of dietary heme on colonic microbiota and on the host mucosa of mice. Whole genome microarrays showed that heme injured the colonic surface epithelium and induced hyperproliferation by changing the surface to crypt signaling. Using 16S rRNA phylogenetic microarrays, we investigated whether bacteria play a role in this changed signaling. Heme increased Bacteroidetes and decreased Firmicutes in colonic contents. This shift was most likely caused by a selective susceptibility of Gram-positive bacteria to heme cytotoxic fecal water, which is not observed for Gram-negative bacteria, allowing expansion of the Gram-negative community. The increased amount of Gram-negative bacteria most probably increased LPS exposure to colonocytes, however, there is no appreciable immune response detected in the heme-fed mice. There was no functional change in the sensing of the bacteria by the mucosa, as changes in inflammation pathways and Toll- like receptor signaling were not detected. This unaltered host-microbe cross-talk indicates that the changes in microbiota did not play a causal role in the observed hyperproliferation and hyperplasia. Keywords: Expression profiling by array Mice were fed a Westernized high fat control diet, or the same diet supplemented with 0.5 M-BM-5mol heme/g diet. After 14 days of intervention, mice were killed and gene expression was profiled in colon.
2012-12-19 | E-GEOD-40672 | biostudies-arrayexpress
Project description:Background and Aims. Dendritic cells (DCs) play a pivotal role in maintaining immunological homeostasis by orchestrating innate and adaptive immune responses via migration to inflamed sites and the lymph nodes (LNs). Plasmacytoid DCs (pDCs) have been reported to accumulate in the colon of inflammatory bowel disease (IBD) patients and dextran sulfate sodium (DSS)-induced colitis mice. However, the role of pDCs in the progression of colonic inflammation remains unclear. Methods. 80 compounds in natural medicines were searched for inhibitors of pDC migration using bone marrow-derived pDCs (BMpDCs) and conventional DCs (BMcDCs). BALB/c mice were given 3% DSS in the drinking water for 7 days to induce acute colitis. Compounds, which specifically inhibited pDC migration, were administrated into DSS-induced colitis mice. Results. Astragaloside IV (As-IV) and oxymatrine (Oxy) suppressed BMpDC migration but not BMcDC migration. In DSS-induced colitis mice, the number of pDCs was markedly increased in the colonic lamina propria (LP), and the expression of CCL21 was obviously observed in colonic isolated lymphoid follicles (ILFs). As-IV and Oxy reduced symptoms of colitis and the accumulation of pDCs in colonic ILFs but not in the colonic LP. Moreover, in a BMpDC adoptive transfer model, BMpDC migration to colonic ILFs was significantly decreased by treatment with As-IV or Oxy. Conclusion. pDCs accumulated in the colon of DSS-induced colitis mice, and As-IV and Oxy ameliorated DSS-induced colitis by suppressing pDC migration to colonic ILFs. Accordingly, the selective inhibition of pDC migration may be a potential therapeutic approach for treating colonic inflammatory diseases.
2021-07-06 | GSE167388 | GEO
Project description:N-nitroso compounds (NOC) are genotoxic compounds and animal carcinogens, and may play a role in human cancer development. Since the gastro-intestinal tract is an important route of exposure, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate this, we analysed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1µM) and N-methyl-N-nitrosurea (MNU, 1mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100mM), N-nitrosopiperidine (NPIP, 40mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 hours of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and pro-inflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon. Keywords: Comparison of genome-wide gene expression between different conditions The study investigated differential gene expression in Caco-2 cell line mRNA following 24 hours of exposure to six different N-nitroso compounds. Four biological replicates per sample compound. One compound per array, hybridized against vehicle control. Dye-swap between biological replicates 1 and 2, and 3 and 4.
2010-04-03 | E-GEOD-14284 | biostudies-arrayexpress
Project description:Clinical cohort data suggest that high consumption of red meat containing N-glycolylneuraminic acid (Neu5Gc) may increase colorectal prevalence, therefore, we investigated the effect of high Neu5Gc intake on colon cancer using the APCMin/+ mouse model . Ten APCMin/+ male mice were divided into two groups and fed normal (control group: 0.0507 mg per mouse per day) and high concentrations (treatment group: 1.014 mg per mouse per day) of Neu5Gc to mimic Normal and excessive consumption of red meat in humans, respectively. After two weeks of feeding, colorectal and liver were collected for histopathological diagnosis and transcriptome analysis.
2023-11-30 | GSE218116 | GEO
Project description:N-nitroso compounds (NOC) are genotoxic compounds and animal carcinogens, and may play a role in human cancer development. Since the gastro-intestinal tract is an important route of exposure, we hypothesize that NOC exposure targets genetic processes relevant in colon carcinogenesis. To investigate this, we analysed the transcriptomic effects of genotoxic concentrations of two nitrosamides, N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, 1µM) and N-methyl-N-nitrosurea (MNU, 1mM), and four nitrosamines, N-nitrosodiethylamine (NDEA, 50mM), N-nitrosodimethylamine (NDMA, 100mM), N-nitrosopiperidine (NPIP, 40mM), and N-nitrosopyrrolidine (NPYR, 100mM), in the human colon carcinoma cell line Caco-2. Gene Ontology gene group, consensus motif gene group and biological pathway analysis revealed that nitrosamides had little effect on gene expression after 24 hours of exposure, whereas nitrosamines had a strong impact on the transcriptomic profile. Analyses showed modifications of cell cycle regulation and apoptosis pathways for nitrosamines which was supported by flow cytometric analysis. We found additional modifications in gene groups and pathways of oxidative stress and inflammation, which suggest an increase in oxidative stress and pro-inflammatory immune response upon nitrosamine exposure, although less distinct for NDMA. Furthermore, NDEA, NPIP and NPYR most strongly affected several developmental motif gene groups and pathways, which may influence developmental processes. Many of these pathways and gene groups are implicated in the carcinogenic process and their modulation by nitrosamine exposure may therefore influence the development of colon cancer. In summary, our study has identified pathway modifications in human colon cells which may be associated with cancer risk of nitrosamine exposure in the human colon. Keywords: Comparison of genome-wide gene expression between different conditions
2009-04-01 | GSE14284 | GEO