Aberrant Crypt Foci Formation Research Articles

A synthetic resveratrol-curcumin hybrid derivative exhibits chemopreventive effects on colon pre-neoplastic lesions by targeting Wnt/β-catenin signaling, anti-inflammatory and antioxidant pathways.

The present study aimed to evaluate the chemopreventive effects of the hybrid against pre-neoplastic lesions induced in the colon of rodents. The doses were determined based on the reduction in DNA damage induced by doxorubicin [15 mg/kg body weight (b.w.)] in peripheral blood of Swiss mice. Doses of 8, 16, 32, and 64 mg/kg b.w. were antimutagenic. For the evaluation of pre-neoplastic lesions in the colon, Wistar rats were treated with PQM-162 at doses of 0.5, 1, and 2 mg/kg b.w. for 6 weeks using three approaches: simultaneous treatment, pre-treatment, and post-treatment. Pre-neoplastic lesions were induced with 1,2 dimethylhydrazine (160 mg/kg b.w.). PQM-162 reduced the formation of aberrant crypt foci in the simultaneous treatment and post-treatment. TNF-α and COX-2 mRNA levels decreased, while Nrf2 mRNA levels increased. PQM-162 also reduced the expression of COX-2, PCNA, and β-catenin protein markers and increased Nrf2 expression. Our findings suggest a chemopreventive potential of PQM-162 in colorectal carcinogenesis, which acts on anti-inflammatory, antioxidant, and cell proliferation pathways.

Association between Probiotics and Modulation of Gut Microbial Community Composition in Colorectal Cancer Animal Models: A Systematic Review (2010-2021).

Colorectal cancer (CRC) is one of the most prevalent gastrointestinal malignancies and is considered the third major cause of mortality globally. Probiotics have been shown to protect against the CRC cascade in numerous studies. The goal of this systematic review was to gather the preclinical studies that examined the impact of probiotics on the alteration of gut microbiota profiles (bacterial communities) and their link to colorectal carcinogenesis as well as the potential processes involved. The search was performed using Scopus, Web of Science, and PubMed databases. Five parameters were used to develop search filters: "probiotics," "prebiotics," "synbiotics," "colorectal cancer," and "animal model." Of the 399 full texts that were screened, 33 original articles met the inclusion criteria. According to the current findings, probiotics/synbiotics could significantly attenuate aberrant crypt foci (ACF) formation, restore beneficial bacteria in the microbiota population, increase short-chain fatty acids (SCFAs), and change inflammatory marker expression. The present systematic review results indicate that probiotics could modulate the gut microbial composition and immune regulation to combat/inhibit CRC in preclinical models. However, where the evidence is more limited, it is critical to transfer preclinical research into clinical data.

Proanthocyanidin and sodium butyrate synergistically modulate rat colon carcinogenesis by scavenging free radicals and regulating the COX-2 and APC pathways

BackgroundThe purpose of this study was to explore the effects of sodium butyrate (NaB), grape seed proanthocyanidin extract (GSPE), or their combination against dimethylhydrazine (DMH)-induced aberrant crypt foci (ACF) formation, which is a proxy for colon carcinogenesis in the rat colon.ResultsAfter inducing colon cancer, all treatments markedly decreased the overall numbers of ACF, with the NaB–GSPE combination eliciting the most pronounced reduction. All the treatments significantly inhibited cell proliferation as indicated by the lower percentages of Ki67-positive cells in the colonic mucosa. Also, caspase-3-immunolabeled cells were found to be significantly increased after all treatments, indicating more apoptotic activity in the initiated colonocytes. Further, the treatments significantly modulated the levels of antioxidant biomarkers, including malondialdehyde, superoxide dismutase, reduced glutathione, and total antioxidant capacity, suggesting a potently induced antioxidant activity, especially after the combination treatment. All treatments, especially the combination, dramatically downregulated the expression of COX-2 and APC, both of which are directly linked to colon cancer.ConclusionsNaB and GSPE exert potent anti-carcinogenic effects, both alone but more effectively in combination, in a rat colon cancer model. They could be important for colon cancer treatment and for adjuvant therapy in humans.

Investigation into the Potential Role of Propionibacterium freudenreichii in Prevention of Colorectal Cancer and Its Effects on the Diversity of Gut Microbiota in Rats.

Colorectal cancer (CRC) accounts for 10% of all cancer diagnoses and cancer-related deaths worldwide. Over the past two decades, several studies have demonstrated the clinical benefits of probiotic supplementation and some studies have shown that certain probiotics can modulate immunity and strengthen gut microbiota diversity. This study aims to assess the impact of the Propionibacterium freudenreichii (PF) probiotic against CRC induced by azoxymethane (AOM), and to investigate its effects on gut microbiota diversity in rats, as well as to evaluate the anti-proliferative activities of PF in HCT116 CRC cells. This experiment was performed using four groups of SD rats: normal control, AOM group, PF group (1 × 109 CFU/mL), and standard drug control (5-fluorouracil, 35 mg/kg). Methylene blue staining of colon tissues showed that the administration of PF significantly reduced the formation of colonic aberrant crypt foci (ACF) compared to the AOM control group. In addition, treated rats had lower levels of malondialdehyde in their colon tissue homogenates, indicating that lipid peroxidation was suppressed by PF supplementation. Furthermore, 16S rRNA gene analysis revealed that probiotic treatment enhanced the diversity of gut microbiota in rats. In vitro study showed that the viability of HCT116 cells was inhibited by the probiotic cell-free supernatant with an IC50 value of 13.3 ± 0.133. In conclusion, these results reveal that consuming PF as probiotic supplements modulates gut microbiota, inhibits the carcinogenic effects of AOM, and exerts anti-proliferative activity against CRC cells. Further studies are required to elucidate the role of PF on the immune response during the development and growth of CRC.

Chemopreventive Effects of Onosma mutabilis against Azoxymethane-Induced Colon Cancer in Rats via Amendment of Bax/Bcl-2 and NF-κB Signaling Pathways.

Onosma species (Boraginaceae) are well known as medicinal plants due to their wide range of pharmaceutical potential. The present study aims to investigate the anticancer (in vitro) and chemo-protective (in vivo) efficacies of Onosma mutabilis extract (OME) in the azoxymethane (AOM)-induced aberrant crypt foci (ACF) in rats. The in vitro antiproliferative effects of OME were determined on two human tumor cell lines (Caco-2 and HT-29) via MTT assay. The in vivo chemoprotective effects of OME were investigated by performing various biochemical analyses in serum and tissue homogenates of albino rats, along with determining oxidative stress biomarkers. Inflammatory biomarkers of colon, colonic gross morphology (by methylene blue), ACF formation, and colonic histopathology (H & E stain) were determined. The immunohistochemistry of colonic tissues was also assessed by Bax and Bcl-2 protein expression. The results showed that the antitumor activity of OME against Caco-2 and HT-29 colorectal cancer cells ranged between 22.28-36.55 µg/mL. OME supplementation caused a significant drop in the ACF values and improved the immunohistochemistry of the rats shown by up-regulation of Bax and down-regulation of Bcl-2 protein expressions. These outcomes reveal that O. mutabilis may have chemoprotective efficiency against AOM-induced colon cancer represented by the attenuation of ACF formation possibly through inhibition of free radicals, inflammation, and stimulation of the colon antioxidant armory (SOD, CAT, and GPx) and positive regulation of the Nrf2-Keap1 pathway.

Dietary Fungal Glucosylceramide and Ceramide Reduce the Formation of Aberrant Crypt Foci in 1,2-Dimethylhydrazine-Treated Mice: Differences in the Role of Glucosylceramide and Ceramide

Glucosylceramide (GlcCer) is composed of a glucose moiety attached to ceramides (Cer). GlcCer was reported to reduce the intestinal impairments in vivo and suppress in vitro intestinal inflammation. In this study, to clarify the effect of GlcCer on intestinal impairments in vivo, we compared the effects of shiitake mushroom-derived GlcCer (fungal GlcCer) on the formation of aberrant crypt foci (ACF) and colon inflammation with those of fungal Cer having the same Cer moiety of the fungal GlcCer. Fungal GlcCer- or Cer-supplemented diets significantly suppressed ACF formation in 1,2-dimethylhydrazine (DMH)-treated mice. Dietary fungal GlcCer reduced the expression of inflammation-related cytokines and apoptosis-related proteins induced by DMH, whereas dietary fungal Cer hardly reduced their expression upon intestinal injuries. Furthermore, when fungal GlcCer was ingested to the mice, only a small amount of fungal Cer was detected in the feces. These results indicate that the ingested fungal GlcCer might be hardly metabolized to fungal Cer and the GlcCer itself might suppress ACF formation in DMH-treated mice by suppressing intestinal inflammation.

Changes in the Fecal Metabolome Accompany an Increase in Aberrant Crypt Foci in the Colon of C57BL/6 Mice Fed with a High-Fat Diet.

High-fat diet (HFD)-induced obesity is a risk factor for colon cancer. Our previous data show that compared to an AIN-93 diet (AIN), a HFD promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation and microbial dysbiosis in C57BL/6 mice. To explore the underlying metabolic basis, we hypothesize that AOM treatment triggers a different fecal metabolomic profile in C57BL/6 mice fed the HFD or the AIN. We found that 65 of 196 identified metabolites were significantly different among the four groups of mice (AIN, AIN + AOM, HFD, and HFD + AOM). A sparse partial least squares discriminant analysis (sPLSDA) showed that concentrations of nine fecal lipid metabolites were increased in the HFD + AOM compared to the HFD, which played a key role in overall metabolome group separation. These nine fecal lipid metabolite concentrations were positively associated with the number of colonic ACF, the cell proliferation of Ki67 proteins, and the abundance of dysbiotic bacteria. These data suggest that the process of AOM-induced ACF formation may increase selective fecal lipid concentrations in mice fed with a HFD but not an AIN. Collectively, the accumulation of these critical fecal lipid species may alter the overall metabolome during tumorigenesis in the colon.

Dietary Energy Intake and Presence of Aberrant Crypt Foci Are Associated with Phospholipid, Purine, and Taurine Metabolite Abundances in C57BL/6N Mouse Colon.

Colon metabolomes associated with high-fat (H) versus energy-restricted (E) diets in early colorectal cancer (CRC) models have never been directly compared. The objectives of this study are to elucidate metabolites associated with diet, aberrant crypt foci (ACF), and diet:ACF interaction, using a lifetime murine model. Three-week-old mice consumed control (C), E, or H initiation diets for 18 weeks. ACF formation is initiated weeks 16-21 with azoxymethane injections, followed by progression diet crossover (to C, E, or H) through week 60. Colon extracts are analyzed using ultra-high-performance liquid chromatography-high resolution mass spectrometry (UHPLC-HRMS). Metabolites associated with diet, ACF, or diet:ACF are determined using regression models (FDR-adjusted p-value <0.05). No metabolites are significantly associated with initiation diets, but concentrations of acylcarnitines and phospholipids are associated with C, E, and H progression diets. Purines, taurine, and phospholipids are associated with ACF presence. No significant associations between metabolites and diet:ACF interaction are observed. These results suggest that recent, rather than early-life, diet is more closely associated with the colon metabolome, particularly lipid metabolism. Results from this study also provide candidate biomarkers of early CRC development and provide support for the importance of early diet on influencing pre-CRC risk.

Alcohol hinders the Anti-Carcinogenic effect of Resveratrol in the Colon of rats

Resveratrol (RESV), a polyphenol present in wine and other natural sources, has potent anti-oxidant and chemopreventive effect against various types of cancer by multiple mechanisms of action. On the other hand, ethanol, which is also one important component of wine, is associated with increased oxidative stress and risk of cancer in general, including the colonic cancer. It is unknown whether the anti-oxidant and anti-carcinogenic effects of RESV could be counterbalanced by alcohol in vivo. Thus, the present study evaluated the anti-neoplastic action of RESV, pure or associated with ethanol on the colon carcinogenesis induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in rats. It was performed a detailed analysis of aberrant crypt foci (ACF) formation and the systemic oxidative stress through malondialdehyde (MDA) dosage. The inflammatory process, which is associated to the colonic carcinogenesis, was estimated by the immune-expression of cyclooxigenase-2 (COX-2). Our experiments were performed in 32 wistar rats, divided into four groups: the group C was the control, the group M received MNNG (5mg/ml), the group MR received MNNG and RESV (1mg/kg/day) and the group MRA received RESV and alcohol (0,377g/kg/day). As a result, RESV decreased the number of ACF and COX-2 expression, but these effects were abolished by the alcohol. RESV reduced the production of MDA in all treated groups, evidencing that its systemic antioxidant effect was also present in the animals treated with alcohol. It was concluded that alcohol hindered the anti-carcinogenic effects of RESV. This effect of alcohol should be attributed to its pro-inflammatory effects, which have avoided the anti-inflammatory properties of RESV.

Faecalibacterium prausnitzii Ameliorates Colorectal Tumorigenesis and Suppresses Proliferation of HCT116 Colorectal Cancer Cells.

Faecalibacterium prausnitzii is one of the most abundant commensals of gut microbiota that is not commonly administered as a probiotic supplement. Being one of the gut’s major butyrate-producing bacteria, its clinical significance and uses are on the rise and it has been shown to have anti-inflammatory and gut microbiota-modulating properties in the treatment of inflammatory bowel illness, Crohn’s disease, and colorectal cancer. Colorectal cancer (CRC) is a silent killer disease that has become one of the leading causes of cancer-related death worldwide. This study aimed to evaluate the anti-tumorigenic and antiproliferative role of F. prausnitzii as well as to study its effects on the diversity of gut microbiota in rats. Findings showed that F. prausnitzii probiotic significantly reduced the colonic aberrant crypt foci frequency and formation in Azoxymethane (AOM)-induced CRC in rats. In addition, the administration of F. prausnitzii lowered the lipid peroxidation levels in the colon tissues. For in vitro 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) assay, the cell-free supernatant of F. prausnitzii suppressed the growth of HCT116 colorectal cancer cells in a time/dose-dependent manner. 16S rRNA gene sequencing using rat stool samples showed that the administration of F. prausnitzii modulated the gut microbiota of the rats and enhanced its diversity. Hence, these findings suggest that F. prausnitzii as a probiotic supplement can be used in CRC prevention and management; however, more studies are warranted to understand its cellular and molecular mechanisms of action.

Hibiscus (Hibiscus sabdariffa L.) supplementation increases butyrate synthesis and reduces inflammatory cells, attenuating the formation of aberrant crypt foci in BALB/c mice induced to pre-neoplastic lesions.

The development of colorectal cancer involves some morphological changes, and in the initial stage, pre-neoplastic lesions called aberrant crypt foci (ACF) appear. Thus, an intervention with sources of bioactive compounds such as Hibiscus sabdariffa L., rich in phenolic compounds and anthocyanins, could attenuate the risk of developing these lesions due to its antioxidant, anti-inflammatory and anti-proliferative properties. Therefore, the aim of this study was to evaluate the effects of 5% and 10% supplementation of dehydrated H. sabdariffa calyces (DHSC) during the development of 1,2-dimethylhydrazine-induced preneoplastic lesions in male BALB/c mice. The characterization of DHSC was carried out. The in vivo experiment lasted 12 weeks, and the animals were randomly divided into 3 experimental groups: the control group (CON) and the supplemented groups with 5% DHSC and 10% DHSC. The activities of liver enzymes catalase and superoxide dismutase were determined. In addition, ACF, short chain fatty acids (SCFA), presence of inflammatory infiltrates, goblet cells and leukocytes in the colonic mucosa were quantified. There was a significant reduction in ACF and the presence of inflammatory infiltrates in the colon of animals in groups 5DHSC and 10DHSC. In addition, the 10DHSC group showed an increase in the activity of the catalse enzyme, in the production of butyrate and in the presence of NK cells in the colon, in addition to more hypertrophied goblet cells. Based on these findings, it is suggested that DHSC supplementation may be recommended to attenuate cellular responses in the early stage of preneoplastic lesions.

Anticarcinogenic activity of methanol extract of Melastoma malabathricum leaves is attributed to the presence of phenolics compounds and the activation of endogenous antioxidant system

Melastoma malabathricum (M. malabathricum) extracts have been reported to exert various pharmacological activities including antioxidants, anti-inflammatory and antiproliferative activities. The objective of the present study was to determine the anticarcinogenic activity of its methanol extract (MEMM) against the azoxymethane (AOM)-induced early colon carcinogenesis in rats. Rats were randomly assigned to five groups (n=6) namely normal control, negative control, and treatment (50, 250 or 500 mg/kg of MEMM) groups. Colon tissues were harvested for histopathological analysis and endogenous antioxidant system determination. MEMM was also subjected to HPLC analysis. Findings showed that MEMM significantly (p<0.05) reversed the AOM-induced carcinogenicity by: i) reducing the formation of aberrant crypt foci (ACF) in colon tissues, and; ii) enhancing the endogenous antioxidant activity (catalase, superoxide dismutase and glutathione peroxidase). Moreover, various phenolics has been identified in MEMM. In conclusion, MEMM exerts the in vivo anticarcinogenic activity via the activation of endogenous antioxidant system and synergistic action of phenolics.

Dietary Alkali-stable Neutral Lipids from Sake Lees Suppress the Formation of Colon Aberrant Crypt Foci in Mice.

We have previously reported that dietary glucosylceramide (GlcCer) and rice extracts containing GlcCer reduce the formation of aberrant crypt foci (ACF) in the colons of 1,2-dimethylhydrazine (DMH)-treated mice, as a precursor model of colon cancer. This study investigated the impact of alkali-stable neutral lipids (NLs) containing free ceramides (Cer) and sterols on the formation of ACF in mice for the purpose of searching for functional components, irrespective of GlcCer, in rice extracts. The fraction was prepared from sake lees as a rice fermentation byproduct. Dietary NLs suppressed the marked increase in colon ACF treated with DMH.

Mathematical model for simulation of morphological changes associated to crypt fission in the colon

<p style='text-indent:20px;'>Morphological changes due to colorectal cancer propagation by an abnormal crypt fission is an interesting application arising in medicine and biology, that we try to analyse by a differential equations model coupled with a discrete crypt fission model. A colonic crypt can slowly change its shape in three steps: growth, bifurcation and fission. Fission is a rare event in a normal tissue, however if transit cells are unable to differentiate, due to an activation of Wnt signaling, then it may become fast and uncontrolled and cause a formation of aberrant crypt foci (ACF), defined as clusters of aberrant crypts. The differential equation system is composed by a convective diffusive equation for transit cell density and an elliptic equation for cell pressure, both defined on a manifold. The discrete crypt fission model acts in a set of adjacent crypts in order to investigate the ACF dynamics, due to a differentiation block. By using a Galerkin finite element method we solve numerically the differential equation model and show some interesting results about an ACF formation caused by a deformation and fission of abnormal crypts.</p>

Early detection of colorectal cancer somatic mutations using cfDNA liquid biopsies in a murine carcinogenesis model.

Colorectal cancer (CRC) is one of the top five cancers in incidence and mortality worldwide. The early detection of this neoplasm through analysis of circulating free DNA (cfDNA), which carries tumor genetic alterations, as a liquid biopsy, could have a major impact in enhancing early detection and reducing the mortality rate. The aim of this work was to demonstrate the feasibility of using cfDNA as a liquid biopsy for the early detection of CRC. For this purpose, we implemented an azoxymethane and dextran sodium sulfate-induced murine carcinogenesis model to detect oncogenic somatic mutations in Ctnnb1 and Kras during CRC development. To enhance the sensitivity in the detection, E-ice-COLD-PCR was utilized to selectively enrich for mutant alleles, followed by massively parallel sequencing. Driving somatic mutations were detected in Ctnnb1 and Kras in the liquid biopsies of early stages of tumor development, corresponding to the formation of aberrant crypt foci, the first histological alterations that can be identified throughout the formation of CRC. The concentration of cfDNA was increased along the carcinogenic process. Polyclonality in Ctnnb1 was found in tumor samples and cfDNA in this model. On the other hand, the use of cfDNA as a non-invasive test resulted in superior early detection compared to microPET/CT imaging. As a proof-of-principle, this study shows the great potential use of allelic-specific PCR for the detection and enrichment of pathogenic alleles present in cfDNA samples, as a test for early non-invasive detection of CRC. This work provides scientific evidence to set methodological bases that allow early detection of mutations in cfDNA obtained from plasma of CRC in humans.

Watermelon powder supplementation reduces colonic cell proliferation and aberrant crypt foci by upregulating p21Waf1/Cip1 expression

• Watermelon supplementation inhibited colonic aberrant crypt foci (ACF) formation. • The inhibition of ACF exhibited in the proximal, middle and distal regions of colon. • Watermelon supplementation lowered colonic cell proliferation. • The decreased proliferation may related to downregulation of p21 Waf1/Cip1 expression. The objective of this study was to examine the effects of watermelon powder supplementation on colonic cell proliferation, aberrant crypt foci, and gene expression of cell cycle regulators. Thirty-two rats were randomly assigned to one of the following isocaloric diets: 0.5% watermelon powder, 0.36% l -arginine, and control for 9 weeks. All animals were injected with azoxymethane (15 mg/kg body weight s.c.). Both watermelon powder and l -arginine groups exhibited lower numbers of aberrant crypt foci (ACF) in all proximal, middle, and distal regions of the colon (P < 0.01). Both groups also showed lower proliferation index and proliferative zone (P < 0.05). In addition, watermelon powder and l -arginine supplementation upregulated p21 Waf1/Cip1 gene expression (P = 0.048). These results suggest that watermelon or l -arginine supplementation may decrease the risk of colorectal cancer as they reduced proliferation by upregulating a cyclin-dependent kinase inhibitor and inhibited ACF formation in all anatomical regions of the colon.

Selenium and the 15kDa Selenoprotein Impact Colorectal Tumorigenesis by Modulating Intestinal Barrier Integrity.

Selenoproteins play important roles in many cellular functions and biochemical pathways in mammals. Our previous study showed that the deficiency of the 15 kDa selenoprotein (Selenof) significantly reduced the formation of aberrant crypt foci (ACF) in a mouse model of azoxymethane (AOM)-induced colon carcinogenesis. The objective of this study was to examine the effects of Selenof on inflammatory tumorigenesis, and whether dietary selenium modified these effects. For 20 weeks post-weaning, Selenof-knockout (KO) mice and littermate controls were fed diets that were either deficient, adequate or high in sodium selenite. Colon tumors were induced with AOM and dextran sulfate sodium. Surprisingly, KO mice had drastically fewer ACF but developed a similar number of tumors as their littermate controls. Expression of genes important in inflammatory colorectal cancer and those relevant to epithelial barrier function was assessed, in addition to structural differences via tissue histology. Our findings point to Selenof’s potential role in intestinal barrier integrity and structural changes in glandular and mucin-producing goblet cells in the mucosa and submucosa, which may determine the type of tumor developing.

Protective Mechanism of Rice-Derived Lipids and Glucosylceramide in an In Vitro Intestinal Tract Model

We previously reported that the ethanol extract from polished rice suppresses inflammation and the formation of aberrant crypt foci in the mouse colon and particularly focused on the plant sphingolipid glucosylceramide (GlcCer). Here, we investigated the effects of rice lipid fractions and GlcCer on differentiated Caco-2 cells treated with lipopolysaccharide (LPS), in particular, we evaluated the mechanism of action of GlcCer using related substances and metabolic enzyme inhibitors. Rice-derived polar lipids suppressed the LPS-induced reduction in the number of cells. The polar lipids with higher GlcCer content exerted a better effect than the other fractions. GlcCer-related substances reversed the LPS-induced reduction in the number of cells, and GlcCer-metabolic inhibitors, including a sphingosine kinase inhibitor, suppressed the beneficial effects of GlcCer-related substances. These results suggest that GlcCer is a rice component with intestinal protection. Secondly, GlcCer is metabolized during inflammation and protects intestinal cells by maintaining the sphingolipid levels in cells and producing sphingoid base-1-phosphate.

Azoxymethane Alters the Plasma Metabolome to a Greater Extent in Mice Fed a High-Fat Diet Compared to an AIN-93 Diet.

Consumption of a high-fat diet (HFD) links obesity to colon cancer in humans. Our data show that a HFD (45% energy fat versus 16% energy fat in an AIN-93 diet (AIN)) promotes azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) formation in a mouse cancer model. However, the underlying metabolic basis remains to be determined. In the present study, we hypothesize that AOM treatment results in different plasma metabolomic responses in diet-induced obese mice. An untargeted metabolomic analysis was performed on the plasma samples by gas chromatography time-of-flight mass spectrometry (GC-TOF-MS). We found that 53 of 144 identified metabolites were different between the 4 groups of mice (AIN, AIN + AOM, HFD, HFD + AOM), and sparse partial least-squares discriminant analysis showed a separation between the HFD and HFD + AOM groups but not the AIN and AIN + AOM groups. Moreover, the concentrations of dihydrocholesterol and cholesterol were inversely associated with AOM-induced colonic ACF formation. Functional pathway analyses indicated that diets and AOM-induced colonic ACF modulated five metabolic pathways. Collectively, in addition to differential plasma metabolomic responses, AOM treatment decreases dihydrocholesterol and cholesterol levels and alters the composition of plasma metabolome to a greater extent in mice fed a HFD compared to the AIN.

Pterostilbene Attenuates High-Fat Diet and Dextran Sulfate Sodium-Induced Colitis via Suppressing Inflammation and Intestinal Fibrosis in Mice

The worldwide prevalence of obesity has significantly increased over the past few decades. It is currently believed that obesity is a risk factor for developing inflammatory bowel disease. Pterostilbene (PTS), a naturally occurring stilbene from blueberries, is known to have anticancer, anti-inflammation, antifibrosis, and antiobesity effects. The preventive effect of PTS on the susceptibility of high-fat diet (HFD) to dextran sulfate sodium (DSS)-induced colitis in mice was investigated. Beginning at 5 weeks of age, C57BL/6J mice were fed a normal diet, 50% HFD alone, or containing PTS, and DSS (2.5%, w/v) was given in drinking water at week 9 and week 11. The results demonstrated that PTS significantly attenuated HFD and DSS-induced plasma interleukin-6 accumulation. Moreover, PTS suppressed HFD/DSS-induced formation of aberrant crypt foci and reduced the colon weight-to-length ratio in HFD/DSS-induced colitis mice. Furthermore, PTS inhibited interleukin-1β (IL-1β), the C/EBP homologous protein (CHOP), cyclooxygenase-2, and transforming growth factor beta-1 (TGF-β1)/mothers against decapentaplegic homolog 2 expression and maintained mucin2 (Muc2) and E-cadherin expressions. In addition, post-treatment with PTS also decreased the colon weight-to-length ratio and loss of Muc2. Moreover, the CHOP, IL-1β, matrix metalloproteinase-2, and TGF-β1 expressions were significantly decreased in HFD/DSS-induced colitis mice after post-treatment with PTS. In conclusion, the results of the present study suggest that PTS is of significant interest for the prevention of HFD/DSS-induced colitis in C57BL/6J mice.