phytosterols and Colitis

Phytosterols are known to reduce plasma cholesterol levels and thereby reduce cardiovascular risk. Studies conducted on human and animal models have demonstrated that these compounds have also anti-inflammatory effects. Recently, an experimental colitis model (dextran sulphate sodium-induced) has shown that pre-treatment with phytosterols decreases infiltration of inflammatory cells and accelerates mucosal healing. This study aims to understand the mechanism underlying the colitis by analysing the end-products of the metabolism in distal colon and liver excised from the same mice used in the previous work. In particular, an unsupervised gas chromatography-mass spectrometry (GC-MS) and NMR based metabolomics approach was employed to identify the metabolic pathways perturbed by the dextran sodium sulphate (DSS) insult (i.e. Krebs cycle, carbohydrate, amino acids, and nucleotide metabolism). Interestingly, phytosterols were able to restore the homeostatic equilibrium of the hepatic and colonic metabolome.

Topics: Animals; Colitis; Colon; Disease Models, Animal; Gas Chromatography-Mass Spectrometry; Liver; Male; Metabolomics; Mice; Mice, Inbred BALB C; Phytosterols

In this study, we evaluated the effects of dietary plant sterols and stanols as their fatty acid esters on the development of experimental colitis. The effects were studied both in high- and low-fat diet conditions in two models, one acute and another chronic model of experimental colitis that resembles gene expression in human inflammatory bowel disease (IBD). In the first experiments in the high fat diet (HFD), we did not observe a beneficial effect of the addition of plant sterols and stanols on the development of acute dextran sulphate sodium (DSS) colitis. In the chronic CD4CD45RB T cell transfer colitis model, we mainly observed an effect of the presence of high fat on the development of colitis. In this HFD condition, the presence of plant sterol or stanol did not result in any additional effect. In the second experiments with low fat, we could clearly observe a beneficial effect of the addition of plant sterols on colitis parameters in the T cell transfer model, but not in the DSS model. This positive effect was related to the gender of the mice and on Treg presence in the colon. This suggests that especially dietary plant sterol esters may improve intestinal inflammation in a T cell dependent manner.

Topics: Acute Disease; Animals; Anti-Inflammatory Agents; Antigens, CD; Brassica rapa; Chronic Disease; Colitis; Colon; Diet, Fat-Restricted; Diet, High-Fat; Dietary Fats; Esters; Fatty Acids; Fatty Acids, Monounsaturated; Female; Inflammation; Inflammatory Bowel Diseases; Male; Mice, Inbred C57BL; Phytosterols; Phytotherapy; Plant Oils; Rapeseed Oil; Sitosterols; T-Lymphocytes

Phytosterols, besides hypocholesterolemic effect, present anti-inflammatory properties. Little information is available about their efficacy in Inflammatory Bowel Disease (IBD). Therefore, we have evaluated the effect of a mixture of phytosterols on prevention/induction/remission in a murine experimental model of colitis. Phytosterols were administered x os before, during and after colitis induction with Dextran Sodium Sulfate (DSS) in mice. Disease Activity Index (DAI), colon length, histopathology score, 18F-FDG microPET, oxidative stress in the intestinal tissue (ileum and colon) and gallbladder ileum and colon spontaneous and carbachol (CCh) induced motility, plasma lipids and plasma, liver and biliary bile acids (BA) were evaluated. A similar longitudinal study was performed in a DSS colitis control group. Mice treated with DSS developed severe colitis as shown by DAI, colon length, histopathology score, 18F-FDG microPET, oxidative stress. Both spontaneous and induced ileal and colonic motility were severely disturbed. The same was observed with gallbladder. DSS colitis resulted in an increase in plasma cholesterol, and a modification of the BA pattern. Phytosterols feeding did not prevent colitis onset but significantly reduced the severity of the disease and improved clinical and histological remission. It had strong antioxidant effects, almost restored colon, ileal and gallbladder motility. Plasmatic levels of cholesterol were also reduced. DSS induced a modification in the BA pattern consistent with an increase in the intestinal BA deconjugating bacteria, prevented by phytosterols. Phytosterols seem a potential nutraceutical tool for gastrointestinal inflammatory diseases, combining metabolic systematic and local anti-inflammatory effects.

Topics: Animals; Anti-Inflammatory Agents; Bile Acids and Salts; Cholesterol; Colitis; Colon; Dextran Sulfate; Disease Models, Animal; Gallbladder; Ileum; Male; Mice; Mice, Inbred BALB C; Oxidative Stress; Peristalsis; Phytosterols; Remission Induction; Severity of Illness Index

We have recently reported that phytosteryl ferulates isolated from rice bran inhibit nuclear factor-kappaB (NF-kappaB) activity in macrophages. In the present study, we investigated the effect of gamma-oryzanol (gamma-ORZ), a mixture of phytosteryl ferulates, cycloartenyl ferulate (CAF), one of the components of gamma-ORZ, and ferulic acid (FA), a possible metabolite of gamma-ORZ in vivo, on a model of colitis in mice.. We induced colitis with dextran sulphate sodium (DSS) in mice and monitored disease activity index (DAI), histopathology score, tissue myeloperoxidase (MPO) activity, mRNA expressions of cytokines and COX-2, colon length, antioxidant potency and NF-kappaB activity in colitis tissue.. Both DAI and histopathology score revealed that DSS induced a severe mucosal colitis, with a marked increase in the thickness of the muscle layer, distortion and loss of crypts, depletion of goblet cells and infiltration of macrophages, granulocytes and lymphocytes. MPO activity, pro-inflammatory cytokines and COX-2 levels, NF-kappaB p65 nuclear translocation and inhibitory protein of nuclear factor-kappaB-alpha degradation levels were significantly increased in DSS-induced colitis tissues. gamma-ORZ (50 mg kg(-1) day(-1) p.o.) markedly inhibited these inflammatory reactions and CAF had a similar potency. In vitro assay demonstrated that gamma-ORZ and CAF had strong antioxidant effects comparable to those of alpha-tocopherol.. Phytosteryl ferulates could be new potential therapeutic and/or preventive agents for gastrointestinal inflammatory diseases. Their anti-inflammatory effect could be mediated by inhibition of NF-kappaB activity, which was at least partly due to the antioxidant effect of the FA moiety in the structure of phytosteryl ferulates.

Topics: alpha-Tocopherol; Animals; Anti-Inflammatory Agents; Antioxidants; Colitis; Coumaric Acids; Dextran Sulfate; Disease Models, Animal; Intestinal Mucosa; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Oryza; Phenylpropionates; Phytosterols

The plant sterol guggulsterone has been shown to have anti-inflammatory properties. It remains unknown, however, whether guggulsterone is effective for the treatment of inflammatory bowel disease (IBD). Therefore, we investigated anti-inflammatory effects of guggulsterone on intestinal epithelial cells (IEC) and on experimental murine colitis models and elucidated its molecular mechanisms.. Human Caco-2 cells and rat non-transformed IEC-18 cells were stimulated with interleukin (IL)-1beta or lipopolysaccharide (LPS) with or without guggulsterone. The effects of guggulsterone on nuclear factor (NF)-kappaB signaling in IEC were examined by intercellular adhesion molecule (ICAM)-1 real-time reverse-transcription polymerase chain reaction, NF-kappaB transcriptional activity assay, Western blotting for IkappaB phosphorylation/degradation, electrophoretic mobility shift assay, and in vitro IkappaB kinase (IKK) assay. For in vivo study, dextran sulfate sodium (DSS)-treated mice were fed with or without guggulsterone. Colitis was quantified by disease activity index and evaluation of macroscopic and microscopic findings. Phosphorylation of IkappaB and IKK in colon mucosa was assessed by Western blotting and immunohistochemistry.. Guggulsterone significantly inhibited LPS- or IL-1beta-induced ICAM-1 gene expression, NF-kappaB transcriptional activity, IkappaB phosphorylation/degradation, and NF-kappaB DNA binding activity in IEC. Moreover, guggulsterone strongly blocked IKK activity. Administration of guggulsterone significantly reduced the severity of DSS-induced murine colitis as assessed by clinical disease activity score, colon length, and histology. Furthermore, tissue upregulation of IkappaB and IKK phosphorylation induced by DSS was attenuated in guggulsterone-treated mice.. Guggulsterone blocks NF-kappaB signaling pathway by targeting IKK complex in IEC and attenuates DSS-induced acute murine colitis, which suggests that guggulsterone could be an attractive therapeutic option in the treatment of IBD.

Topics: Animals; Colitis; DNA; Enterocytes; Female; Humans; I-kappa B Kinase; I-kappa B Proteins; Intercellular Adhesion Molecule-1; Interleukin-1beta; Lipopolysaccharides; Mice; Mice, Inbred C57BL; NF-kappa B; Phosphorylation; Phytosterols; Phytotherapy; Pregnenediones; Rats; RNA, Messenger; Signal Transduction; Transcription, Genetic

Topics: Adult; Colitis; Drug Combinations; Female; Humans; Lymphocytosis; Phytosterols; Plant Extracts; Vitamin E