linoleic-acid and Colitis

Inflammatory bowel disease (IBD) is one of the most common intestinal disorders, with increasing global incidence and prevalence. Numerous therapeutic drugs are available but require intravenous administration and are associated with high toxicity and insufficient patient compliance. Here, an oral liposome that entraps the activatable corticosteroid anti-inflammatory budesonide was developed for efficacious and safe IBD therapy. The prodrug was produced via the ligation of budesonide with linoleic acid linked by a hydrolytic ester bond, which was further constrained into lipid constituents to form colloidal stable nanoliposomes (termed budsomes). Chemical modification with linoleic acid augmented the compatibility and miscibility of the resulting prodrug in lipid bilayers to provide protection from the harsh environment of the gastrointestinal tract, while liposomal nanoformulation enables preferential accumulation to inflamed vasculature. Hence, when delivered orally, budsomes exhibited high stability with low drug release in the stomach in the presence of ultra-acidic pH but released active budesonide after accumulation in inflamed intestinal tissues. Notably, oral administration of budsomes demonstrated favorable anti-colitis effect with only ∼7% mouse body weight loss, whereas at least ∼16% weight loss was observed in other treatment groups. Overall, budsomes exhibited higher therapeutic efficiency than free budesonide treatment and potently induced remission of acute colitis without any adverse side effects. These data suggest a new and reliable approach for improving the efficacy of budesonide. Our

Topics: Animals; Budesonide; Colitis; Drug-Related Side Effects and Adverse Reactions; Inflammatory Bowel Diseases; Linoleic Acid; Liposomes; Mice; Prodrugs

Orai2 is a component of store-operated Calcium channels (SOCCs) and exerts a pivotal role in immunity. In intestinal macrophages (Mφs), Orai2 deficiency influenced linoleic acid (LA)-arachidonic acid (ARA) derivatives by regulating Pla2g6 and Alox5. 16S rRNA sequencing showed that deleting Orai2 facilitated the prevalence of Akkermansia muciniphila, and untargeted metabolomics confirmed the suppressed level of leukotriene A. Moreover, Orai2 deficiency ameliorated the progression of experimental murine colitis, as shown by attenuated structural collapse of colon and pro-inflammatory cytokine concentrations, and rescued dysbiosis. The administration of a Pla2g6 inhibitor (Bromoenol lactone) not only inhibited the relative abundance of A. muciniphila in the feces of Orai2 knockout (Orai2

Topics: Akkermansia; Animals; Arachidonic Acid; Calcium; Calcium Channels; Colitis; Cytokines; Group VI Phospholipases A2; Leukotriene A4; Linoleic Acid; Mice; ORAI2 Protein; RNA, Ribosomal, 16S

A linoleate isomerase complex including myosin-cross-reactive antigen, short-chain dehydrogenase/oxidoreductase, and acetoacetate decarboxylase has been confirmed as the pivotal factor for conjugated linoleic acid (CLA) production in

Topics: Animals; Colitis; Dextran Sulfate; Isomerases; Lactobacillus; Lactobacillus plantarum; Linoleic Acid; Mice; Probiotics

Dietary intake of linoleic acid (LA, 18:2ω-6) has risen dramatically in recent decades. Previous studies have suggested a high intake of LA could increase tissue concentrations of proinflammatory and protumorigenic ω-6-series eicosanoid metabolites, increasing risks of inflammation and associated diseases. However, the effects of a LA-rich diet on in vivo profiles of eicosanoids and development of inflammatory diseases are understudied. Here, we treated spontaneous colitis-prone (

Topics: Animals; Colitis; Eicosanoids; Humans; Interleukin-10; Linoleic Acid; Liver; Male; Mice; Mice, Knockout

Dietary supplementation with conjugated linoleic acid (CLA) has been proposed for weight management and to prevent gut inflammation. However, some animal studies suggest that supplementation with CLA leads to the development of nonalcoholic fatty liver disease. The aims of this study were to test the efficiency of CLA in preventing dextran sulfate sodium (DSS)-induced colitis, to analyze the effects of CLA in the liver function, and to access putative liver alterations upon CLA supplementation during colitis. So, C57BL/6 mice were supplemented for 3 weeks with either control diet (AIN-G) or 1% CLA-supplemented diet. CLA content in the diet and in the liver of mice fed CLA containing diet were accessed by gas chromatography. On the first day of the third week of dietary treatment, mice received ad libitum a 1.5%-2.5% DSS solution for 7 days. Disease activity index score was evaluated; colon and liver samples were stained by hematoxylin and eosin for histopathology analysis and lamina propria cells were extracted to access the profile of innate cell infiltrate. Metabolic alterations before and after colitis induction were accessed by an open calorimetric circuit. Serum glucose, cholesterol, triglycerides and alanine aminotransaminase were measured; the content of fat in liver and feces was also accessed. CLA prevented weight loss, histopathologic and macroscopic signs of colitis, and inflammatory infiltration. Mice fed CLA-supplemented without colitis induction diet developed steatosis, which was prevented in mice with colitis probably due to the higher lipid consumption as energy during gut inflammation. This result suggests that CLA is safe for use during gut inflammation but not at steady-state conditions.

Topics: Alanine Transaminase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Colon; Dextran Sulfate; Dietary Supplements; Female; Immunity, Innate; Linoleic Acid; Linoleic Acids, Conjugated; Liver; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease

Gut microbial metabolites of polyunsaturated fatty acids have attracted much attention because of their various physiological properties. Dysfunction of tight junction (TJ) in the intestine contributes to the pathogenesis of many disorders such as inflammatory bowel disease. We evaluated the effects of five novel gut microbial metabolites on tumor necrosis factor (TNF)-α-induced barrier impairment in Caco-2 cells and dextran sulfate sodium-induced colitis in mice. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a gut microbial metabolite of linoleic acid, suppressed TNF-α and dextran sulfate sodium-induced changes in the expression of TJ-related molecules, occludin, zonula occludens-1, and myosin light chain kinase. HYA also suppressed the expression of TNF receptor 2 (TNFR2) mRNA and protein expression in Caco-2 cells and colonic tissue. In addition, HYA suppressed the protein expression of TNFR2 in murine intestinal epithelial cells. Furthermore, HYA significantly up-regulated G protein-coupled receptor (GPR) 40 expression in Caco-2 cells. It also induced [Ca(2+)]i responses in HEK293 cells expressing human GPR40 with higher sensitivity than linoleic acid, its metabolic precursor. The barrier-recovering effects of HYA were abrogated by a GPR40 antagonist and MEK inhibitor in Caco-2 cells. Conversely, 10-hydroxyoctadacanoic acid, which is a gut microbial metabolite of oleic acid and lacks a carbon-carbon double bond at Δ12 position, did not show these TJ-restoring activities and down-regulated GPR40 expression. Therefore, HYA modulates TNFR2 expression, at least partially, via the GPR40-MEK-ERK pathway and may be useful in the treatment of TJ-related disorders such as inflammatory bowel disease.

Topics: Animals; Caco-2 Cells; Colitis; Epithelial Cells; Female; Flow Cytometry; Humans; Immunohistochemistry; Intestines; Linoleic Acid; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Oleic Acids; Receptors, G-Protein-Coupled

Here, we investigated the impact of mulberry fruit (MBF) extracts on lipopolysaccharide (LPS)-induced inflammatory responses in RAW 264.7 macrophages, and the therapeutic efficacy of MBF diet in mice with dextran sulfate sodium (DSS)-induced acute colitis and MUC2(-/-) mice with colorectal cancer. In vitro, LPS-induced nitric oxide (NO) production was significantly inhibited by MBF extracts via suppressing the expression of proinflammatory molecules, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), interleukin-1 beta (IL-β) and IL-6. Particularly, a dose-dependent inhibition on LPS-induced inflammatory responses was observed following treatment with MBF dichloromethane extract (MBF-DE), in which linoleic acid and ethyl linolenate were identified as two active compounds. Moreover, we elucidated that MBF-DE attenuated LPS-induced inflammatory responses by blocking activation of both NF-κB/p65 and pERK/MAPK pathways. In vivo, DSS-induced acute colitis was significantly ameliorated in MBF-fed mice as gauged by weight loss, colon morphology and histological damage. In addition, MBF-fed MUC2(-/-) mice displayed significant decrease in intestinal tumor and inflammation incidence compared to control diet-fed group. Overall, our results demonstrated that MBF suppressed the development of intestinal inflammation and tumorgenesis both in vitro and in vivo, and supports the potential of MBF as a therapeutic functional food for testing in human clinical trials.

Topics: Animals; Cell Line, Tumor; Cell Survival; Cell Transformation, Neoplastic; Colitis; Colorectal Neoplasms; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Fruit; Gene Expression Regulation; Inflammation Mediators; Linoleic Acid; Linolenic Acids; Lipopolysaccharides; Macrophages; Mice; Mice, Knockout; Mitogen-Activated Protein Kinases; Morus; Mucin-2; NF-kappa B; Nitric Oxide; Phosphorylation; Plant Extracts; Protein Transport; Signal Transduction

Imbalances in the dietary n-6 and n-3 polyunsaturated fatty acids have been implicated in the increased prevalence of inflammatory bowel disease. This study investigated the effects of substitution of linoleic acid with long chain n-3 polyunsaturated fatty acids and hence decreasing n-6:n-3 fatty acid ratio on inflammatory response in dextran sulfate sodium induced colitis. Male weanling Sprague Dawley rats were fed diets with n-6:n-3 fatty acid in the ratios of 215,50,10 or 5 for 3 months and colitis was induced by administration of dextran sulfate sodium in drinking water during last 11 days. Decreasing the dietary n-6:n-3 fatty acid ratio to 10 and 5 significantly attenuated the severity of colitis as evidenced by improvements in clinical symptoms, reversal of shortening of colon length, reduced severity of anemia, preservation of colonic architecture as well as reduced colonic mucosal myeloperoxidase activity. This protection was associated with suppression of colonic mucosal proinflammatory mediators such as TNFα, IL-1β and nitric oxide. These findings suggest that long chain n-3 polyunsaturated fatty acids at a level of 3.0 g/kg diet (n-6:n-3 ratio of 10) prevents dextran sulfate sodium induced colitis by suppressing the proinflammatory mediators.

Topics: Animals; Colitis; Colon; Dextran Sulfate; Dietary Fats; Disease Models, Animal; Fatty Acids, Omega-3; Interleukin-1beta; Intestinal Mucosa; Linoleic Acid; Male; Nitric Oxide; Peroxidase; Rats; Rats, Sprague-Dawley; Tumor Necrosis Factor-alpha

Numerous reports have shown that a diet containing large amounts of trans fatty acids (TFAs) is a major risk factor for metabolic disorders. Although recent studies have shown that TFAs promote intestinal inflammation, the underlying mechanisms are unknown. In this study, we examined the effects of dietary fat containing TFAs on dextran sodium sulphate (DSS)-induced colitis. C57 BL/6 mice were fed a diet containing 1·3% TFAs (mainly C16:1, C18:1, C18:2, C20:1, C20:2 and C22:1), and then colitis was induced with 1·5% DSS. Colonic damage was assessed, and the mRNA levels of proinflammatory cytokines and major regulators of T cell differentiation were measured. The TFA diet reduced survival and exacerbated histological damage in mice administered DSS compared with those fed a TFA-free diet. The TFA diet significantly elevated interleukin (IL)-6, IL-12p40, IL-23p19 and retinoic acid-related orphan receptor (ROR)γt mRNA levels in the colons of DSS-treated animals. Moreover, IL-17A mRNA levels were elevated significantly by the TFA diet, with or without DSS treatment. We also examined the expression of proinflammatory cytokines in lipopolysaccharide (LPS)-stimulated RAW264.7 cells and peritoneal macrophages. These cells were exposed to TFAs (linoelaidic acid or elaidic acid) with or without LPS and the mRNA levels of various cytokines were measured. IL-23p19 mRNA levels were increased significantly by TFAs in the absence of LPS. Cytokine expression was also higher in LPS-stimulated cells exposed to TFAs than in unexposed LPS-stimulated cells. Collectively, our results suggest that TFAs exacerbate colonic inflammation by promoting Th17 polarization and by up-regulating the expression of proinflammatory cytokines in the inflamed colonic mucosa.

Topics: Animals; Cell Differentiation; Cell Line; Colitis; Cytokines; Dextran Sulfate; Female; Inflammation; Interleukin-12 Subunit p40; Interleukin-17; Interleukin-23 Subunit p19; Interleukin-6; Linoleic Acid; Lipopolysaccharides; Macrophages; Mice; Mice, Inbred C57BL; Nuclear Receptor Subfamily 1, Group F, Member 3; Oleic Acid; Oleic Acids; RNA, Messenger; Th17 Cells; Trans Fatty Acids; Up-Regulation

Increasing prevalence of inflammatory bowel disease may be due to imbalance in the intake of n-6 and n-3 PUFA in the diet. This study investigates the impact of varying ratios of dietary linoleic acid (LA, 18 : 2n-6) to α-linolenic acid (ALA, 18 : 3n-3) on the inflammatory response in dextran sulphate sodium (DSS)-induced colitis. Weanling male Sprague-Dawley rats were divided into five groups: a non-colitic group with a LA:ALA ratio of 215 (CON-215), and colitic groups with LA:ALA ratios of 215 (DSS-215), 50 (DSS-50), 10 (DSS-10) and 2 (DSS-2). Blends of groundnut, palmolein and linseed oils were used to provide varying LA:ALA ratios. All the rats were fed the respective experimental isoenergetic diets containing 10 % fat for 90 d and DSS was administered during the last 11 d. Colonic inflammation was evaluated by clinical, biochemical and histological parameters. The results showed attenuation of colitis in the DSS-2 group as evidenced by significant reductions in disease activity index, mucosal myeloperoxidase activity (P < 0·05), alkaline phosphatase activity (P < 0·01) and increase in colon length (P < 0·01) compared to the groups fed with higher ratios (DSS-215). This was accompanied by significant reductions in mucosal proinflammatory cytokines TNF-α (P < 0·01) and IL-1β (P < 0·01) and improvement in the histological score. Further, ALA supplementation increased long-chain (LC) n-3 PUFA and decreased LC n-6 PUFA in colon structural lipids. These data suggest that substitution of one-third of LA with ALA (LA:ALA ratio 2) mitigates experimental colitis by down-regulating proinflammatory mediators.

Topics: alpha-Linolenic Acid; Animals; Anti-Inflammatory Agents, Non-Steroidal; Biomarkers; Colitis; Colon; Cytokines; Dextran Sulfate; Dietary Supplements; Disease Models, Animal; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Inflammatory Bowel Diseases; Intestinal Mucosa; Linoleic Acid; Male; Neutrophil Infiltration; Random Allocation; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Weaning

Excessive intake of saturated fatty acids and/or linoleic acid favors the induction of an array of lipid mediators and cytokines enhancing inflammatory responses. Conversely, dietary supplementation with (n-3) fatty acids or vitamin D ameliorates inflammation and autoimmune diseases. Although it was well accepted that conjugated linoleic acid (CLA) prevented diseases with a common inflammatory pathogenesis (i.e., cancer and atherosclerosis), no studies were available on the roles of CLA in mucosal inflammation. The present study was designed to investigate the anti-inflammatory actions and molecular mechanisms underlying the regulation of colonic health by CLA. We hypothesized that colonic inflammation can be ameliorated by dietary CLA supplementation. To test this hypothesis, inflammation of the colonic mucosa was triggered by challenging pigs fed either soybean oil-supplemented or CLA-supplemented diets with an enteric bacterial pathogen (i.e., Brachyspira hyodysenteriae). Immunoregulatory cytokines and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) mRNA expression were assayed in colonic lymph nodes and colon of pigs. Colonic mucosal lesions and lymphocyte subset distribution were evaluated by histology and immunohistochemistry. Supplementation of CLA in the diet before the induction of colitis decreased mucosal damage; maintained cytokine profiles (i.e., interferon-gamma and interleukin-10) and lymphocyte subset distributions (i.e., CD4+ and CD8+), resembling those of noninfected pigs; enhanced colonic expression of PPAR-gamma; and attenuated growth failure. Therefore, CLA fed preventively before the onset of enteric disease attenuated inflammatory lesion development and growth failure.

Topics: Animal Nutritional Physiological Phenomena; Animals; Colitis; Colon; Cytokines; Diet; Dietary Fats; Fatty Acids; Growth Disorders; Intestinal Mucosa; Linoleic Acid; Lymphocyte Subsets; Receptors, Cytoplasmic and Nuclear; RNA, Messenger; Spirochaetales Infections; Swine; Swine Diseases; Transcription Factors

Rabbit colitis has been induced by injection of muramyl dipeptide emulsified with a long-chain fatty acid. The muramyl dipeptide emulsion was injected submucosally at six portions of the rectum and colon, 10 cm proximal to the anus, using a flexible endoscope. Six rabbits were injected six times every 2 weeks and subsequently killed 2 weeks after the last injection. The histological changes of the colon that occurred in all 6 rabbits were mononuclear cell and histiocyte infiltration with sporadic eosinophils, transmural infiltration, and well-maintained goblet cell populations. These changes were different in degree. In 4 of 6 rabbits histological examination of the liver showed pericholangitis and periductal fibrosis mimicking the pericholangitis frequently seen in patients with inflammatory bowel disease. Fibrosis bridging between the portal and portal veins occurred in 2 rabbits, and noncaseating granuloma was seen in 1 rabbit. These histological changes in our model have led to the suggestion that continuous stimulation with bacterial cell wall fragments may be involved in chronic intestinal inflammation and extraintestinal manifestations such as pericholangitis.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Bile Ducts, Intrahepatic; Cell Wall; Cholangitis; Colitis; Colon; Emulsions; Linoleic Acid; Linoleic Acids; Liver; Male; Rabbits