linoleic-acid and Crohn-Disease

Since the discovery in 1929 that certain polyunsaturated fatty acids (PUFA) are essential for life and health, intense investigation has revealed the multiplicity of members in each of several families of PUFA, no two of which are equivalent. The quantified nutrient requirements for the essential dietary precursors of the two dominant families of PUFA have been estimated, and the general functions of these families are slowly becoming known. The PUFA are essential components of structural membrane lipids. The functions of the individual members are not yet differentiated, except as they act as precursors of synthesis of unique octadecanoid, eicosanoid, and docosanoid products of oxidation that have potent biological properties. The PUFA occur in animals and higher plants as ubiquitous and essential components of structural lipid that are in a dynamic equilibrium with the pool of dietary acyl groups. Many human diseases have been found to involve unique essential fatty acid (EFA) deficiencies or distortions of the normal equilibrium pattern. The equilibrium is influenced by the level of dietary intake or precursors, by the presence of competing essential and nonessential acyl groups, by nonoptimum intake of other essential nutrients, by hormonal effects, by drug therapy, and by other effects upon physiological condition. With the many variables already known to modulate or control the equilibrium, it should be possible with more precise understanding of each variable to shift abnormal equilibria in the direction of normalcy. This perhaps will be the next area of intensive investigation in this field of nutrition and metabolism.

Topics: Acrodermatitis; alpha-Linolenic Acid; Arachidonic Acid; Arachidonic Acids; Aspirin; Child; Crohn Disease; Cystic Fibrosis; DDT; Dicofol; Ethanol; Fatty Acids, Essential; Fatty Acids, Unsaturated; Female; Humans; Ichthyosis; Indomethacin; Isomerism; Linoleic Acid; Linoleic Acids; Linolenic Acids; Lipid Metabolism; Lipolysis; Liver Cirrhosis, Alcoholic; Models, Chemical; Myocardial Infarction; Protein-Energy Malnutrition; Reye Syndrome; Structure-Activity Relationship

Dietary fat has been suggested to determine the therapeutic effect of enteral diets in Crohn's disease.. To assess the efficacy of two whole protein based diets with different fat compositions (n6 polyunsaturated fatty acids v monounsaturated fatty acids) in inducing clinical remission in active Crohn's disease compared with steroids.. Sixty two patients with active Crohn's disease were randomised to receive, for not more than 4 weeks: (a) a polymeric enteral diet containing 35 g of lipids per 1000 kcal, high in oleate (79%) and low in linoleate (6.5%) (PEN1), (b) an identical enteral diet except for the type of fat which was high in linoleate (45%) and low in oleate (28%) (PEN2), or (c) oral prednisone (1 mg/kg/day). Diets were double blindly administered. The steroid group received a conventional ward diet. Treatment failure was considered when remission was not achieved at week 4. Clinical activity and biological and nutritional parameters were monitored. Independent predictors of remission were identified by stepwise logistic regression analysis.. Overall remission rates (by intention to treat) were 20% (4/20) for PEN1, 52% (12/23) for PEN2, and 79% (15/19) for steroids (overall p=0.001; p<0.0005 steroids v PEN1, and p=0.056 PEN2 v PEN1). After excluding those patients who were non-compliant during the first week (per protocol analysis), remission rates were 27%, 63%, and 79%, respectively (p=0.008, steroids and PEN2 v PEN1). After adjusting for confounding variables, PEN1 remained significantly associated with a poor response.. The type of dietary fat may be of importance for the primary therapeutic effect of enteral nutrition in active Crohn's disease.

Topics: Acute Disease; Adolescent; Adult; Crohn Disease; Dietary Fats; Double-Blind Method; Enteral Nutrition; Europe; Female; Food, Formulated; Glucocorticoids; Humans; Linoleic Acid; Male; Middle Aged; Oleic Acid; Regression Analysis

Patients with Crohn's disease may become zinc-deficient and, in such patients, an altered metabolism of radiolabelled long-chain fatty acids has been reported. We have investigated the possible reversal by zinc supplementation of altered long-chain fatty acid profiles of red cells in Crohn's disease. Twenty patients with long-standing Crohn's disease in clinical remission received 200 mg of zinc sulphate daily for 6 weeks. Phospholipid fatty acid profiles of washed red cells were analysed before and after zinc treatment and compared to those of 20 unsupplemented healthy controls. Plasma zinc levels in Crohn's were 72 +/- 8 micrograms/dL before zinc treatment and increased to 114 +/- 10 micrograms/dl after the therapy. Prior to zinc supplementation, the percentage of palmitic, stearic and oleic acids was significantly higher in Crohn's disease, while linoleic, arachidonic and n-3 fatty acids were reduced in Crohn's disease compared to healthy controls. Zinc supplementation abolished these pre-treatment differences in red-cell long-chain fatty acid profiles but did not affect plasma fatty acid values. Further studies are needed to clarify whether these fatty acid changes can be related to the clinical course of the disease.

Topics: Adult; Arachidonic Acid; Crohn Disease; Erythrocytes; Fatty Acids; Female; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Oleic Acid; Oleic Acids; Palmitic Acid; Palmitic Acids; Stearic Acids; Sulfates; Zinc Compounds; Zinc Sulfate

Recent studies have shown a close relationship between the gut microbiota and Crohn's disease (CD). This study aimed to determine whether mesenchymal stem cell (MSC) treatment alters the gut microbiota and fecal metabolite pathways and to establish the relationship between the gut microbiota and fecal metabolites. Patients with refractory CD were enrolled and received 8 intravenous infusions of MSCs at a dose of 1.0 × 106 cells/kg. The MSC efficacy and safety were evaluated. Fecal samples were collected, and their microbiomes were analyzed by 16S rDNA sequencing. The fecal metabolites at baseline and after 4 and 8 MSC infusions were identified by liquid chromatography-mass spectrometry (LC--MS). A bioinformatics analysis was conducted using the sequencing data. No serious adverse effects were observed. The clinical symptoms and signs of patients with CD were substantially relieved after 8 MSC infusions, as revealed by changes in weight, the CD activity index (CDAI) score, C-reactive protein (CRP) level, and erythrocyte sedimentation rate (ESR). Endoscopic improvement was observed in 2 patients. A comparison of the gut microbiome after 8 MSC treatments with that at baseline showed that the genus Cetobacterium was significantly enriched. Linoleic acid was depleted after 8 MSC treatments. A possible link between the altered Cetobacterium abundance and linoleic acid metabolite levels was observed in patients with CD who received MSCs. This study enabled an understanding of both the gut microbiota response and bacterial metabolites to obtain more information about host-gut microbiota metabolic interactions in the short-term response to MSC treatment.

Topics: Crohn Disease; Humans; Linoleic Acid; Mesenchymal Stem Cells; Microbiota; Treatment Outcome

Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn disease (CD), is a disorder characterized by diffuse inflammation of the gastrointestinal tract. The immune response and inflammation are mediated by polyunsaturated fatty acids and influenced by dietary fats and lipid metabolism. This study examined the qualitative and quantitative fat intake of IBD patients and healthy controls on plasma phospholipid and erythrocyte membrane phospholipid (EMP) fatty acid content. Measurement of the fatty acid composition of plasma phospholipid and EMP were performed in 29 UC patients, 20 CD patients, and 31 healthy controls. Anthropometric characteristics and data on dietary intake were also collected. We observed significantly lower lipid intake in UC and CD patients vs controls. The UC and CD patients had significantly higher levels of linoleic acid in their EMP than did controls. There were no significant differences in the levels of n-3 polyunsaturated fatty acids, but there were significantly higher levels of the n-6 in the EMP of UC and CD patients compared with controls. The significant differences persisted after the data were adjusted for potential confounders and lipid intake. Higher levels of linoleic acids and n-6 fatty acids, which are involved in production of proinflammatory mediators, were found in IBD patients compared with controls, thereby implicating n-6 fatty acids in the pathophysiology of the disease.

Topics: Adult; Anthropometry; Case-Control Studies; Colitis, Ulcerative; Crohn Disease; Erythrocyte Membrane; Fatty Acids, Omega-6; Female; Humans; Inflammatory Bowel Diseases; Linoleic Acid; Male; Phospholipids; Surveys and Questionnaires

Previously we reported that linoleic acid (LA), but not oleic acid, caused a marked increase in the secretion of IL-8 by Crohn's human intestinal smooth muscle (HISM) cells. Antioxidants inhibited this response, implicating a role for oxidative stress and NF-kappaB, a transcription factor for IL-8 that is activated by oxidative stress. In this study, we examined two mechanisms whereby LA, the dietary precursor for arachidonic acid (AA), could increase the production of IL-8 via activation of AA pathways: 1) by generation of reactive oxygen species by the AA-pathway enzymes to activate NF-kappaB or 2) by AA metabolites. Normal and Crohn's HISM cells were exposed to LA, oxidizing solution (Ox), or oxidizing solution enriched with LA (OxLA). Exposure of cells to Ox or OxLA induced oxidative stress as determined by thiobarbituric acid reactive substances. In normal cells, Ox but not LA activated NF-kappaB as determined by transfection experiments and Western blot. In Crohn's cells, NF-kappaB was spontaneously activated and was not further activated by Ox or LA. In contrast, TNF-alpha markedly increased activation of NF-kappaB in both normal and Crohn's cells. These results indicated that LA did not increase IL-8 by activating NF-kappaB, so we evaluated the second mechanism of an effect of AA metabolites. In normal cells, OxLA, but not LA, markedly stimulated IL-8, whereas in Crohn's cells, both OxLA and LA stimulated IL-8. OxLA, also stimulated production of AA metabolites leukotriene B(4) (LTB(4)), PGE(2), and thromboxane B(2) (TXB(2)) by normal and Crohn's cells. To determine whether AA metabolites mediated the IL-8 response, cells were treated with OxLA plus indomethacin (Indo), a cyclooxygenase inhibitor, and nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor. Both Indo and NDGA blocked the IL-8 response to OxLA. To determine more specifically a role for AA metabolites, AA was used. Similar to OxLA, OxAA stimulated production of IL-8 and AA metabolites. Pinane thromboxane, a selective thromboxane synthase inhibitor and receptor blocker, inhibited OxAA stimulation of TXB(2) and IL-8 in a dose-response manner. MK886, a selective 5-lipoxygenase inhibitor, inhibited OxAA stimulation of LTB(4) and IL-8 also in a dose-response manner. Analysis of specific gene products by RT-PCR demonstrated that HISM cells expressed receptors for both thromboxane and LTB(4). We conclude that AA metabolites mediated the IL-8 response to LA in HISM cells. Both cyclooxyge

Topics: Arachidonic Acid; Blotting, Western; Cells, Cultured; Crohn Disease; Cyclooxygenase Inhibitors; Genes, Reporter; Humans; Indomethacin; Interleukin-8; Intestinal Mucosa; Intestines; Leukotriene B4; Linoleic Acid; Luciferases; Muscle, Smooth; NF-kappa B; Oxidative Stress; Receptors, Thromboxane; RNA, Messenger

Enteral nutrition is effective in inducing remission in active Crohn's disease. Speculation on the underlying mechanism of action has moved away from the presentation of nitrogen and towards the fat content of the various enteral feeds. Evidence is accumulating that additional long-chain triglyceride in such feeds impairs the response rate in active Crohn's disease, whereas no deleterious effects of additional medium-chain triglyceride have been identified. It has been proposed that long-chain triglycerides composed from n-6 fatty acids may be the most harmful, since such fatty acids are substrates for inflammatory eicosanoid production. However, recent studies comparing different enteral feeds are not consistent in identifying which additional fatty acids impair response rates to the greatest extent. Despite meta-analyses concluding that polymeric diets (typically containing large amounts of fat) are as effective as elemental diets, it would seem sensible to use enteral feeds with minimal fat content when treating active Crohn's disease.

Topics: Crohn Disease; Eicosanoids; Enteral Nutrition; Food, Formulated; Humans; Linoleic Acid; Remission Induction; Triglycerides

Crohn's disease is a chronic inflammatory bowel disease (IBD) of unknown etiology. In this study, we investigated the hypothesis that dietary fatty acids, linoleic acid (LA) and oleic acid (OA), could be involved in the inflammatory response through stimulation of the neutrophil chemokine, IL-8.. Human intestinal smooth muscle (HISM) cells were isolated from normal patients and patients with Crohn's disease and cultured for 24h with LA or OA in the presence or absence of oxidative stress. The concentrations of IL-8 were measured in the media and cellular oxidative stress was quantitated by measurement of thiobarbituric acid reactive substances (TBARSs).. Spontaneous production of IL-8 was significantly higher in HISM cells isolated from Crohn's bowel compared to control bowel. LA caused a marked, nine-fold, increase in IL-8 secretion by Crohn's cells, an effect that could be simulated in normal HISM cells by co-incubation of LA with an oxidizing solution (Ox) composed of hypoxanthine+xanthine oxidase+FeSO(4) (OxLA). These effects were inhibited by vitamins C and E. Treatment of Crohn's cells with OxLA did not further increase IL-8 over that of LA alone. The effect of LA alone was not associated with an increase in cellular oxidative stress as quantitated by TBARSs. In contrast to the results with LA, treatment with OA or OxOA did not increase IL-8 in either normal or Crohn's cells. In addition, OA protected Crohn's cells from the increase in TBARSs induced by Ox. In contrast to IL-8, spontaneous production of monocyte chemotactic protein (MCP-1) was significantly lower in Crohn's HISM cells as compared to normal cells and exposure to OxLA did not increase its production.. LA, but not OA, increased the production of IL-8 by HISM cells. These results suggest that replacement of LA by OA in the diet of Crohn's patients and increased intake of a diet rich in antioxidants could be beneficial in decreasing inflammatory activity in Crohn's disease.

Topics: Analysis of Variance; Antineoplastic Agents; Antioxidants; Cell Separation; Crohn Disease; Humans; Interleukin-8; Intestinal Mucosa; Intestines; Linoleic Acid; Lipid Peroxidation; Myocytes, Smooth Muscle; Oleic Acid; Oxidative Stress; Thiobarbituric Acid Reactive Substances; Time Factors; Up-Regulation

Patients with chronic intestinal disorders causing malabsorption, nutritional losses through diarrhea, or catabolic illness would be expected to have essential fatty acid (EFA) deficiency (EFAD), but such deficiency has not been demonstrated in patients treated in accordance with the prevailing standard of care. We studied plasma fatty acid patterns of 56 reference or control subjects and 47 patients with chronic intestinal disorders (mostly Crohn's disease) using high-resolution capillary column gas-liquid chromatography. Patients exhibited a shift in fatty acid metabolism similar to that previously shown to be associated with EFAD. Compared with control subjects, patients had (1) decreased polyunsaturated fatty acid (PUFA) levels (43.7% v 50.4%, P < .0001), (2) increased monounsaturated fatty acid (MUFA) levels (25.8% v 22.0%, P < .0001), (3) higher ratios of mead (20:3 omega 9) to arachidonic (20:4 omega 6) acid (0.020 v 0.013, P < .04), and (4) lower concentrations of total (214 v 284 mg/dL, P < .01), saturated ([SFA] 63 v 75 mg/dL, P < .001), MUFA (56 v 63 mg/dL, P < .001), and PUFA (93 v 143 mg/dL, P < .001). Patients had metabolic shifts toward increased production of MUFA and an increased ratio of derivatives to precursors of omega 6 fatty acids, shifts that occur when cells are EFA-deficient. More than 25% of the patients had biochemical evidence of EFAD according to at least one criterion. Optimal diagnosis requires a concurrent evaluation of concentrations of fatty acids in plasma and in lipoproteins (percent fatty acids). On indices of EFA status that depend on percents, ratios, or concentrations of fatty acids or on the production of abnormal fatty acids, the patients were between patients with severe whole-body EFAD and healthy subjects, a state referred to as absolute EFA insufficiency. Patients with chronic intestinal disease should be evaluated for likely EFA deficiencies and imbalances, and treated with substantial amounts of supplements rich in EFAs, such as oral vegetable and fish oils, or intravenous lipids if necessary.

Topics: Adolescent; Adult; Analysis of Variance; Chronic Disease; Crohn Disease; Fatty Acids, Essential; Fatty Acids, Monounsaturated; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Gastrointestinal Diseases; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Multivariate Analysis; Reference Values

Fish oil, rich in n-3 polyunsaturated fatty acids, can alter leukotriene production and hence neutrophil function, factors which may be important in the inflammation of Crohn's disease (CD). Therefore we studied the effect of dietary PUFA on neutrophil mediated ileal inflammation and neutrophil function in the rat.. Animals were ad libitum-fed pellet diets containing 9.5% fish oil (menhaden oil, rich in n-3 PUFA) with 0.5% safflower oil, 10% safflower oil (rich in n-6 PUFA) or standard chow (6% fat) for 50 days prior to the study. Weight and circulating leukocyte and total neutrophil counts were identical in all three groups. Neutrophil mediated ileal inflammation induced by formyl-methionyl-leucyl-phenylalanine (fMLP) perfusion was evaluated by measuring macromolecular uptake of radiolabelled dextran (MW 70,000) and changes in mucosal neutrophil infiltration.. The fish oil diet group showed no difference in fMLP-induced permeability changes relative to the Chow Control group. However, the Safflower Oil supplemented diet group had a reduced permeability response (p < 0.01). Mirroring the permeability changes, there was diminished mucosal neutrophil infiltration in the Safflower Oil group following ileal perfusion with fMLP (< .005). Chemotaxis and chemiluminescence, two important neutrophil functions, were also significantly suppressed in the Safflower Oil animals (p < 0.05).. The failure of a n-3 PUFA enriched diet to diminish the ileal inflammatory response to a bacterial peptide and suppress neutrophil function in the rat suggests such therapy would not be expected to be highly successful in CD. However, it requires confirmation in man, especially under the more complicated inflammatory conditions found in CD. On the other hand, the decreased neutrophil mediated responses with a high linoleic acid (n-6 PUFA) diet warrant further investigation.

Topics: Animals; Chemotaxis, Leukocyte; Crohn Disease; Dextrans; Disease Models, Animal; Fatty Acids, Omega-3; Food, Fortified; Ileum; Leukotrienes; Linoleic Acid; Linoleic Acids; Luminescent Measurements; Male; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Permeability; Rats; Rats, Sprague-Dawley

Peripheral blood leucocytes from patients with Crohn's disease have been shown to have lower zinc content than those from a normal population. Since zinc influences essential fatty acid metabolism, incorporation of 14C-linoleic and 3H-arachidonic acids was studied in peripheral blood leucocytes from controls and patients with Crohn's disease. The zinc content of the leucocytes was also measured. After incubation for 2 h, content of 3H-arachidonic acid, but not 14C-linoleic acid, was greater in Crohn's disease leucocytes than in controls. In the Crohn's disease leucocytes, incorporation of both labelled fatty acids into the phosphatidylcholine fraction was significantly lower than in controls, whereas the amount of both fatty acids remaining in the leucocytes as free fatty acids was increased by 70%. In Crohn's disease, leucocyte zinc level was positively associated with the percentage of 3H-arachidonic acid incorporation into phosphatidylcholine. We conclude that peripheral blood leucocytes from patients with Crohn's disease have abnormal essential fatty acid metabolism and that 3H-arachidonic acid incorporation into the phosphatidylcholine fraction of leucocyte lipids in Crohn's disease varies as the zinc content of the leucocytes.

Topics: Adult; Arachidonic Acid; Arachidonic Acids; Crohn Disease; Fatty Acids, Essential; Female; Humans; Leukocytes; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Phosphatidylcholines; Phosphatidylethanolamines; Phospholipids; Zinc

Topics: Adolescent; Adult; Bile Acids and Salts; Cholesterol; Colitis, Ulcerative; Crohn Disease; Fatty Acids; Female; Humans; Linoleic Acid; Linoleic Acids; Male; Middle Aged; Serum Albumin