title: Dietary Marine n-3 PUFAs Do Not Affect Stress-Induced Visceral Hypersensitivity in a Rat Maternal Separation Model.
abstract: BACKGROUND
  Although never evaluated for efficacy, n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS).
  
  
  OBJECTIVE
  This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor γ (PPARG) activation.
  
  
  METHODS
  Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg · kg⁻¹ · d⁻¹). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor α (TNF-α) and β-hexosaminidase release.
  
  
  RESULTS
  Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 ± 4 vs. 128 ± 12 (P < 0.05) vs. 115 ± 14 and 82 ± 5 vs. 127 ± 16 (P < 0.01) vs. 113 ± 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 ± 6 vs. 103 ± 13 (P < 0.05) vs. 115 ± 17 and 66 ± 3 vs. 103 ± 10 (P < 0.05) vs. 117 ± 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore-induced TNF-α release but not degranulation of HMC-1 cells.
  
  
  CONCLUSIONS
  Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution.
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Sophie A
authors.initials: SA
authors.lastname: van Diest
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;
authors.forename: Lieke W J
authors.initials: LW
authors.lastname: van den Elsen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Klok
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Olaf
authors.initials: O
authors.lastname: Welting
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Francisca W
authors.initials: FW
authors.lastname: Hilbers
authors.affiliation: Nutricia Research, Utrecht, The Netherlands;
authors.forename: Bert J
authors.initials: BJ
authors.lastname: van de Heijning
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Gaemers
authors.affiliation: Division of Gastroenterology, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; and.
authors.forename: Guy E
authors.initials: GE
authors.lastname: Boeckxstaens
authors.affiliation: Department of Pharmacology, Biological Sciences Section, Federal University of Paraná, Curitiba, Brazil.
authors.forename: Maria F
authors.initials: MF
authors.lastname: Werner
authors.affiliation: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;
authors.forename: Linette E M
authors.initials: LE
authors.lastname: Willemsen
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Wouter J
authors.initials: WJ
authors.lastname: de Jonge
authors.affiliation: Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands; R.vandenWijngaard@amc.uva.nl.
authors.forename: René M
authors.initials: RM
authors.lastname: van den Wijngaard
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001341:Autonomic Nervous System / Q000187:drug effects / Q000276:immunology / Q000503:physiopathology*; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000294:innervation* / Q000378:metabolism; D019587:Dietary Supplements; D004195:Disease Models, Animal; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D005395:Fish Oils / Q000008:administration & dosage / Q000378:metabolism / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000294:innervation / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000178:diet therapy* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008407:Mast Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008426:Maternal Deprivation; D047495:PPAR gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D020318:Rats, Long-Evans; D014413:Tuna
chemical_list: D015415:Biomarkers; D015525:Fatty Acids, Omega-3; D005395:Fish Oils; D007004:Hypoglycemic Agents; D047495:PPAR gamma
keywords: diet; irritable bowel syndrome; long-chain polyunsaturated fatty acids; mast cells; maternal separation model; omega-3; omega-6; visceral hypersensitivity