van Diest Sophie A, van den Elsen Lieke W J, Klok Allison J, Welting Olaf, Hilbers Francisca W, van de Heijning Bert J, Gaemers Ingrid C, Boeckxstaens Guy E, Werner Maria F, Willemsen Linette E M, de Jonge Wouter J, van den Wijngaard René M
Tytgat Institute for Liver and Intestinal Research, Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands;
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands;
J Nutr. 2015 May;145(5):915-22. doi: 10.3945/jn.114.201731. Epub 2015 Feb 25.
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).
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.
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.
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.
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.
尽管从未对n-3（ω-3）长链多不饱和脂肪酸（LCPUFAs）的疗效进行评估，但它们已作为肠易激综合征（IBS）的治疗方法在市场上销售。
本研究旨在利用肥大细胞依赖性内脏超敏反应模型，研究饮食中LCPUFAs通过激活过氧化物酶体增殖物激活受体γ（PPARG）治疗是否能逆转这种病理生理机制。
成年后，对母婴分离的大鼠施加诱导超敏反应的急性应激。通过补充金枪鱼油的饮食方案（4%大豆油（SO）和3%金枪鱼油（SO-T3）或3% SO和7%金枪鱼油（SO-T7））尝试逆转，并在应激4周后与对照SO饮食（7%或10% SO）进行比较。在为期1周的预防方案（30 mg·kg⁻¹·d⁻¹）中评估PPARG激动剂罗格列酮。评估红细胞以确认LCPUFAs摄取以及脂蛋白脂肪酶和甘油激酶的组织表达作为PPARG激活的指标。通过甲苯胺蓝染色评估结肠肥大细胞脱颗粒。在体外，用人肥大细胞系1（HMC-1）细胞用罗格列酮、二十碳五烯酸或二十二碳六烯酸预处理，用佛波醇12-肉豆蔻酸酯13-乙酸酯（PMA）和钙离子载体或化合物48/80刺激，并评估肿瘤坏死因子α（TNF-α）和β-己糖胺酶释放。
应激导致所有组出现内脏超敏反应。SO-T3或对照治疗均未逆转超敏反应[应激前与应激后24小时与治疗后曲线下面积；分别为76±4与128±12（P<0.05）与115±14以及82±5与127±16（P<0.01）与113±19]。SO-T7与其对照的比较显示了相似的结果[分别为74±6与103±13（P<0.05）与115±17以及66±3与103±10（P<0.05）与117±11]。在没有结肠PPARG激活的情况下，红细胞显示出显著的LCPUFAs摄取。罗格列酮诱导PPARG靶基因表达增加，但未预防超敏反应。各组之间肥大细胞脱颗粒没有差异。罗格列酮和LCPUFAs显著降低PMA/钙离子载体诱导的TNF-α释放，但未降低HMC-1细胞的脱颗粒。
饮食中的LCPUFAs不能逆转母婴分离大鼠应激诱导的内脏超敏反应。尽管需要进一步研究，但关于LCPUFAs作为IBS治疗选择的说法目前无法得到证实，应谨慎对待。
