Suzuki Takuya, Yoshida Shoko, Hara Hiroshi
Division of Applied Bioscience, Graduate School of Agriculture, Hokkaido University, Sapporo, Japan.
Br J Nutr. 2008 Aug;100(2):297-305. doi: 10.1017/S0007114508888733. Epub 2008 Mar 18.
Colonic fermentation products, SCFA, have various effects on colonic functions. Here, we found that physiological concentrations of SCFA immediately promote epithelial barrier function in the large intestine. Solutions of mixed and individual SCFA were applied to the caecal walls mounted on Ussing-type chambers. Transepithelial electrical resistance (TER) increased rapidly and reached a peak 35 % higher than that in the control specimen within 10 min post application of the SCFA mixture (80 acetate, 40 propionate, 20 butyrate (mmol/l)). The Lucifer yellow permeability, a paracellular transport marker, was dose-dependently reduced by the mixed SCFA, acetate and propionate solutions. Inhibition of monocarboxylate transporter-1 did not influence the increase in TER with acetate; however, lowering the pH (from 7.5 to 5.5) clearly enhanced the effect of acetate. Non-metabolizable, bromo and chloro derivatives of SCFA also increased TER. These results suggest that passive diffusion of SCFA is dominant and the metabolism of SCFA is not required for the promotive effect of SCFA on barrier function. We also observed that individual SCFA dose-dependently increased TER in T84 and Caco-2 cells, which indicates that SCFA directly stimulate epithelial cells. Depletion of membrane cholesterol and inhibitors of phosphatidylinositol-3 kinase and Gq protein attenuated the acetate-mediated promotive effect. Finally, we found that the mucosal application of the SCFA mixture dose-dependently suppressed [3H] mannitol transport from the caecal lumen to the mesenteric blood in the anaesthetized rats. We conclude that physiological concentrations of SCFA immediately enhance barrier function of the colonic epithelium through cholesterol-rich microdomain in the plasma membrane.
结肠发酵产物短链脂肪酸（SCFA）对结肠功能有多种影响。在此，我们发现生理浓度的SCFA能立即促进大肠上皮屏障功能。将混合及单一SCFA溶液应用于安装在尤斯灌流小室上的盲肠壁。在应用SCFA混合物（80 mmol/L乙酸盐、40 mmol/L丙酸盐、20 mmol/L丁酸盐）后10分钟内，跨上皮电阻（TER）迅速增加，并达到比对照标本高35%的峰值。作为细胞旁转运标志物的路西法黄通透性，被混合SCFA、乙酸盐和丙酸盐溶液呈剂量依赖性降低。抑制单羧酸转运蛋白-1并不影响乙酸盐引起的TER增加；然而，将pH值从7.5降至5.5明显增强了乙酸盐的作用。SCFA的非代谢性溴代和氯代衍生物也增加了TER。这些结果表明，SCFA的被动扩散起主导作用，SCFA对屏障功能的促进作用并不需要其代谢。我们还观察到，单一SCFA在T84和Caco-2细胞中呈剂量依赖性增加TER，这表明SCFA直接刺激上皮细胞。膜胆固醇的耗竭以及磷脂酰肌醇-3激酶和Gq蛋白的抑制剂减弱了乙酸盐介导的促进作用。最后，我们发现，在麻醉大鼠中，向盲肠黏膜应用SCFA混合物呈剂量依赖性抑制[3H]甘露醇从盲肠腔向肠系膜血液的转运。我们得出结论，生理浓度的SCFA通过质膜中富含胆固醇的微结构域立即增强结肠上皮的屏障功能。
