Velázquez O C, Seto R W, Choi J, Zhou D, Breen F, Fisher J D, Rombeau J L
Harrison Department of Surgical Research, University of Pennsylvania Medical Center, Philadelphia 19104, USA.
Dis Colon Rectum. 1997 Nov;40(11):1368-75. doi: 10.1007/BF02050825.
Crypt surface hyperproliferation is an intermediate biomarker of colon cancer risk. In vitro studies indicate that the short-chain fatty acid and antineoplastic agent butyrate may reverse the crypt surface hyperproliferation induced by the secondary bile acid and tumor promoter, deoxycholate. We hypothesized that butyrate may reverse deoxycholate-induced crypt surface proliferation in vivo.
Thirty-one Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, butyrate, deoxycholate, or butyrate plus deoxycholate (all solutions, 2 ml; pH 7; total sodium = 20 mM). Study variables included colon weight, mucosal DNA, mucosal protein, and proliferating cell nuclear antigen immunohistochemistry, labeling of which was determined in five crypt compartments from base to surface (12 crypts per rat). Labeling indexes were calculated as proliferating cell nuclear antigen immunohistochemistry-labeled cells divided by total counted cells in the whole colonic crypt and each of five crypt compartments. The phi(h) value (an index of premalignant risk) was calculated as the ratio of labeled cells in the two surface compartments divided by the total labeled cells.
Deoxycholate significantly increased colon wet weight, mucosal protein, total crypt labeling indexes, crypt surface labeling indexes, and the phi(h) value and raised the mucosal DNA content. Butyrate alone slightly reduced total mucosal DNA and protein content. The combination of butyrate plus deoxycholate significantly decreased mucosal DNA and tended to reduce mucosal protein compared with deoxycholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate did not reverse the deoxycholate-induced surface hyperproliferative changes as measured by proliferating cell nuclear antigen labeling.
Because co-treatment with butyrate plus deoxycholate inhibits deoxycholate-induced increases in total mucosal DNA and protein content, we conclude that butyrate may play a role in maintaining the proliferative balance of the colonic mucosa, in vivo. However, co-treatment with butyrate plus deoxycholate does not reverse the deoxycholate-induced increases in colon weight and proliferating cell nuclear antigen labeling indexes under the studied experimental conditions.
隐窝表面过度增殖是结肠癌风险的一种中间生物标志物。体外研究表明，短链脂肪酸和抗肿瘤药物丁酸盐可能会逆转由次级胆汁酸和肿瘤促进剂脱氧胆酸盐诱导的隐窝表面过度增殖。我们推测丁酸盐可能在体内逆转脱氧胆酸盐诱导的隐窝表面增殖。
31只Sprague-Dawley大鼠（250 - 300克）接受结肠手术分离，并在管腔内滴注24小时氯化钠、丁酸盐、脱氧胆酸盐或丁酸盐加脱氧胆酸盐（所有溶液，2毫升；pH 7；总钠 = 20毫摩尔）。研究变量包括结肠重量、黏膜DNA、黏膜蛋白以及增殖细胞核抗原免疫组织化学，其标记在从底部到表面的五个隐窝区室中测定（每只大鼠12个隐窝）。标记指数计算为增殖细胞核抗原免疫组织化学标记的细胞数除以整个结肠隐窝及五个隐窝区室中每个区室的总计数细胞数。phi(h)值（一种癌前风险指数）计算为两个表面区室中标记细胞数与总标记细胞数的比值。
脱氧胆酸盐显著增加结肠湿重、黏膜蛋白、总隐窝标记指数、隐窝表面标记指数以及phi(h)值，并提高黏膜DNA含量。单独使用丁酸盐略微降低总黏膜DNA和蛋白含量。与单独使用脱氧胆酸盐相比，丁酸盐加脱氧胆酸盐的组合显著降低黏膜DNA，并倾向于降低黏膜蛋白。与先前的体外研究结果相反，通过增殖细胞核抗原标记测量，丁酸盐加脱氧胆酸盐并未逆转脱氧胆酸盐诱导的表面过度增殖变化。
由于丁酸盐加脱氧胆酸盐联合处理可抑制脱氧胆酸盐诱导的总黏膜DNA和蛋白含量增加，我们得出结论，丁酸盐可能在体内维持结肠黏膜增殖平衡中发挥作用。然而，在研究的实验条件下，丁酸盐加脱氧胆酸盐联合处理并未逆转脱氧胆酸盐诱导的结肠重量增加和增殖细胞核抗原标记指数增加。
