BUTYRATE INHIBITS DEOXYCHOLATE-INDUCED INCREASE IN COLONIC MUCOSAL DNA AND PROTEIN-SYNTHESIS IN-VIVO

PURPOSE: 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 ma) reverse the crypt sur face hyperproliferation induced by the secondary bile acid and tumor p romoter, deoxycholate. We hypothesized that butyrate may reverse deoxy cholate-induced crypt surface proliferation in vivo. METHODS: Thirty-o ne Sprague-Dawley rats (250-300 g) underwent surgical isolation of the colon and 24-hour luminal instillation of either sodium chloride, but yrate, deoxycholate, or but) rate plus deoxycholate (all solutions, 2 mi, 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 indexe s were calculated as proliferating cell nuclear antigen immunohistoche mistry-labeled cells divided by total counted cells in the whole colon ic crypt and each of five crypt compartments. The phi h value (an inde x of premalignant risk) was calculated as the ratio of labeled cells i n the two surface compartments divided by the total labeled cells. RES ULTS: Deoxycholate significantly increased colon wet weight, mucosal p rotein, 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 combinati on of butyrate plus deoxycholate significantly decreased mucosal DNA a nd tended to reduce mucosal protein compared with deoxy cholate alone. In contrast to prior in vitro findings, butyrate plus deoxycholate di d not reverse the deoxycholate-induced surface hyperproliferative chan ges as measured by proliferating cell nuclear antigen labeling. CONCLU SIONS: Because co-treatment with butyrate plus deoxycholate-inhibits d eoxycholate-induced increases in total mucosal DNA and protein content , we conclude that butyrate may play a role in maintaining the prolife rative balance of the colonic mucosa, in vivo. However, co-treatment w ith butyrate plus deoxycholate does not reverse the deoxycholate-induc ed increases in colon weight and proliferating cell nuclear antigen la beling indexes under the studied experimental conditions.