Comparisons of the anti-proliferative effects of butyrate and aspirin on human colonic mucosa in vitro

The short-chain fatty acid butyrate is regarded as a regulative agent in haemostasis of mucosal cell turnover. Inhibition of prostaglandin E₂ synthesis is particularly involved in this regulation process. In the present study, proliferation was stimulated in colonic biopsies of 12 healthy subjects (age 51.3 years, range 25-81) by incubation with deoxycholic acid (5 µmol/1 DCA). The anti-proliferative and cyclo-oxygenase-inhibiting properties of butyrate (10 mmol/1 BUT) and of aspirin (555 µmol/1 ASA) were investigated. Colonic cell proliferation was determined by bromodeoxyuridine immunohistochemistry. PGE₂ release into the incubation medium was measured by radioimmunoassay. Incubation with DCA /ASA, DCA /BUT and DCA /ASA /BUT revealed a significant reduction in crypt cell proliferation as measured by the labelling index of the whole crypt in comparison to incubation with DCA alone (DCA /ASA: 0.14, P < 0.01; DCA /BUT: 0.15, P < 0.05; DCA/ ASA/BUT: 0.15, P < 0.05, versus DCA: 0.18). The labelling index for the upper 40% of the crypt was only lower after incubation with DCA/ASA (0.023) compared to DCA (0.028) (P < 0.05). PGE₂ release from biopsy specimens was only significantly decreased in the incubation media where ASA was added (DCA/ASA: 29.0 pg/mg mucosa/h, P < 0.005; DCA/ASA/BUT: 31.4 pg/mg mucosa/h, P < 0.01 versus DCA: 56.9 pg/mg mucosa/h). Butyrate and aspirin showed no synergistic effects. The results indicate a normalization of DCA-induced hyperproliferation of colonic mucosa by butyrate, and, even more efficiently, by aspirin. The data support the hypothesis that butyrate and aspirin can act as chemopreventive agents in colon carcinogenesis.