PRE-TREATMENT WITH NON ABSORBABLE GLUCIDS AND BOVINE GLYCOMACROPEPTIDE AMELIORATES 5-FLUOROURACIL-INDUCED INTESTINAL MUCOSITIS IN RATS.

A Anzola1, E Guadix2, A Zarzuelo1, O Martínez4, F Sánchez1, R González0. 1University of Granada, Pharmacology 18071, Spain, 2University of Granada, Chemical Engineering 18071, Spain, 3CIBEREHD, Pharmacology 18071, Spain, 4University of Granada, Biochemistry and Molecular Biology 18071, Spain

Different products considered functional foods, such as non absorbable glucids (NAGs) and bovine glycomacropeptide (GMP), could generate beneficial effects on intestinal mucositis, a common side-effect of high-dose chemotherapy regimens, given their ability to exert direct actions on intestinal mucosal cells, to modulate the inflammatory response and possibly to contribute to intestinal maturation and defense. Here we investigated the effects of goat’s milk oligosaccharides (GMOs) and GMP on 5-fluorouracil (5-FU) induced mucositis in rats. Female Dark Agouti rats (150 g) were treated with the products at the dose of 500 mg/kg for 14 days and received an intraperitoneal injection of 150 mg/kg 5-FU on day 7. Animals were killed on day 14 for assessment of intestinal damage and repair. Compared to normal controls, 5-FU produced a significant loss of body weight, which was reduced in the group treated with GMOs (145±0,957 vs. 152,5±2,217 g), and an increase of ileon weight-length ratio, that was completely reversed by GMOs as well (0,045±0,001 vs. 0,055±0,005 g/cm, p<0,05). On the other hand, biochemical markers like alkaline phosphatase activity, representing epithelial stress, is increased in 5-FU group compared to the control group (46,58±4,596 vs. 36,388±3,534 U/mg protein) an effect that was prevented by GMOs (29,083±1,388 vs. 46,58±4,596 U/mg protein, p<0,01). Myeloperoxidase activity (MPO) was measured as a marker of leukocyte infiltration, showing a decrease of almost 80% in the 5-FU group (3,62±2,43 vs. 18,83±7,51 mU/mg protein) that is slightly reduced by GMOs (4,54±4,05 vs. 3,62±2,43 mU/mg protein). Other biochemical parameters analyzed in ileum were the activity of the disaccharidases sucrase, lactase, and maltase, as markers of epithelial dysfunction, which was again decreased in the 5-FU group compared to the control group (1572,114±479,891 vs. 2552,439±587,384 mU/mg protein, 890,464±392,733 vs. 1369,246±399,529 mU/mg protein and 29499,132±5588,123 vs. 41238,123±5588,123 mU/mg protein, respectively) and normalized by both GMOs and GMP. Finally, we determined the ileum expression of mucins; mucins act as the main structural component of the mucus layer, giving rise to its polymeric, viscoelastic and protective properties. The expression of MUC3 and MUC4 was determined by real time PCR with an increase by the administration of 5-FU that is reversed by the different treatments. In conclusion, GMOs and GMP exert beneficial effects in the model of mucositis induced by 5-FU and these effects appear to be due to its direct action on various parameters of immune defense and maturation of intestinal epithelial cells.