背景:5-氟尿嘧啶(5-FU)在不同类型的癌症中用作抗肿瘤剂。越来越多的证据表明,肠道微生物群可能调节5-FU的功效和毒性,可能影响患者的预后。目前的实验研究调查了5-FU诱导的微生物群改变,以及益生元纤维混合物(M1-M4)抵消这些变化的潜力。
方法:来自10名健康捐献者的集合微生物联盟,接种在结肠的体外模型中,用5-FU治疗,有或没有益生元纤维混合物72小时。测试了四种不同的益生元纤维混合物:M1含有短链半乳寡糖(scGOS),长链低聚果糖(LcFOS),和低粘度果胶(lvPect),M2由阿拉伯木聚糖组成,β-葡聚糖,果胶,和抗性淀粉,M3是scGOS和lcFOS的混合物,含有阿拉伯木聚糖的M4,β-葡聚糖,果胶,抗性淀粉,还有菊粉.
结果:我们确定了5-FU诱导的肠道菌群组成变化,但不是微生物多样性。在5-FU期间施用益生元纤维混合物影响肠道微生物群组成和分类群丰度。其中,益生元纤维混合物成功地刺激了潜在的有益细菌(双歧杆菌,乳酸菌,厌氧症,Weissella,Olsenella,Senegalimassilia)并抑制潜在致病菌(克雷伯菌,肠杆菌属)在5-FU存在下。短链脂肪酸(SCFA)乙酸酯在5-FU期间略有增加,但在使用益生元纤维混合物的5-FU期间,而丙酸盐由于有或没有益生元纤维混合物的5-FU而较低,与控制相比。SCFA丁酸盐和戊酸盐在所有条件中没有显示出差异。支链脂肪酸(BCFA)异丁酸和异戊酸在5-FU中含量较高,但5-FU+益生元含量较低,与控制相比。
结论:这些数据表明,益生元纤维混合物代表了一种有希望的策略,可以将5-FU诱导的微生物菌群失调调节为更有利的微生物群,从而可能提高5-FU的疗效和降低毒性,这应该在临床研究中进一步评估。
BACKGROUND: 5-Fluorouracil (5-FU) is used as an antineoplastic agent in distinct cancer types. Increasing evidence suggests that the gut microbiota might modulate 5-FU efficacy and toxicity, potentially affecting the patient\'s prognosis. The current experimental study investigated 5-FU-induced microbiota alterations, as well as the potential of prebiotic fibre mixtures (M1-M4) to counteract these shifts.
METHODS: A pooled microbial consortium was derived from ten healthy donors, inoculated in an in vitro model of the colon, and treated with 5-FU, with or without prebiotic fibre mixtures for 72 h. Four different prebiotic fibre mixtures were tested: M1 containing short-chain galacto-oligosaccharides (sc GOS), long-chain fructo-oligosaccharides (lcFOS), and low viscosity pectin (lvPect), M2 consisting of arabinoxylan, beta-glucan, pectin, and resistant starch, M3 which was a mixture of scGOS and lcFOS, and M4 containing arabinoxylan, beta-glucan, pectin, resistant starch, and inulin.
RESULTS: We identified 5-FU-induced changes in gut microbiota composition, but not in microbial diversity. Administration of prebiotic fibre mixtures during 5-FU influenced gut microbiota composition and taxa abundance. Amongst others, prebiotic fibre mixtures successfully stimulated potentially beneficial bacteria (Bifidobacterium, Lactobacillus, Anaerostipes, Weissella, Olsenella, Senegalimassilia) and suppressed the growth of potentially pathogenic bacteria (Klebsiella, Enterobacter) in the presence of 5-FU. The short-chain fatty acid (SCFA) acetate increased slightly during 5-FU, but even more during 5-FU with prebiotic fibre mixtures, while propionate was lower due to 5-FU with or without prebiotic fibre mixtures, compared to control. The SCFA butyrate and valerate did not show differences among all conditions. The branched-chain fatty acids (BCFA) iso-butyrate and iso-valerate were higher in 5-FU, but lower in 5-FU + prebiotics, compared to control.
CONCLUSIONS: These data suggest that prebiotic fibre mixtures represent a promising strategy to modulate 5-FU-induced microbial dysbiosis towards a more favourable microbiota, thereby possibly improving 5-FU efficacy and reducing toxicity, which should be evaluated further in clinical studies.