Hirayama K, Baranczewski P, Akerlund J E, Midtvedt T, Möller L, Rafter J
Departments of Medical Nutrition and Biosciences, Karolinska Institutet, NOVUM, S-141 86 Huddinge, Sweden.
Carcinogenesis. 2000 Nov;21(11):2105-11. doi: 10.1093/carcin/21.11.2105.
Although the intestinal flora is believed to have a critical role in carcinogenesis, little is known about the role of the human intestinal flora on the effects of mutagens in vivo. The aim of the present study was to address a possible role of the human intestinal flora in carcinogenesis, by exploiting human-flora-associated (HFA) mice. The capacity of human faeces to activate or inactivate 2-amino-3-methyl-3H:-imidazo[4,5-f]quinoline (IQ) and 2-nitrofluorene was determined using the Ames assay. Human faecal suspensions that were active in this regard were then selected and orally inoculated into germfree NMRI mice to generate HFA mice. HFA, germfree, conventionalized and conventional mice were administered IQ, 2-amino-9H:-pyrido[2,3-b]indole (2-amino-alpha-carboline; AAC) and 2-nitrofluorene. The activity of human intestinal flora against mutagens could be transferred into the mice. In comparing germfree mice and mice harbouring an intestinal flora, the presence of a flora was essential for the activities of faeces against mutagens. After administration of IQ and 2-nitrofluorene, DNA adducts were observed in the mice with a flora, while adducts were extremely low or absent in germfree animals. DNA adducts after AAC treatment were higher in germfree mice in some tissues including colon than in mice with bacteria. Differences in DNA adduct formation were also observed between HFA mice and mice with mouse flora in many tissues. These results clearly indicate that the intestinal flora have an active role in DNA adduct formation and that the role is different for the different chemicals to which the animals are exposed. The results also demonstrate that the human intestinal flora have different effects from the mouse flora on DNA adduct formation as well as in vitro metabolic activities against mutagens. Studies using HFA mice could thus provide much-needed information on the role of the human intestinal flora on carcinogenesis in vivo.
尽管肠道菌群被认为在致癌过程中起关键作用，但关于人类肠道菌群在体内对诱变剂作用的影响却知之甚少。本研究的目的是通过利用人源菌群相关（HFA）小鼠来探讨人类肠道菌群在致癌过程中可能发挥的作用。使用艾姆斯试验测定了人类粪便激活或灭活2-氨基-3-甲基-3H-咪唑并[4,5-f]喹啉（IQ）和2-硝基芴的能力。然后选择在这方面有活性的人类粪便悬液，经口接种到无菌NMRI小鼠体内以产生HFA小鼠。给HFA小鼠、无菌小鼠、常规化小鼠和常规小鼠施用IQ、2-氨基-9H-吡啶并[2,3-b]吲哚（2-氨基-α-咔啉；AAC）和2-硝基芴。人类肠道菌群对诱变剂的活性可以转移到小鼠体内。在比较无菌小鼠和有肠道菌群的小鼠时，菌群的存在对于粪便对诱变剂的活性至关重要。施用IQ和2-硝基芴后，在有菌群的小鼠中观察到DNA加合物，而在无菌动物中加合物极低或不存在。在包括结肠在内的一些组织中，AAC处理后无菌小鼠的DNA加合物高于有细菌的小鼠。在许多组织中，HFA小鼠和有小鼠菌群的小鼠之间也观察到DNA加合物形成的差异。这些结果清楚地表明，肠道菌群在DNA加合物形成中起积极作用，并且对于动物接触的不同化学物质，该作用是不同的。结果还表明，人类肠道菌群与小鼠菌群在DNA加合物形成以及对诱变剂的体外代谢活性方面具有不同的影响。因此，使用HFA小鼠的研究可以提供关于人类肠道菌群在体内致癌作用方面急需的信息。
