Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects
Aspirin Reduces Colorectal Tumor Development in Mice and Gut Microbes Reduce its Bioavailability and Chemopreventive Effects
复制标题
DOI：
10.1053/j.gastro.2020.05.004
复制
发表时间：
2020-09-01
期刊：
影响因子：
29.4
通讯作者：
Yu, Jun
中科院分区：
文献类型：
--
作者：
Zhao, Risheng;Coker, Olabisi Oluwabukola;Yu, Jun
背景与目的：肠道菌群的改变影响结直肠癌的发展和药物代谢。我们研究了肠道微生物群是否影响阿司匹林减少小鼠结肠肿瘤发展的能力。方法：采用APCmin/ thorn小鼠和氧化偶氮甲烷和葡聚糖硫酸钠诱导小鼠结直肠癌发生。在整个实验过程中，一些小鼠被给予抗生素以消耗肠道微生物，有或没有阿司匹林。在验证实验中研究了无菌小鼠。收集结肠组织并通过组织病理学、定量逆转录聚合酶链反应和免疫印迹进行分析。通过液相色谱/质谱法和芳基酯酶活性测定法分析血液样品和肠腔内容物。粪便样品通过16 S核糖体RNA基因和鸟枪宏基因组测序进行分析。研究结果：给予小鼠阿司匹林减少了APCmin/ thorn小鼠和给予氧化偶氮甲烷和葡聚糖硫酸钠的小鼠的结肠直肠肿瘤数量和负荷，这些小鼠已经给予了抗生素（耗尽的肠道微生物群），但在具有完整微生物群的小鼠中没有。给予阿司匹林的无菌小鼠比给予阿司匹林的常规无菌小鼠患结肠直肠肿瘤的次数少。给予抗生素的小鼠的阿司匹林血浆水平高于肠道菌群完整的小鼠。管腔内容物的分析表明，需氧肠道微生物，包括球形赖氨酸芽孢杆菌，降解阿司匹林。喂食球形乳杆菌的无菌小鼠的血浆阿司匹林水平低于未喂食这种细菌的无菌小鼠。阿司匹林剂量与常规小鼠结直肠肿瘤的发生呈负相关，但随着球形乳杆菌丰度的增加，这种相关性消失。来自喂食阿司匹林的小鼠的粪便样品富含双歧杆菌属和乳杆菌属，这被认为是有益的，并且减少了被认为是致病性的Alistipes finegoldii和Bacteroides fragili。结论：阿司匹林减少APC min/ thorn小鼠和给予氧化偶氮甲烷和葡聚糖硫酸钠的小鼠的结肠直肠肿瘤的发展，这取决于肠道微生物的存在。肠道中的球形乳杆菌降解阿司匹林并降低其在小鼠中的化学预防作用。喂食阿司匹林的小鼠的粪便样本富含有益细菌，而致病菌则减少。
BACKGROUND & AIMS: Alterations in the intestinal microbiota affect development of colorectal cancer and drug metabolism. We studied whether the intestinal microbiota affect the ability of aspirin to reduce colon tumor development in mice. METHODS: We performed studies with APCmin/ thorn mice and mice given azoxymethane and dextran sulfate sodium to induce colorectal carcinogenesis. Some mice were given antibiotics to deplete intestinal microbes, with or without aspirin, throughout the entire experiment. Germ-free mice were studied in validation experiments. Colon tissues were collected and analyzed by histopathology, quantitative reverse-transcription polymerase chain reaction, and immunoblots. Blood samples and gut luminal contents were analyzed by liquid chromatography/ mass spectrometry and an arylesterase activity assay. Fecal samples were analyzed by 16S ribosomal RNA gene and shotgun metagenome sequencing. RESULTS: Administration of aspirin to mice reduced colorectal tumor number and load in APCmin/ thorn mice and mice given azoxymethane and dextran sulfate sodium that had been given antibiotics (depleted gut microbiota), but not in mice with intact microbiota. Germfree mice given aspirin developed fewer colorectal tumors than conventionalized germ-free mice given aspirin. Plasma levels of aspirin were higher in mice given antibiotics than in mice with intact gut microbiota. Analyses of luminal contents revealed that aerobic gut microbes, including Lysinibacillus sphaericus, degrade aspirin. Germ-free mice fed L sphaericus had lower plasma levels of aspirin than germ-free mice that were not fed this bacterium. There was an inverse correlation between aspirin dose and colorectal tumor development in conventional mice, but this correlation was lost with increased abundance of L sphaericus. Fecal samples from mice fed aspirin were enriched in Bifidobacterium and Lactobacillus genera, which are considered beneficial, and had reductions in Alistipes finegoldii and Bacteroides fragili, which are considered pathogenic. CONCLUSIONS: Aspirin reduces development of colorectal tumors in APCmin/ thorn mice and mice given azoxymethane and dextran sulfate sodium, depending on the presence of intestinal microbes. L sphaericus in the gut degrades aspirin and reduced its chemopreventive effects in mice. Fecal samples from mice fed aspirin were enriched in beneficial bacteria, with reductions in pathogenic bacteria.