High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome
High-Fat Diet Accelerates Carcinogenesis in a Mouse Model of Barrett's Esophagus via Interleukin 8 and Alterations to the Gut Microbiome
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DOI：
10.1053/j.gastro.2019.04.013
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发表时间：
2019-08-01
期刊：
影响因子：
29.4
通讯作者：
Quante, Michael
中科院分区：
文献类型：
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作者：
Muench, Natasha Stephens;Fang, Hsin-Yu;Quante, Michael
背景与目的：Barrett食管（BE）是食管腺癌（EAC）的前兆。从BE到癌症的进展与肥胖有关，可能是由于腹部压力增加和胃食管反流病，尽管这种致病机制尚未得到证实。我们研究了与肥胖相关的环境或饮食因素是否有助于小鼠从BE到EAC的进展。方法：Tg(ED-L2-IL1RN/IL1B)#Tcw小鼠（BE模型，称为L2-IL1B小鼠）饲喂饲料（对照）或高脂饲料（HFD）或与表达人白细胞介素（IL） 8的小鼠（L2-IL1B/IL8小鼠）杂交。收集食管组织并通过定量聚合酶链反应、免疫组织化学和流式细胞术分析基因表达谱。从小鼠BE组织中建立类器官，并与瘦或肥胖个体的血清或L2-IL1B小鼠的中性粒细胞培养。采用16s核糖体RNA测序对小鼠粪便进行分析，并与异型增生或BE患者的16s测序数据进行比较。L2-IL1B小鼠在无菌条件下饲养。结果：饲喂HFD的L2-IL1B小鼠发生食管发育不良和肿瘤的速度快于饲喂对照组的小鼠；肿瘤的发展速度与体重无关。与饲喂对照饮食的小鼠相比，HFD在L2-IL1B小鼠中加速发育不良与肠道微生物群的变化和食管组织中中性粒细胞与自然杀伤细胞的比例增加有关。我们在进展为EAC的BE患者与未发展为癌症的BE患者的微生物组中观察到类似的差异。饲喂HFD的L2-IL1B发育不良小鼠的组织中含有增加的细胞因子水平，这些细胞因子是对CXCL1 （IL8的功能性小鼠同源物，也称为KC）的反应产生的。肥胖患者血清引起L2-IL1B/IL8小鼠类器官产生IL8。与对照组相比，饲喂HFD的L2-IL1B小鼠和饲喂HFD的L2-IL1B/IL8小鼠的BE组织中含有更多的髓系细胞和表达Cxcr2和Lgr5信使rna（上皮祖细胞）的细胞。与在标准条件下饲养的L2-IL1小鼠相比，在无菌环境中饲养的L2-IL1B小鼠的BE组织具有更少的祖细胞和更少的发育不良；将饲喂HFD的L2-IL1B小鼠的粪便微生物群暴露给饲喂对照饮食的L2-IL1B小鼠，加速了肿瘤的发展。结论：在BE小鼠模型中，我们发现HFD通过改变食管微环境和肠道微生物组来促进发育不良，从而诱导炎症和干细胞扩增，而不依赖于肥胖。
BACKGROUND & AIMS: Barrett's esophagus (BE) is a precursor to esophageal adenocarcinoma (EAC). Progression from BE to cancer is associated with obesity, possibly due to increased abdominal pressure and gastroesophageal reflux disease, although this pathogenic mechanism has not been proven. We investigated whether environmental or dietary factors associated with obesity contribute to the progression of BE to EAC in mice. METHODS: Tg(ED-L2-IL1RN/IL1B)#Tcw mice (a model of BE, called L2-IL1B mice) were fed a chow (control) or high-fat diet (HFD) or were crossbred with mice that express human interleukin (IL) 8 (L2-IL1B/IL8 mice). Esophageal tissues were collected and analyzed for gene expression profiles and by quantitative polymerase chain reaction, immunohistochemistry, and flow cytometry. Organoids were established from BE tissue of mice and cultured with serum from lean or obese individuals or with neutrophils from L2-IL1B mice. Feces from mice were analyzed by 16s ribosomal RNA sequencing and compared to 16s sequencing data from patients with dysplasia or BE. L2-IL1B were mice raised in germ-free conditions. RESULTS: L2-IL1B mice fed an HFD developed esophageal dysplasia and tumors more rapidly than mice fed the control diet; the speed of tumor development was independent of body weight. The acceleration of dysplasia by the HFD in the L2-IL1B mice was associated with a shift in the gut microbiota and an increased ratio of neutrophils to natural killer cells in esophageal tissues compared with mice fed a control diet. We observed similar differences in the microbiomes from patients with BE that progressed to EAC vs patients with BE that did not develop into cancer. Tissues from dysplasias of L2-IL1B mice fed the HFD contained increased levels of cytokines that are produced in response to CXCL1 (the functional mouse homolog of IL8, also called KC). Serum from obese patients caused organoids from L2-IL1B/IL8 mice to produce IL8. BE tissues from L2-IL1B mice fed the HFD and from L2-IL1B/IL8 mice contained increased numbers of myeloid cells and cells expressing Cxcr2 and Lgr5 messenger RNAs (epithelial progenitors) compared with mice fed control diets. BE tissues from L2-IL1B mice raised in germfree housing had fewer progenitor cells and developed less dysplasia than in L2-IL1 mice raised under standard conditions; exposure of fecal microbiota from L2-IL1B mice fed the HFD to L2-IL1B mice fed the control diet accelerated tumor development. CONCLUSIONS: In a mouse model of BE, we found that an HFD promoted dysplasia by altering the esophageal micro-environment and gut microbiome, thereby inducing inflammation and stem cell expansion, independent of obesity.