PO.PR01.02 · 预防研究
生命早期抗生素暴露与早发性结直肠癌
Early life exposure to antibiotics and early onset colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
结直肠癌（CRC）是美国及全球癌症相关死亡的第二大原因。近年来，CRC的总体发病率一直在下降，推测归因于早期筛查和健康生活方式。然而，50岁以下个体的CRC，即早发性结直肠癌（EOCRC），自20世纪80年代以来一直以惊人的速度上升。这是一场日益严重的全球流行病，病例比例在1995至2019年间从11%升至20%，预计到2030年将增加140%。关于原本健康的年轻成人为何易感的根本原因和机制仍知之甚少。基于我们对该疾病的现有认识，我们假设EOCRC是由暴露组暴露所致——这些暴露组在全球范围内随每个出生队列与EOCRC的上升平行增加；它们影响肠道微生物组，在EOCRC的解剖部位——远端结肠和直肠——引起菌群失调和炎症；并能在从受孕到成年的不同发育阶段影响人体。在潜在因素中，抗生素的使用（尤其在生命早期）尤为突出。在本研究中，我们假设存在易感发育窗口期，在此期间暴露于常用儿科处方抗生素（β-内酰胺类或大环内酯类）可增加发生EOCRC的风险。利用EOCRC小鼠模型，我们界定了个体一生中相应的易感发育窗口期。在此，我们检验在围产期和幼年窗口暴露于单轮抗生素是否能影响发生EOCRC的风险。将围产期的A/J小鼠通过灌胃喂养哺乳母鼠进行处理，母鼠随后将抗生素传递给后代。断奶后，用致癌物氧化偶氮甲烷（AOM）处理后代，并在肿瘤生长后测定肿瘤负荷。对四周龄小鼠灌胃喂养抗生素，暴露于AOM，并如上评估肿瘤负荷。我们的发现提示，抗生素对EOCRC风险的影响受特定易感发育窗口暴露的影响。母体抗生素给药改变了后代的肠道菌群，且这种改变长期持续。此效应与肠道微生物结构和丰度的变化以及促炎菌株的增加相关，后者又与后代炎症升高和肿瘤负荷升高相关。
查看英文原文 English abstract
Colorectal cancer (CRC) is the second leading cause of cancer related deaths in the United States and worldwide. Recently, the overall incidence of CRC has been decreasing presumably due to early screening and healthy lifestyles. However, CRC in individuals under 50 years old, known as early-onset colorectal cancer (EOCRC) , has been increasing at an alarming rate in the since the 1980s. It is a growing global epidemic with cases rising from 11% to 20 % between 1995 to 2019 and is expected to increase by 140% by 2030. The underlying causes and mechanisms as to why otherwise healthy young adults are susceptible is poorly understood. Based on our current knowledge of the disease, we hypothesized that EOCRC is caused exposure to exposomes that have been increasing globally in parallel with increases in EOCRC with each birth cohort; that impact the gut microbiome causing dysbiosis and inflammation in the distal colon and rectum, the anatomical site of EOCRC; and those that can affect humans at different development stages from conception to adulthood. Among the potential factors is the use of antibiotics, particularly in the early stages of life.In this study, we hypothesize that there are development windows of susceptibility wherein exposure to commonly prescribed pediatric antibiotics (beta-lactams or macrolides) can increase the risk of developing EOCRC. Using a mouse model of EOCRC, we defined corresponding developmental windows of susceptibility over an individual's lifetime. Here, we test if exposure to a single round of antibiotics at the perinatal and juvenile windows can impact risk of developing EOCRC. A/J mice at the perinatal stage were treated by gavage-feeding lactating dams who then passed the antibiotics to their offspring. After weaning, the offspring were treated with azoxymethane (AOM), a carcinogen, and tumor burden was determined after tumor outgrowth. Four-week-old mice were gavage-fed the antibiotics, exposed to AOM and tumor burden assessed as above. Our findings suggest that the impact of antibiotics on EOCRC risk was affected by exposure at specific developmental windows of susceptibility. Maternal antibiotic administration altered the gut microbiota in offspring which persisted over the long term. This effect was associated with changes in gut microbial structure and abundance, and an increase in pro-inflammatory bacterial strains, which correlated with elevated inflammation and tumor burden in offspring.
利益披露 Disclosure
Q. Mao, None..
V. Gowda, None..
T. Mote, None..
A. Bassler, None..
S. Ganesh Babu, None..
V. Zottoli, None..
H. Villanueva, None..
M. Maja, None..
M. Richardson, None.