妊娠晚期使用抗生素可增加后代炎症性肠病的风险

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感控热点丨妊娠晚期使用抗生素可增加后代炎症性肠病的风险

原创 2017-08-01 孔晓明 刘金淑 SIFIC感染官微

检索丨刘金淑 濮阳市油田总医院

翻译丨孔晓明 溧阳市人民医院

          刘金淑 濮阳市油田总医院

审核丨陈志锦 东莞市厚街医院

芝加哥大学医学研究人员的一项研究表明，存在炎症性肠病（IBD）遗传易感倾向的小鼠，在围产期使用抗生素后，其后代更有可能发生结肠炎症性疾病，类似人类的IBD。

抗生素治疗导致了母鼠肠道微生物菌群的持续变化，这些变化传给了他们的后代。虽然他们的后代发病了，但是给予抗生素的成年母鼠的IBD并没有增加。这表明抗生素暴露的时机至关重要，特别是出生后的发育早期，此时免疫系统尚未成熟。

该研究近期发表在《细胞》杂志上，芝加哥大学马丁博耶尔医学教授、微生物中心微生物医学计划主任Eugene B. Chang博士说：“新生小鼠遗传了一个多变的、微不足道的微生物菌群。尽管母鼠和幼崽有相同的遗传背景，但是母鼠并没有出现IBD。在这个关键的免疫发育时期，具有多变微生物组的后代非常容易发生结肠炎。”

不过，Chang警告，这些动物研究结果不应该被视为孕妇或哺乳新生儿在需要治疗危险细菌感染时避免使用抗生素的原因。相反，它应该提示人们最佳做法是规避打着“只是为了安全”旗号的滥用抗生素，例如病毒引起的普通感冒。

肠道微生物菌群的持续变化

几项流行病学研究表明，围产期（孕晚期和出生后的护理期）使用抗生素会增加人体IBD的风险。然而，由于个体肠道微生物菌群的巨大差异、控制变量的挑战以及在孕妇和婴儿进行临床实验的局限性，因此缺乏这种联系的直接证据。

为了解决这些问题，该研究团队设计了一系列用于IBD标准遗传小鼠模型的实验，以研究围产期期间抗生素治疗时机与对后代肠道微生物菌群和免疫系统发育的影响。研究人员在母鼠妊娠后期到哺乳期给予头孢哌酮，即模拟人类早期抗生素暴露的常见临床情况。用抗生素治疗的成年鼠都没有发生结肠炎，但是与没有用抗生素治疗的母鼠相比，它的后代显示出发生结肠炎的高风险。

该小组还使用最先进的高通量测序技术，分析了母鼠及其后代的肠道微生物群落结构。母鼠表现出细菌多样性下降，某些细菌群体绝对数发生变化，如拟杆菌属、厚壁菌门和疣孢菌数量减少。令人惊讶的是，这些变化在停止抗生素治疗后四到八周内仍在持续。

后代小鼠在肠道细菌中也有相似的变化，微生物菌群在出生时与母鼠一致。这些小鼠的微生物菌群多样性与未用抗生素治疗的小鼠相比具有显著性差异，并且这些差异持续到成年期。

致力于健康促进

在非健康状态下更多地了解微生物菌群，可以帮助科学家开始学会如何促进发展健康免疫系统的微生物菌群。

这项研究显示了“不健康”的微生物菌群是什么样的，所以推测缺失的菌群可能就是促进健康的重要因素。想要最终开发出一种“微生物鸡尾酒”，以确保婴儿能正确进行新陈代谢和免疫系统发育。通过减少许多疾病的风险来促进健康，这将对人类健康产生重大影响。

来源：芝加哥大学医学中心

原文：

Antibiotics Taken Late in Pregnancy CanIncrease Risk for Inflammatory Bowel Diseases in Offspring

A study by researchers at the Universityof Chicago Medicine shows that when mice that are genetically susceptible todeveloping inflammatory bowel disease (IBD) were given antibiotics during latepregnancy and the early nursing period, their offspring were more likely todevelop an inflammatory condition of the colon that resembles human IBD.

The antibiotic treatment also causedlasting changes in the gut microbiome of mothers that were passed on to theiroffspring. While their offspring developed disease, adult mice givenantibiotics did not see an increase in IBD. This suggests that the timing ofantibiotic exposure is crucial, especially during the early developmentalperiod after birth when the immune system is undergoing maturation.

“The newborn mice inherited a veryaltered, skewed population of microbes,” said Eugene B. Chang, MD, the MartinBoyer Professor of Medicine at the University of Chicago, director of theMicrobiome Medicine Program of the Microbiome Center, and senior author of thestudy, published this week in the journal Cell Reports. “None of the mothersdeveloped IBD, but even though they had the same genetic background, theoffspring with an altered microbiome during this critical period of immunedevelopment became highly susceptible to the development of colitis.”

Chang cautioned, however, that theseresults from an animal study should not be taken as a reason for pregnant womenor those nursing newborn infants to avoid antibiotics when they are needed totreat dangerous bacterial infections. Instead, he said, it should serve as areminder that best practices dictate avoiding casual, indiscriminant over usage‘just to be safe’, say, for a common cold that is most likely caused by avirus.

“Antibiotics should absolutely be usedjudiciously when they’re indicated,” Chang said. “But we as physicians shouldkeep in mind the importance of antimicrobial stewardship, because this studysuggests that it may have long term consequences that potentially impact healthand risk for certain diseases.”

Lasting changes in the gut microbiome

Several epidemiological studies havesuggested that exposure to antibiotics during the peripartum period (latepregnancy and the nursing period after birth) increases the risk for IBD inhumans. Direct evidence for this association has been lacking, however, becauseof vast differences in individual gut microbiomes, challenges in controllingfor variables, and the limits of conducting clinical experiments in pregnantwomen and infants.

To address these issues, Jun Miyoshi,MD, PhD, a postdoctoral scholar, and Alexandria Bobe, a graduate student inChang’s lab, designed a series of experiments with a standard genetic mousemodel for IBD to study the timing of antibiotic treatment during the peripartumperiod and its impact on gut microbes and immune system development inoffspring. The researchers gave cefoperazone, a commonly-used antibiotic, tomouse mothers in the late stages of pregnancy through the period that theynursed their pups, i.e. to mimic a common clinical scenario of early antibioticexposure in humans. None of the adult mice treated with antibiotics developedcolitis, but their pups exhibited a high risk for developing colitis comparedto those from mothers that were not treated with antibiotics.

Using state-of-the-art, high-throughputsequencing technologies, the team also analyzed the gut microbial populationstructures of mothers and their offspring. The mothers showed a decrease indiversity of bacteria, and changes in the relative numbers of certain groups ofbacteria. For example, there were fewer populations of Bacteroidetes and morefrom the phyla Firmicutes and Verrucomicrobia. Surprisingly, these changespersisted even four to eight weeks after stopping the antibiotic treatment.

The mouse pups also had similar changesin their gut bacteria, with microbial communities matching their mothers atbirth. The diversity of microbes in these pups was significantly different fromthat of mice not treated with antibiotics, and these differences lasted intoadulthood.

“What this should tell us is, at leastas physicians, is that antibiotics are not as innocuous as we think they are,and injudicious, casual use of them can have consequences,” Chang said. “Whenthey’re used during pregnancy or early childhood, they can disturb thedevelopment of a normal gut microbiome which would otherwise be essential forproper immune development. In genetically susceptible hosts, the inability todevelop the immune system properly can have negative consequences like inflammatorybowel disease or any other kinds of complex immune disorders.”

Working toward a definition of health

Chang said that understanding more aboutthe microbiome in an unhealthy state can help scientists begin to learn how topromote the development of a microbiome that sets the stage for a healthyimmune system.

“What this study showed is what an‘unhealthy’ microbiome looks like, so presumably whatever is missing may beimportant to promote health,” he said. “What we want to eventually develop is amicrobial cocktail we can give to infants that ensures that they developproperly, metabolically and immunologically. That’s going to have a significantimpact on human health, by reducing risk for many types of diseases and bypromoting wellness.”

The study, “Peripartum Exposure toAntibiotics Promotes Persistent Gut Dysbiosis, Immune Imbalance, and Colitis inGenetically Prone Offspring,” was supported by the NIDDK Digestive Disease CoreResearch Center, the Microbiome Medicine Program of the Microbiome Center atthe University of Chicago, the Peter and Carol Goldman Family Research Fund,and the GI Research Foundation of Chicago. Additional authors include, SawakoMiyoshi, Yong Huang, Nathaniel Hubert, Tom O. Delmont, A. Murat Eren andVanessa Leone from the University of Chicago.

Source: University of Chicago MedicalCenter

中原一点红

原来是这样的啊。学习了，谢谢老师的分享。

小白天使

孕妇减少抗生素的使用只能是好处多多