摘要

背景：最近的研究集中在婴儿早期肠道微生物组，表明抗生素抗性基因 (ARGs) 可以在生命早期获得并可能产生长期后遗症。在不引发其他耐药机制的情况下限制抗菌素耐药性的传播将具有巨大的临床价值。在这里，我们提出了 2 项分析，重点介绍了早产儿和足月婴儿中 ARG 的丰度，以及调节微生物组以促进足月婴儿早期稳定和减少 ARG 的概念证明。方法：对来自 10 个国家的 2,141 个微生物组样本（90% 来自早产儿）进行大规模宏基因组分析；大多数来自美国 (87%)，并从综合抗生素耐药性数据库 (CARD) 中获得。我们评估了存在的 ARG 的丰度和特定类型。在第二项研究中，健康的母乳喂养婴儿从出生后第 7 天开始喂食婴儿双歧杆菌 EVC001 3 周。在第 21 天收集粪便样本，并利用鸟枪宏基因组学进行处理。对选定的抗微生物菌种进行分离、测序并测试其对临床相关抗生素的最小抑制浓度。结果：在第一项研究中，在全球范围内确定了 417 个不同的 ARG。所有样品中最丰富的基因被注释为 msrE，这是一种已知赋予大环内酯 - 林可酰胺 - 链球菌素 B (MLSB) 抗生素抗性的质粒基因。其余最丰富的 ARG 是与多药耐药相关的外排泵基因。在出生后第一个月考虑分娩方式或抗生素治疗时，未发现抗菌素耐药性存在显着关联。在第二项研究中，与对照组相比，EVC001 喂养组的 ARG 显着降低 (90%) (P < .0001)。预计组间差异显着的 ARG 会导致对 β-内酰胺类、氟喹诺酮类或多种药物类别的耐药性。最低抑菌浓度测定证实了分离株中的耐药表型 值得注意的是，我们发现从未接触过抗生素的健康、经阴道分娩的母乳喂养婴儿对超广谱 β-内酰胺酶具有耐药性。结论：在这项研究中，我们表明足月和早产儿微生物组包含与临床相关抗生素相关的 ARG 水平令人担忧，这些抗生素通常是导致医院感染的细菌。母乳喂养婴儿肠道被单株 B. longum subsp infantis 定植对粪便宏基因组产生深远影响，包括减少 ARGs 和减少潜在病原体。这些发现强调了开发新方法以限制 ARG 在临床相关细菌中传播的重要性，以及在全球解决 AR 的其他方法的相关性。

Background: Recent studies have focused on the early infant gut microbiome, indicating that antibiotic resistance genes (ARGs) can be acquired in early life and may have long-term sequelae. Limiting the spread of antimicrobial resistance without triggering the development of additional resistance mechanisms would be of immense clinical value. Here, we present 2 analyses that highlight the abundance of ARGs in preterm and term infants and a proof of concept for modulating the microbiome to promote early stabilization and reduction in ARGs in term infants. Methods: Large-scale metagenomic analysis was performed on 2,141 microbiome samples (90% from pre-term infants) from 10 countries; most were from the United States (87%) and were obtained from the Comprehensive Antibiotic Resistance Database (CARD). We assessed the abundance and specific types of ARGs present. In the second study, healthy, breastfed infants were fed B. infantis EVC001 for 3 weeks starting at postnatal day 7. Stool samples were collected at day 21 and were processed utilizing shotgun metagenomics. Selected antimicrobial-resistant bacterial species were isolated, sequenced, and tested for minimal inhibitory concentrations to clinically relevant antibiotics. Results: In the first study, globally, 417 distinct ARGs were identified. The most abundant gene among all samples was annotated as msrE, a plasmid gene known to confer resistance to macrolide-lincosamide-streptogramin B (MLSB) antibiotics. The remaining most-abundant ARGs were efflux-pump genes associated with multidrug resistance. No significant association in antimicrobial resistance was found when considering delivery mode or antibiotic treatment in the first month of life. In the second study, the EVC001-fed group showed a significant decrease (90%) in ARGs compared to controls (P < .0001). ARGs that differed significantly between groups were predicted to confer resistance to β-lactams, fluoroquinolones, or multiple drug classes. Minimal inhibitory concentration assays confirmed resistance phenotypes among isolates Notably, we found resistance to extended-spectrum β-lactamases among healthy, vaginally delivered breastfed infants who had never been exposed to antibiotics. Conclusions: In this study, we show that the term and preterm infant microbiome contains alarming levels of ARGs associated with clinically relevant antibiotics harbored by bacteria commonly responsible for nosocomial infections. Colonization of the breastfed infant gut by a single strain of B. longum subsp infantis had profound impacts on the fecal metagenome, including reduction in ARGs and reduction of potential pathogens. These findings highlight the importance of developing novel approaches to limit the spread of ARGs among clinically relevant bacteria and the relevance of an additional approach in the effort to solve AR globally.

https://www.cambridge.org/core/journals/infection-control-and-hospital-epidemiology/article/microbiomebased-solution-to-address-alarming-levels-of-drugresistant-bacteria-in-the-newborn-infant-gut/861AFCB8EF01A5110B5D81880668F78B?__cf_chl_jschl_tk__=5ef7380a8483f583ad680da15bd5677c06b70b89-1622516622-0-AUCW6UwABVKXwUXLUS3QQrHQPRyY-wLu6Ibdpen679Yx8HTxTcRzSzn3V43BIEKktdl765t7meWuJ9Rvt82tqjnNl44ARfMfo8IPDQ-7dbpuJdu-P30MKoXhigiO201J3SRSDXaAWXmLnVLoTavVfIBykoFCHQkIM2yjghqIqXfAY8xfRj9Zb-CwGkLh_Fxq0OpOZeMSu8xiaKHFTk1kqY5HcHaVrqsJd9qSqL4G0nayhXy12TOivDnkih3Lxz5dH5ioQTs3k0hG8m9RatR0JAHcOUXiXiuizjLoCHuKs16aY-R-nMiXFAgGGIMLgPl5xNwxRv4l8p7ucP1qIvbIGdkvh0uTWuon3qYzjXqNKVZwLMzqlJQ62AD3xHIbEsDwdhl6quZFVPh4-u_jRc80U7tqdhNe4TAaCQulr7ipF-4msnVporqKKhZSl7tTsZ3rhJA3iNvlZq3dUTTs-zKRJaxMbQTMBASKjdMjfS2R4y98ImackbcmgBhfKRitYeWl7WdmT4ssaU_wbLpemzypIGNV1vl7kYqBBbBtz4wlIwaabkOa1zfPWHm8yXUuaEaa8c7M8b2vAbnLWUSb7Nag7HrQ1oJltzRNhioMXcw6-tnFiZgtKjAam0P_xQBpRKwHxEnqHclNL0aPOxpYzHXQdrtOVKqIRv4qdOoWBc27BJDva_e5xypmSr5zpefOdbcR8xE5n2d5jvnu5gxc_-REvTE