摘要
      抗生素对微生物组的附带影响越来越受到关注。然而，长期接触抗生素对肠道微生物组的生态影响，包括抗生素耐药性，仍然有限。在这里，我们研究了长期接触阿莫西林对人类肠道微生物组和耐药性的影响。作为挪威慢性腰痛多中心临床试验（AIM研究）的一部分，从20名接受3个月阿莫西林或安慰剂治疗的患者身上采集粪便样本。在基线、治疗的最后一天和抗生素停用后9个月采集样本。利用全鸟枪和功能宏基因组测序数据对微生物和抗性组分的丰度和多样性进行了表征。虽然安慰剂受试者的微生物组特征随着时间的推移是稳定的，但在阿莫西林治疗后观察到多样性和整体微生物组组成的明显变化。特别是，与健康相关的短链脂肪酸产生物种的比例显著下降。然而，这些变化是短暂的，因为微生物组在治疗后9个月显示出总体恢复。另一方面，长期暴露于阿莫西林与抗微生物耐药性基因总载量和抗微生物耐药基因多样性的增加有关，即使在治疗后9个月也会持续变化。此外，β-内酰胺耐药性是受影响最大的抗生素类别，这表明对阿莫西林有靶向反应，尽管基因水平的变化因个体而异。总体而言，我们的研究结果表明，与微生物组组成相比，长期接触阿莫西林对粪便耐药组的影响更为明显和持久。这些信息与设计合理的抗生素治疗给药指南有关。
ABSTRACT
The collateral impact of antibiotics on the microbiome has attained increasing attention. However, the ecological consequences of long-term antibiotic exposure on the gut microbiome, including antibiotic resistance, are still limited. Here, we investigated long-term exposure effects to amoxicillin on the human gut microbiome and resistome. Fecal samples were collected from 20 patients receiving 3-months of amoxicillin or placebo treatment as part of a Norwegian multicenter clinical trial on chronic low back pain (AIM study). Samples were collected at baseline, last day of treatment, and 9 months after antibiotic cessation. The abundance and diversity of microbial and resistome composition were characterized using whole shotgun and functional metagenomic sequencing data. While the microbiome profiles of placebo subjects were stable over time, discernible changes in diversity and overall microbiome composition were observed after amoxicillin treatment. In particular, health-associated short-chain fatty acid producing species significantly decreased in proportion. However, these changes were short-lived as the microbiome showed overall recovery 9 months post-treatment. On the other hand, exposure to long-term amoxicillin was associated with an increase in total antimicrobial resistance gene load and diversity of antimicrobial resistance genes, with persistent changes even at 9 months post-treatment. Additionally, beta-lactam resistance was the most affected antibiotic class, suggesting a targeted response to amoxicillin, although changes at the gene level varied across individuals. Overall, our results suggest that the impact of prolonged amoxicillin exposure was more explicit and long-lasting in the fecal resistome than in microbiome composition. Such information is relevant for designing rational administration guidelines for antibiotic therapies.

https://www.tandfonline.com/doi/full/10.1080/19490976.2022.2157200