The human microbiota contributes to health and well-being. Antimicrobials (AM) have an immediate effect on microbial diversity and composition in the gut, but next to nothing is known about their long-term contribution to saliva microbiota. Our objectives were to investigate the long-term impact of AM use on saliva microbiota diversity and composition in preadolescents. We compared the lifetime effects by gender and AMs. We used data from 808 randomly selected children in the Finnish Health In Teens (Fin-HIT) cohort with register-based data on AM purchases from the Social Insurance Institution of Finland. Saliva microbiota was assessed with 16S rRNA (V3-V4) sequencing. The sequences were aligned to the SILVA ribosomal RNA database and classified and counted using the mothur pipeline. Associations between AM use and alpha-diversity (Shannon index) were identified with linear regression, while associations between beta-diversity (Bray-Curtis dissimilarity) and low, medium or high AM use were identified with PERMANOVA. Of the children, 53.6% were girls and their mean age was 11.7 (0.4) years. On average, the children had 7.4 (ranging from 0 to 41) AM prescriptions during their lifespan. The four most commonly used AMs were amoxicillin (n = 2622, 43.7%), azithromycin (n = 1495, 24.9%), amoxicillin-clavulanate (n = 1123, 18.7%) and phenoxymethylpenicillin (n = 408, 6.8%). A linear inverse association was observed between the use of azithromycin and Shannon index (b − 0.015, p value = 0.002) in all children, the effect was driven by girls (b − 0.032, p value = 0.001), while not present in boys. Dissimilarities were marked between high, medium and low users of all AMs combined, in azithromycin users specifically, and in boys with amoxicillin use. Amoxicillin and amoxicillin-clavulanate use was associated with the largest decrease in abundance of Rikenellaceae. AM use in general and phenoxymethylpenicillin specifically were associated with a decrease of Paludibacter and pathways related to amino acid degradations differed in proportion between high and low AM users. A systematic approach utilising reliable registry data on lifetime use of AMs demonstrated long-term effects on saliva microbiota diversity and composition. These effects are gender- and AM-dependent. We found that frequent lifelong use of AMs shifts bacterial profiles years later, which might have unforeseen health impacts in the future. Our findings emphasise a concern for high azithromycin use, which substantially decreases bacterial diversity and affects composition as well. Further studies are needed to determine the clinical implications of our findings.

中文翻译：

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生命最初十年的抗菌药物使用会影响唾液微生物群的多样性和组成。


人类微生物群有助于健康和福祉。抗菌药物 (AM) 对肠道微生物多样性和组成有直接影响，但对其对唾液微生物群的长期贡献却知之甚少。我们的目标是调查 AM 使用对青春期前儿童唾液微生物群多样性和组成的长期影响。我们比较了性别和 AM 对终生的影响。我们使用了芬兰青少年健康 (Fin-HIT) 队列中 808 名随机选择的儿童的数据，以及芬兰社会保险机构购买 AM 的登记数据。通过 16S rRNA (V3-V4) 测序评估唾液微生物群。将序列与 SILVA 核糖体 RNA 数据库进行比对，并使用 mothur pipeline 进行分类和计数。 AM 使用和 α 多样性（香农指数）之间的关联通过线性回归确定，而 β 多样性（Bray-Curtis 相异性）和低、中或高 AM 使用之间的关联通过 PERMANOVA 确定。在这些儿童中，53.6% 是女孩，她们的平均年龄为 11.7 (0.4) 岁。平均而言，这些孩子一生中开过 7.4 次（范围从 0 到 41 次）AM 处方。四种最常用的 AM 是阿莫西林（n = 2622，43.7%）、阿奇霉素（n = 1495，24.9%）、阿莫西林克拉维酸（n = 1123，18.7%）和苯氧甲基青霉素（n = 408，6.8%）。在所有儿童中观察到阿奇霉素的使用与香农指数 (b − 0.015，p 值 = 0.002) 之间存在线性负相关，该效应由女孩驱动 (b − 0.032，p 值 = 0.001)，而男孩中不存在。所有 AM 的高、中和低使用者之间存在显着差异，特别是在阿奇霉素使用者中，以及在使用阿莫西林的男孩中。 阿莫西林和阿莫西林克拉维酸盐的使用与理肯氏菌科丰度的最大下降有关。 AM的一般使用和苯氧基甲基青霉素的具体使用与Paludibacter的减少有关，并且与氨基酸降解相关的途径在高和低AM使用者之间比例不同。利用关于 AM 终生使用的可靠登记数据的系统方法证明了对唾液微生物群多样性和组成的长期影响。这些影响与性别和 AM 相关。我们发现，终生频繁使用 AM 会在数年后改变细菌特征，这可能会在未来产生不可预见的健康影响。我们的研究结果强调了对阿奇霉素大量使用的担忧，这大大降低了细菌多样性并影响了组成。需要进一步的研究来确定我们的研究结果的临床意义。