The gut metagenome harbors metabolic and antibiotic resistance signatures of established asthma

Asthma is a common allergic airway disease that develops in association with the human microbiome early in life. Both the composition and function of the infant gut microbiota have been linked to asthma risk, but functional alterations in the gut microbiota of older patients with established asthma remain an important knowledge gap. Here, we performed whole metagenomic shotgun sequencing on 95 stool samples from 59 healthy and 36 subjects with moderate-to-severe asthma to characterize the metagenomes of gut microbiota in children and adults 6 years and older. Mapping of functional orthologs revealed that asthma contributes to 2.9% of the variation in metagenomic content even when accounting for other important clinical demographics. Differential abundance analysis showed an enrichment of long-chain fatty acid (LCFA) metabolism pathways which has been previously implicated in airway smooth muscle and immune responses in asthma. We also observed increased richness of antibiotic resistance genes in people with asthma accompanied by increased abundance of a macrolide resistance marker, ermF. ErmF significantly co-occurred with the Bacteroides fragilis toxin, suggesting a possible relationship between enterotoxigenic B. fragilis, antibiotic resistance, and asthma. Lastly, we found multiple virulence factors and antibiotic resistance gene pairs that co-occurred in both cohorts suggesting that virulence and antibiotic resistance traits are co-selected in the fecal microbiota of asthmatics. Overall, our results show functional alterations in LCFA biosynthesis and increases in antibiotic resistance in the gut microbiota of subjects with moderate-to-severe asthma and could have implications asthma management and treatment.

哮喘是一种常见的过敏性气道疾病，其发病与生命早期的人体微生物组（human microbiome）密切相关。既往研究已证实，婴儿肠道微生物群（infant gut microbiota）的组成与功能均与哮喘发病风险存在关联，但针对已确诊哮喘的年长患者肠道微生物群的功能改变，目前仍存在重要的研究空白。本研究对59名健康个体与36名中度至重度哮喘患者的95份粪便样本开展全宏基因组鸟枪法测序（whole metagenomic shotgun sequencing），以表征6岁及以上儿童与成人的肠道微生物群宏基因组特征。功能同源物（functional orthologs）注释分析显示，即便校正其他关键临床人口统计学变量，哮喘仍可解释宏基因组组成2.9%的变异度。差异丰度分析结果表明，长链脂肪酸（long-chain fatty acid, LCFA）代谢通路显著富集——此前已有研究指出该通路与哮喘患者的气道平滑肌功能及免疫应答相关。本研究同时观察到，哮喘患者体内的抗生素抗性基因（antibiotic resistance genes）丰富度显著升高，同时伴随大环内酯类抗性标记基因ermF的丰度增加。ErmF与脆弱拟杆菌毒素（Bacteroides fragilis toxin）显著共现，提示产肠毒素脆弱拟杆菌、抗生素抗性与哮喘三者之间可能存在潜在关联。最后，本研究在两个队列中均发现了多种毒力因子（virulence factors）与抗生素抗性基因的共现组合，表明哮喘患者粪便微生物群中的毒力与抗生素抗性性状存在共选择现象。总体而言，本研究结果显示中度至重度哮喘患者的肠道微生物群存在长链脂肪酸生物合成功能异常，且抗生素抗性基因丰度升高，该发现或可为哮喘的临床管理与治疗提供参考依据。