In the absence of antibiotics, it is essential that antibiotic resistance has a fitness cost for microorganisms if suspending antibiotics treatment is to be a useful strategy for reducing antibiotic resistance. However, the cost of antibiotic resistance within the complex ecosystem of the mammalian gut is not well understood. Here, using mice, we show that the same antibiotic resistance mutation can reduce fitness in one host, while being neutral or even increasing fitness in other hosts. Such antagonistic pleiotropy is shaped by the microbiota because resistance in germ-free mice is consistently costly across all hosts, and the host-specific effect on antibiotic resistance is reduced in hosts with similar microbiotas. Using an eco-evolutionary model of competition for resources, we identify a general mechanism that underlies between-host variation and predicts that the dynamics of compensatory evolution of resistant bacteria should be host specific, a prediction that was supported by experimental evolution in vivo. The microbiome of each human is close to unique, and our results suggest that the short-term cost of resistances and their long-term within-host evolution are also highly personalized, a finding that may contribute to the observed variable outcome of withdrawing antibiotics to reduce resistance levels.

在没有抗生素的情况下，如果暂停抗生素治疗是减少抗生素耐药性的有用策略，那么抗生素耐药性对微生物的适应性成本至关重要。然而，哺乳动物肠道复杂生态系统中抗生素耐药性的成本尚不清楚。在这里，使用小鼠，我们表明相同的抗生素抗性突变可以降低一个宿主的适应度，同时保持中性甚至增加其他宿主的适应度。这种拮抗性多效性是由微生物群形成的，因为无菌小鼠的耐药性在所有宿主中始终是昂贵的，并且宿主对抗生素耐药性的特异性影响在具有相似微生物群的宿主中降低。使用竞争资源的生态进化模型，我们确定了宿主间变异的一般机制，并预测抗性细菌的补偿进化动力学应该是宿主特异性的，这一预测得到了体内实验进化的支持。每个人的微生物组几乎是独一无二的，我们的研究结果表明，耐药性的短期成本及其在宿主内的长期进化也是高度个性化的，这一发现可能有助于观察到的不同结果降低阻力水平。