Dysbiosis individualizes the fitness effect of antibiotic resistance in the mammalian gut.

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.