Why do collateral effects of antibiotics on the human microbiome matter?

Why do collateral effects of antibiotics on the human microbiome matter? For almost every drug, there is a trade-off between benefits and risks. For antibiotics, prescription to humans has been largely based on a better safe than sorry or just in case approach, with little attention paid to risks. In the wake of the antibiotic crisis and the increased focus on a balanced microbiome for health, our attention is now turning to risks, including the unwanted collateral effects on the microbiome. The microbiome in humans is so rich that, in many ways, we are not just humans. Each of us is an ecosystem for trillions of microbes comprising bacteria, archaea, fungi, and viruses.

In some sites, like the lungs, most microbes are occasional visitors, while in the gut, skin, mouth, vagina, and some other sites, a rich microbiome is found at all times. A common misconception is that healthy individuals carry only harmless bacteria. The truth is that pathogens and harmless bacteria share more than often a common address in the human microbiome. These pathogens are usually opportunistic bacteria. They affect most often immunocompromised individuals or take advantage of other breaches in protective mechanisms, such as microbiome imbalances, to cause infections. While imbalances in the microbiome may arise through different selective pressures, antibiotics are the ones causing the most acute disturbances.

Although antibiotics are used to target specific bacteria in the site of infection, off-target effects are virtually unavoidable. What happens when you take antibiotics is that your microbiome is hit by different antibiotic concentrations. Although these are usually lower than in the target infection sites, these concentrations can affect the microbiome and can select for and promote the development of antibiotic resistance. Recent estimates show that over 80% of opportunistic pathogen exposure to antibiotics occur in this way. Modelling of microbiome disturbance by antibiotics suggests effects that can be compared to kicking a ball in a valley. Certain antibiotics can kick the gut microbiome up, and the microbiome returns to its initial state of diversity.

Others can kick so strong that the microbiome gets into another valley, in a state of reduced diversity. Since diversity in the gut is associated with health, this new state raises concerns about the long-term effect of antibiotic use. Such concerns are supported by recent studies showing, for instance, that antibiotic use during infancy promotes microbiome disturbance associated with the development of asthma and obesity later in life. Antibiotic resistance, enrichment of antibiotic resistant bacteria and antibiotic resistance genes in off-target sites have been observed for various antibiotics in different studies. Results show enrichment of major pathogens through collateral effects at different sites, including, for instance, the gut, the skin, and the nasal cavity.

Other bacteria are also commonly affected, and since they can serve as a reservoir of antibiotic resistance genes that can be transmitted to pathogens, such effects are of special concern. In conclusion, antibiotics can disrupt microbiomes and enrich for antibiotic-resistant bacteria. This can be bacteria with high pathogenic potential, which can become the source of resistant infections. Others are bacteria that rarely cause infections. They are nevertheless of concern, as they represent a reservoir of resistance genes. These are exciting times for research, and as the field moves forward, we expect discoveries that will reduce collateral effects for those with real need for antibiotics.