Introduction: Mental illnesses continue to be a global health burden and only recently has the intimate physiological connection between the gut microbiome and brain become clear. Gut microbes not only affect host physiology, but also drug metabolism, and it has been demonstrated that the gut microbiome is particularly affected by antidepressant and antipsychotic drugs. As the gut microbiome plays a pivotal role in signaling across the gut-brain axis, it is plausible that the therapeutic and adverse effects of psychotropic drugs may be influenced by the microbiome. Consequently, interpersonal differences in treatment outcome (intensity, duration, onset, and side effects) may be explained by compositional variation of the microbiome from person to person.

Methods: To decipher the extent of these complex drug-microbiome interactions, a representative group of human gut bacterial species were tested in a high-throughput in vitro anerobic screening of over 1000 marketed drugs, which revealed a remarkably strong and direct antibacterial effect of antipsychotics on gut microbes. Following up on this therapeutic drug class, 1641 agents targeting neuronal signaling were tested on six phylogenetically diverse gut microbes, including commensals, pathobionts and pathogens.

Results and outlook: 14% of the 1614 compounds exhibited antibacterial potential against at least one of the tested strains. Strains that play a crucial role in keeping the human gut healthy, such as butyrate and propionate producers, were significantly more inhibited by these compounds. 40 marketed antidepressants and antipsychotics have been chosen to be screened in both a synthetic model bacterial community and ex vivo (patient stool samples) complex microbiome communities. A detail understanding of the underlying mechanisms may create new opportunities to enhance treatment methods and foster the development of innovative microbial treatment strategies for mental illnesses.