gutMAP · Gut microbiome-mediated activities of psychotropic drugs

Mental illnesses are among the most prevalent health burdens, with major depression ranking fourth among the leading causes of disease worldwide. Although diverse psychotropic drugs are available, the delayed onset of drug action, high non-responder rates and frequent side effects still pose significant challenges. Several observations suggest the gut microbiome as major contributor to high inter-individual differences in drug responses. While there is evidence that these drugs lead to changes in the microbiome composition of patients, it has not yet been explored whether these effects are part of the drug mode of action and/or whether they contribute to side effects. The aim of this project is to investigate to what extent gut microbes are involved in the therapeutic outcome of psychotropic drugs by employing model synthetic and patient derived microbiome communities (from stool of drug responders, non-responders and healthy controls), and in vivo gnotobiotic mouse models. We will systematically characterize the reciprocal interactions between gut microbes and commonly used psychotropic drugs ex vivo – from microbial drug metabolism to drug-induced bacterial secretion of neuroactive compounds. For intriguing interactions, we will elucidate the underlying mechanisms and use the knowledge to design engineered microbiomes. We will then employ gnotobiotic knockout mice deficient for primary drug targets of psychotropic drugs and colonize them with microbiome communities carrying the different mapped traits to separate the contribution of drug effects originating from the microbiome from those of the host. Overall, our results will inform microbiome-guided therapeutic strategies whose improved efficacy we will test in vivo. Due to the transferability of the developed technology and if successful, this new research direction could not only revolutionize psychotropic drug therapy, but also pave new ways for improving personalized drug therapy for many other diseases.