Gut microbiome: Deciphering the metabolic interplay with psychoactive compounds

• On the one hand, antipsychotic drugs can affect microbes in the gut, resulting in changes in microbial composition and metabolite production. This can cause both local gastrointestinal complications and altered signaling along the gut-brain axis mediated by bacterial metabolic products, such as short-chain fatty acids, serotonin precursors, neurotransmitters, and hormones;
• On the other hand, gut microbes can chemically modify antipsychotic drugs, which can affect drug efficacy and toxicity.

In her project supported by AXA Research Fund, Dr Zimmermann-Kogadeeva proposes to test her hypotheses using a bottom-up approach that focuses on the microbiome, and to combine computational modelling and laboratory experiments to investigate molecular interactions between gut bacteria and antipsychotic drugs. Using genome-scale metabolic models that connect bacterial genes to their metabolic functions, she will predict the effect of psychoactive compounds on bacterial metabolism and growth, and the capacity of bacteria to metabolize psychoactive compounds. She will then test the model predictions with large-scale metabolomics experiments by measuring bacterial growth and metabolites during incubation with psychoactive compounds. This combination of computational and experimental approaches will provide reliable predictive models of microbiota-psychoactive compound interactions, which will identify candidate bacteria and their genes potentially contributing to interpersonal differences in antipsychotic drug response. With this information in hand, Dr. Zimmermann-Kogadeeva will assess the models’ ability to predict antipsychotic drug metabolism by complete human gut communities; and develop pharmacokinetic models that describe the fate of psychoactive compounds in the body after oral administration to quantify microbiota contribution to antipsychotic drug metabolism on the organism scale.  

This project aims at providing causal links between antipsychotics, gut bacteria, bacterial genes, and the psychoactive metabolites circulating in the body. “These causal links could open new avenues for personalized mental health therapies”, explains Dr. Zimmermann-Kogadeeva. “Our results could help to select the most suitable medication and avoid side effects based on the patient’s microbiota composition. Moreover, in contrast to human genes, the gut microbiota can be modified with prebiotics (dietary supplements that promote growth of certain types of bacteria), probiotics (products containing living bacteria) and antibiotics (drugs affecting microbial growth), what allows to combine these interventions with mental health treatments to control microbiota activity, thus improving treatment efficacy for the long-term benefit of the patients, the healthcare system and the society”.