Mental Health & Neurology

Post-Doctoral Fellowships


Gut microbiome: Deciphering the metabolic interplay with psychoactive compounds

Depression, psychotic disorders and schizophrenia are severe mental conditions that affect more than 100 million people in Europe alone and are leading causes of disability worldwide. One out of ten people worldwide has taken antidepressant or antipsychotic medication over the past 12 months, and this proportion continues to increase. These medicines often cause side effects which impact patients’ quality of life, including weight gain and gastrointestinal complications. Although side effects are mainly explained by differences in human physiology, an increasing number of studies suggest that certain complications are mediated by the gut microbiota – the bacteria living in our intestine. Most antipsychotic drugs are taken orally and can reach the intestine and affect or be affected by the gut microbiota. “Genetic diversity of the gut microbiota is much larger than human genetic diversity”, notes Dr Maria Zimmermann-Kogadeeva, an AXA post-doctoral grantee at EMBL Heidelberg. “Two individuals share about 99.9% of genetic code, however, the genetic content of their gut microbiota can be only 10-30% identical. Understanding the mechanisms of interactions between diverse gut bacteria and psychoactive compounds could explain interpersonal differences in medication response and improve the outcome of mental health therapies.”
Dr Zimmermann-Kogadeeva hypothesizes that the gut microbiota can contribute to a patients’ response to antipsychotic drugs and their side effects in two ways:
  • 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”.



European Molecular Biology Laboratory





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