Effects of psychotropic drugs on the microbiota-gut-liver-brain axis
University College Cork
There is a growing recognition of the involvement of the gut microbiota in drug metabolism and vice versa the impact of drug intake on the microbiome. In this thesis, we focus our attention on psychotropic medications (from the Greek root psychè = mind and tropòs = turning). With few isolated studies showing that brain-targeting medications can have antimicrobial activity in vitro, we sought to investigate the impact of psychotropics on the microbiome and intestinal physiology in vivo. Across a range of psychotropic medications, lithium, valproate, aripiprazole and fluoxetine significantly impacted the microbiome composition and diversity. These effects were not directly linked to changes in intestinal permeability or short-chain fatty acids levels (Chapter 2). The mood stabilisers lithium and valproate significantly impacted bile acid metabolism and targeted a set of bile-metabolising bacteria. Two mechanisms hypothesised as possible players in the bile-targeted effects of lithium and valproate, hepatic inflammation and intestinal permeability, did not seem to play any overt role in the disruption of bile pathways (Chapter 3). We next investigated whether perturbations of the microbiome, through administration of probiotics or antibiotics, could alter the pharmacokinetics of olanzapine and risperidone, two antipsychotic medications. Antibiotics increased the blood levels of olanzapine (AUC, area under the curve) but did not influence the absorption of risperidone. The antibiotics did not have a direct effect on the expression of CYPs involved in the metabolism of antipsychotics. Among the bacterial genera detected by 16S sequencing, the relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone, suggesting that this bacterium might play a role in the pharamacokinetic alterations observed in olanzapine-treated rats (Chapter 4). Lastly, intrigued by the findings of Chapter 2, we moved on to look at the microbiome-targeting effects of psychotropic drugs in a human population, the Dutch LifeLines DEEP cohort. Although the small sample size and certain limitations which should be addressed in future population-based studies, minor effects of drug consumption on the human gut microbiota were detected (Chapter 5). Overall, these results provide novel insight on the role exerted by psychotropic medications on the microbiota-gut-liver-brain axis. Possible implications of this work include optimisation of drug efficacy or toxicity, use of the microbiome as a tool to distinguish responders from non-responders and improvement of personalised medicine.
Psychotropic drugs , Microbiota , Pharmacokinetics , Liver and bile acids
Cussotto, S. 2019. Effects of psychotropic drugs on the microbiota-gut-liver-brain axis. PhD Thesis, University College Cork.