Effects of psychotropic drugs on the microbiota-gut-liver-brain axis

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

Psychotropics and the microbiome: A chamber of secrets…

The human gut contains trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. Psychotropic medications act on the central nervous system (CNS) and are used in the treatment of various psychiatric disorders. There is increasing emphasis on the bidirectional interaction between drugs and the gut microbiome. An expanding body of evidence supports the notion that microbes can metabolise drugs and vice versa drugs can modify the gut microbiota composition. In this review, we will first give a comprehensive introduction about this bidirectional interaction, then we will take into consideration different classes of psychotropics including antipsychotics, antidepressants, antianxiety drugs, anticonvulsants/mood stabilisers, opioid analgesics, drugs of abuse, alcohol, nicotine and xanthines. The varying effects of these widely used medications on microorganisms are becoming apparent from in vivo and in vitro studies. This has important implications for the future of psychopharmacology pipelines that will routinely need to consider the host microbiome during drug discovery and development

The neuroendocrinology of the microbiota-gut-brain axis: a behavioural perspective

The human gut harbours trillions of symbiotic bacteria that play a key role in programming different aspects of host physiology in health and disease. These intestinal microbes are also key components of the gut-brain axis, the bidirectional communication pathway between the gut and the central nervous system (CNS). In addition, the CNS is closely interconnected with the endocrine system to regulate many physiological processes. An expanding body of evidence is supporting the notion that gut microbiota modifications and/or manipulations may also play a crucial role in the manifestation of specific behavioural responses regulated by neuroendocrine pathways. In this review, we will focus on how the intestinal microorganisms interact with elements of the host neuroendocrine system to modify behaviours relevant to stress, eating behaviour, sexual behaviour, social behaviour, cognition and addiction

Association between the indole pathway of tryptophan metabolism and subclinical depressive symptoms in obesity: a preliminary study

12partially_openInternationalInternational coauthor/editorConverging data support the role of chronic low-grade inflammation in depressive symptomatology in obesity. One mechanism likely to be involved relies on the effects of inflammation on tryptophan (TRP) metabolism. While recent data document alterations in the indole pathway of TRP metabolism in obesity, the relevance of this mechanism to obesity-related depressive symptoms has not been investigated. The aim of this preliminary study was to assess the association between plasma levels of TRP and indole metabolites and depressive symptoms in 44 subjects with severe or morbid obesity, free of clinically relevant neuropsychiatric disorders. The interaction effect of inflammation, reflected in serum high-sensitive C-reactive protein (hsCRP) levels, and indoles on depressive symptoms was also determined. Higher serum levels of hsCRP and lower concentrations of TRP and indoles, particularly indole-3-carboxaldehyde (IAld), correlated with more severe depressive symptoms. Interestingly, the effect of high hsCRP levels in predicting greater depressive symptoms was potentiated by low IAld levels. These results comfort the link between inflammation, the indole pathway of TRP metabolism, and obesity-related depressive symptomsmixedDelgado, Inês; Cussotto, Sofia; Anesi, Andrea; Dexpert, Sandra; Aubert, Agnès; Aouizerate, Bruno; Beau, Cédric; Forestier, Damien; Ledaguenel, Patrick; Magne, Eric; Mattivi, Fulvio; Capuron, LucileDelgado, I.; Cussotto, S.; Anesi, A.; Dexpert, S.; Aubert, A.; Aouizerate, B.; Beau, C.; Forestier, D.; Ledaguenel, P.; Magne, E.; Mattivi, F.; Capuron, L

Tryptophan metabolic pathways are altered in obesity and are associated with systemic inflammation

Background: Obesity is a condition with a complex pathophysiology characterized by both chronic low-grade inflammation and changes in the gut microbial ecosystem. These alterations can affect the metabolism of tryptophan (TRP), an essential amino acid and precursor of serotonin (5-HT), kynurenine (KYN), and indoles. This study aimed to investigate alterations in KYN and microbiota-mediated indole routes of TRP metabolism in obese subjects relatively to non-obese controls and to determine their relationship with systemic inflammation. Methods: Eighty-five obese adults (avg. BMI = 40.48) and 42 non-obese control individuals (avg. BMI = 24.03) were recruited. Plasma levels of TRP catabolites were assessed using Ultra High Performance Liquid Chromatography-ElectroSpray-Ionization-Tandem Mass Spectrometry. High-sensitive C-reactive protein (hsCRP) and high-sensitive interleukin 6 (hsIL-6) were measured in the serum as markers of systemic inflammation using enzyme-linked immunosorbent assay. Results: Both KYN and microbiota-mediated indole routes of TRP metabolism were altered in obese subjects, as reflected in higher KYN/TRP ratio and lower 5-HT and indoles levels, relatively to non-obese controls. HsIL-6 and hsCRP were increased in obesity and were overall associated with TRP metabolic pathways alterations. Conclusion: These results indicate for the first time that KYN and indole TRP metabolic pathways are concomitantly altered in obese subjects and highlight their respective associations with obesity-related systemic inflammation.A Menu for Brain Responses Opposing Stress-Induced Alterations in CognitionMetabolic HEALTH through nutrition, microbiota and tryptophan bioMARKer

The gut microbiome influences the bioavailability of olanzapine in rats

peer-reviewedBackground The role of the gut microbiome in the biotransformation of drugs has recently come under scrutiny. It remains unclear whether the gut microbiome directly influences the extent of drug absorbed after oral administration and thus potentially alters clinical pharmacokinetics. Methods In this study, we evaluated whether changes in the gut microbiota of male Sprague Dawley rats, as a result of either antibiotic or probiotic administration, influenced the oral bioavailability of two commonly prescribed antipsychotics, olanzapine and risperidone. Findings The bioavailability of olanzapine, was significantly increased (1.8-fold) in rats that had undergone antibiotic-induced depletion of gut microbiota, whereas the bioavailability of risperidone was unchanged. There was no direct effect of microbiota depletion on the expression of major CYP450 enzymes involved in the metabolism of either drug. However, the expression of UGT1A3 in the duodenum was significantly downregulated. The reduction in faecal enzymatic activity, observed during and after antibiotic administration, did not alter the ex vivo metabolism of olanzapine or risperidone. The relative abundance of Alistipes significantly correlated with the AUC of olanzapine but not risperidone. Interpretation Alistipes may play a role in the observed alterations in olanzapine pharmacokinetics. The gut microbiome might be an important variable determining the systemic bioavailability of orally administered olanzapine. Additional research exploring the potential implication of the gut microbiota on the clinical pharmacokinetics of olanzapine in humans is warranted. Funding This research is supported by APC Microbiome Ireland, a research centre funded by Science Foundation Ireland (SFI), through the Irish Government's National Development Plan (grant no. 12/RC/2273 P2) and by Nature Research-Yakult (The Global Grants for Gut Health; Ref No. 626891).Science Foundation Irelan

The microbiota-gut-brain axis

The importance of the gut-brain axis in maintaining homeostasis has long been appreciated. However, the past 15 yr have seen the emergence of the microbiota (the trillions of microorganisms within and on our bodies) as one of the key regulators of gut-brain function and has led to the appreciation of the importance of a distinct microbiota-gut-brain axis. This axis is gaining ever more traction in fields investigating the biological and physiological basis of psychiatric, neurodevelopmental, age-related, and neurodegenerative disorders. The microbiota and the brain communicate with each other via various routes including the immune system, tryptophan metabolism, the vagus nerve and the enteric nervous system, involving microbial metabolites such as short-chain fatty acids, branched chain amino acids, and peptidoglycans. Many factors can influence microbiota composition in early life, including infection, mode of birth delivery, use of antibiotic medications, the nature of nutritional provision, environmental stressors, and host genetics. At the other extreme of life, microbial diversity diminishes with aging. Stress, in particular, can significantly impact the microbiota-gut-brain axis at all stages of life. Much recent work has implicated the gut microbiota in many conditions including autism, anxiety, obesity, schizophrenia, Parkinson's disease, and Alzheimer's disease. Animal models have been paramount in linking the regulation of fundamental neural processes, such as neurogenesis and myelination, to microbiome activation of microglia. Moreover, translational human studies are ongoing and will greatly enhance the field. Future studies will focus on understanding the mechanisms underlying the microbiota-gut-brain axis and attempt to elucidate microbial-based intervention and therapeutic strategies for neuropsychiatric disorders

Niche construction and the transition to herbivory: Phenotype switching and the organization of new nutritional modes

Gut microbiota have played important roles in the evolutionary transition from carnivory to herbivory. In the evolution of ruminants, three modes of macrobe-microbe symbiosis have facilitated the phenotypic switch into a new nutritional mode. Mutualistic microbes acquired during birth enable the building of the rumen (developmental symbiosis), the digestion of plant fiber (nutritional symbiosis), and the detoxification of plant toxins (protective symbiosis). These symbioses created a new plant dietary niche through two types of niche construction: “perturbational niche construction,” a phenotypic process whereby gut microbes initiate the building of a mature rumen from the non-functional anlagen of this stomach region; and “mediational niche construction,” whereby microbe-induced changes alter how the animal experiences environmental resources without actual modification of the environment. Thanks to microbes, plants are now edible. We argue that the reciprocal niche construction of the host and its associated microbial organisms (i.e. the “holobiont”) scaffold each other’s developmental and phenotypic processes as well as organize a new selective environment of the holobiont as a whole