Univ.-Prof. Dr. Michael Trauner
The overall expertise and research interest of the Hans Popper Laboratory of Molecular Hepatology is focused on understanding how bile acid (BA) transport and signaling regulates lipid and glucose metabolism, food intake behaviour and mood. Our translational research approach within the Division of Gastroenterology and Hepatology and Department of Internal Medicine will allow us to explore the clinical relevance of key findings obtained in mouse and cell/organoid models in patients with metabolic liver diseases (MASLD), diabetes and obesity.
Bile acids (BAs) are amphipathic molecules with a steroid structure which are synthesized from cholesterol and have recently been recognized to act as signaling molecules throughout the body including the brain in addition to their digestive functions in the gut (PMID: 35165436). In the hypothalamus BA suppress food intake in mice through the G-protein coupled BA receptor TGR5 in AgRP/NPY but not in POMC neurons (PMID: 34031591). Moreover, TGR5 also regulates excitability of GABAergic neurons in a lateral hypothalamus-dCA3-dorsolateral septum circuit mediating depressive-like behavior in male mice (PMID: 38518778). Changes in BA homeostasis have been observed not only in metabolic disorders (obesity, diabetes, MASLD) but also in several neurological and mental disorders including depression and anxiety, but their signaling function regulating neural activities, in particular in GABA neurons in different neuronal circuits regulating mood and behaviour in humans, are still poorly understood.
Focal points of interest
Our overall goal is to determine how BAs interact with distinct types of GABA neurons within neuronal networks / circuits that underlie nutritional behavior and mood changes in response to modern lifestyle (dietary patterns, circadian rhythm disruption) and resulting metabolic disorders such as diabesity and MASLD.
More specifically we will adress if chronic stress / sensitizing factors such as obesity, addicitive alcohol consumption, circadian rhythm disruption and inflammation affects specific subsets of GABA neurons through BA activated GPCRs (e.g., TGR5, sphingosine-1 phosphate receptor) or nuclear receptors (e.g. FXR, PXR) in adult mice as well as during pregnancy or lactation potentially impacting on brain development of offsprings. We will explore the effects of conjugated (BBB restricted) versus unconjugated BAs which could have direct access to the brain and modulate GABA network dynamics. Our research questions will be adressed in mouse and cell/organoid models lacking specific bile acid receptors (eg. Fxr, Tgr5), transporters (e.g. Ntcp, Oatps, Bsep), synthetic enzymes (e.g. Cyp2c70, Baat). In addition to whole body knockouts, mice lacking BA receptors (Fxr, Tgr5) in specific neuronal subsets are also available to us. In addition to mice, CRISPR/Cas9 engineered cells/organoids lacking specific BA receptors will be explored after BA challenge in close cooperation with Knoblich. At the cellular level we will explore BA effects on GABA neurotransmission using electrophysiologic studies and Ca2+ imaging in close collaboration with Harkany, Our in vivo experimental approach will include comprehensive behavioral, molecular (RNA seq, proteomics) and metabolic phenotyping. Moreover, together with Haubensak, we will apply resting-state functional magnetic resonance imaging (fMRI) and brain-wide blood oxygen-level dependent (BOLD) graph-theoretical networks to study in mice how BA affect functional connectivity in the limbic system, brainstem, and basal ganglia. Using these techniques in mice we (Haubensak/Trauner lab, unpublished) could demonstrate that the novel conjugation-resistant therapeutic BA derivative norUDCA reversed aversive limbic functional connectivity induced by high-fat diet, but the impact in humans and patients with metabolic disorders (obesity, diabetes, MASLD) is still unknown. These studies will be extended by PET analysis of already (e.g [N-methyl-(11)C]cholylsarcosine) and novel BA PET tracers (to be established by us, e.g. radiolabeled norUDCA) in combination with standard metabolic (glucose, fatty acid) tracers.
Technical proficiency and instrumentation
Our experimental methods include metabolic (lipidomics, BA metabolomics), immunological (FACS) and molecular (RNAseq, proteomics) phenotyping of mouse models, cell and organoids. To explore the role of BA signaling, mice with genetically altered BA composition (e.g. humanized (Cyp2c70-null mice, CYP2C9-humanized mice), BA conjugation-deficient mice (BAAT siRNA), polyhydroxylated BA pool (Bsep/Abcb11-deficient) mice), mice lacking the key BA uptake systems Ntcp and Oatps in the liver resulting in increased systemic/brain BA exposure, feeding conjugation-resistant BAs (e.g. norUDCA in comparison to CA, UDCA, TUDCA) altering their access / signaling in the brain and mice lacking specific BA receptors (e.g. FXR, TGR5) globally or in neurons (SynCre, NesCre) or specific neuronal subsets (AgRPCre; PomcCre) will be used. Moreover, CRISPR/Cas9 technology is available to us for gene editing of specific BA receptors, enzymes and transporters in cells and organoids.
The effects of sensitizing factors such as obesity (high fat diet), alcohol, disrupted circadian rhythm (Rev-erbalpha knock-out mice) and cholestatic (bile duct ligation) as well as inflammatory stress (LPS, polyIC) will be adressed in established mouse models.
In collaboration with Haubensack we will apply resting-state functional magnetic resonance imaging (fMRI) and brain-wide blood oxygen-level dependent (BOLD) graph-theoretical networks to explore the impact of different BAs on functional connectivity over different brain regions (sensory cortex, thalamus, hippocampus, limbic system, basal ganglia and brainstem). In collaboration with Nuclear Medicine we will link our fMRI results to PET studies exploring brain uptake of already available (e.g [N-methyl-(11)C]cholylsarcosine PMID: 31330413 ) and novel (to be established by us) BA PET tracers ( e.g. radiolabeled norUDCA).
Human translational studies: key findings obtained in mice will be studied in humans with pathopysiologically (cholestasis, MASLD, T2M, obesity) or therapeutically altered BA pool composition.
Aspirations for the next 5 years
Within the next 5 years we aim to uncover the molecular, cellular and functional mechanisms how BAs regulate GABA neurons in health (e.g. gut microbiota-derived BAs) and disease (metabolic/inflammatory stress, disruption of circadian rhythm). As near future perspective we aim to crossvalidate the key findings obatined in cells/organoids and mice to humans in investigator-initiated translational studies (e.g. dietary interventions, BA treatment) with a specific focus on neuroimaging (fMRI, PET) studies in humans. As future ambition for the next funding period, we are also prepared to adress the pathophysiological and therapeutic role of BAs in neurodegenerative and neuroimmune disorders. As such, our preliminary data have uncovered that norUDCA alleviates TH17-mediated inflammation not only in the liver and intestine intestine, but also in an antigen-specific T cell transfer-induced experimental autoimmune encephalomyelitis (EAE) model. Intriguingly, UDCA (used widely in the treatment of liver diseases) has also been shown to prevent the accumulation of amyloid β peptides in Alzheimer’s disease, protect against mitochondrial damage in Parkinson’s and Huntington’s disease, and protect against apoptosis in Huntington’s disease and amyotrophic lateral sclerosis. However, the underlying cellular / molecular mechanisms and in particularthe role of BA in modulating GABA neurons in regenarative circuit plasticity remain to be explored.
References
- PMID: 35165436. Role of bile acids and their receptors in gastrointestinal and hepatic pathophysiology. Fuchs CD, Trauner M. Nat Rev Gastroenterol Hepatol. 2022 Jul;19(7):432-450. doi: 10.1038/s41575-021-00566-7.
- PMID: 34031591. Central anorexigenic actions of bile acids are mediated by TGR5. Perino A, Velázquez-Villegas LA, Bresciani N, Sun Y, Huang Q, Fénelon VS, Castellanos-Jankiewicz A, Zizzari P, Bruschetta G, Jin S, Baleisyte A, Gioiello A, Pellicciari R, Ivanisevic J, Schneider BL, Diano S, Cota D, Schoonjans K. Nat Metab. 2021 May;3(5):595-603. doi: 10.1038/s42255-021-00398-4.
- PMID: 38518778. TGR5-mediated lateral hypothalamus-dCA3-dorsolateral septum circuit regulates depressive-like behavior in male mice. Li XY, Zhang SY, Hong YZ, Chen ZG, Long Y, Yuan DH, Zhao JJ, Tang SS, Wang H, Hong H. Neuron. 2024 Jun 5;112(11):1795-1814.e10. doi: 10.1016/j.neuron.2024.02.019.
