Metabolic interactions between the host and the gut microbiota in the entero-hepatic cycle

Diplôme Thèse Metabolic interactions between the host and the gut microbiota in the entero-hepatic cycle eng 2025-03-06 2025-03-06 author Brauer Amber Stine Ida 0000-0003-4146-2458 967957 director Gavin Perrin Anne-Claude 23293 Département de physiologie cellulaire et métabolisme (PHYME) director Zimmermann Michael 106 10.13097/archive-ouverte/unige:185030 urn:nbn:ch:unige-1850304 Sc. Vie - Bioméd. 331 The enterohepatic cycle describes the recycling and exchange of compounds between the liver, gallbladder, and gastrointestinal (GI) tract. The GI tract harbors the gut microbiota—a complex community of microorganisms essential for host health. These microbes help extract energy from food and produce a wide array of metabolites, some of which participate in enterohepatic circulation. This cycle thus represents a metabolic handshake between host and microbiota, shaped by intestinal absorption, liver metabolism, and microbial activity. This interplay is particularly relevant in drug metabolism. Most drugs are administered orally, making them subject to interaction with the gut microbiota before entering systemic circulation. These interactions are bidirectional: drugs can alter microbial composition and activity, while microbes can biotransform drugs, modifying their bioavailability, efficacy, or toxicity. Once absorbed, both parent drugs and their microbial metabolites undergo liver metabolism and may be excreted into bile, re-entering the cycle. The enterohepatic circulation thus critically influences drug pharmacokinetics. In this thesis, we investigate metabolic host-microbiota interactions through intestinal permeability assays, liver metabolism studies, and microbiome profiling. We developed a novel in vitro workflow to assess absorption of bacterial (drug) metabolites across a monolayer of intestinal epithelial cells. Using this system, we screened 482 drugs and 170 bacterial drug metabolites. We observed that, in most cases, bacterial biotransformation did not significantly alter permeability. Complementing this, untargeted metabolomics of 7,240 compounds revealed that most bacterial metabolites do not cross the intestinal barrier unchanged, emphasizing the role of the gut barrier in shaping host-microbe metabolic exchange. To study microbial effects on liver metabolism, we used gnotobiotic mouse models colonized with stool samples from three human donors. Liver transcriptomics and metabolomics analyses revealed microbiota-induced changes in key metabolic pathways, particularly lipid and drug metabolism. Notably, a significant fraction of drug-metabolizing enzymes and transporter genes were differentially expressed. By integrating transcriptomic and metabolomic data within metabolic networks, we identified four Cyp-gene–associated reactions consistently altered across all donor groups, along with 37 donor-specific metabolic neighborhoods—highlighting the influence of microbiome composition on liver metabolism and interindividual variability. Together, these findings deepen our understanding of the molecular dialogue between host and microbiota and underscore its importance in drug disposition, metabolic individuality, and personalized medicine. Dewey 612 134 Département de physiologie cellulaire et métabolisme 21C false 1276 Métabolisme des lipides 1001 11c32d27-aa12-4f13-9d4d-32ff2ba473dc Thesis Restricted Thesis_manuscript_brauer_250129.pdf 10890787 application/pdf Private 2026-12-31 ffd07c05e8dc0a093c948c21bf455796f55f4ae1ccb675acb827e07d542e0207 72ff17eb-6b87-4199-a20a-efa4764f489f Imprimatur Public file.pdf 172040 application/pdf 3dbc393648e9074406fb80452b30bcedb15214c30066caae5a785afb0c41ce2b embargoedAccess Faculté de médecine / Section de médecine fondamentale / Département de physiologie cellulaire et métabolisme

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Brauer, Amber Stine Ida

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