Favaron, Alessia;
(2025)
Interactions between medicines and the human gut microbiome.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
In recent years, there has been increasing evidence of the critical role the human microbiome plays in maintaining host health. However, interactions between gut microbiota and commonly prescribed medicines remain a research area mainly underexplored. This thesis investigates these interactions, focusing on anti-inflammatory drugs, specifically Janus kinase (JAK) inhibitors and sphingosine 1-phosphate (S1P) receptor modulators, which are approved for the treatment of inflammatory bowel disease (IBD). The first part of this work assessed the effects of these drugs on the gut microbiota sourced from a healthy human donor. Using isothermal microcalorimetry, optical density measurements, and metagenomics, it was found that JAK inhibitors (tofacitinib citrate, baricitinib, and filgotinib) had minimal impact on microbial growth and function. In contrast, the S1P receptor modulator ozanimod, significantly altered bacterial composition, promoting the growth of Enterococcus, a species linked to IBD. Given that these drugs are approved for IBD, it was essential to test them in a more clinically relevant environment. In collaboration with ProDigest, the advanced short-term colon model was used to simulate the gut microbiota of IBD patients. Tofacitinib citrate was tested in this model and demonstrated a reduction in specific pro-inflammatory markers, underscoring its therapeutic potential for managing IBD-related inflammation. Lastly, as drug effects on the gut microbiota are concentration-dependent, physiologically based pharmacokinetic (PBPK) modelling, coupled with in vitro dissolution testing, was employed to predict the clinically relevant concentration in the large intestine of the JAK inhibitor upadacitinib, from its modified-release formulation. The predicted concentration showed no significant adverse effects on bacterial growth.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Interactions between medicines and the human gut microbiome |
| Language: | English |
| Additional information: | Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10203144 |
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