Modulating the gut microbiome to enhance drug efficacy

Project Information

BugDrug

Grant agreement ID: 101001678

DOI

10.3030/101001678

EC signature date 25 June 2021

Start date 1 September 2021

End date 31 August 2027

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 999 676,00

EU contribution

€ 1 999 676,00

Coordinated by

ACADEMISCH ZIEKENHUIS GRONINGEN
Netherlands

Periodic Reporting for period 2 - BugDrug (Modulating the gut microbiome to enhance drug efficacy)

Reporting period: 2023-03-01 to 2024-08-31

Summary of the context and overall objectives of the project

Individual response rates to drugs that are widely prescribed to treat common diseases are typically in the range of 50-75%, yet the slow progress and high costs associated with new drug development do not meet the urgent need for new treatment options, particularly given the rapidly increasing burden of chronic diseases. In recent years, the gut microbiome (the trillions of micro-organisms that reside in the human gut) has been recognized as a vital “organ” that plays an important role in health and disease.

While evidence for the role of the gut microbiome in drug metabolism dates back to the 1930s, the rise of next-generation sequencing and new technologies to culture anaerobic bacteria have put the gut microbiome at the forefront of a new domain of personalized medicine in which genetics and the gut microbiome together can better predict drug response and optimize clinical outcomes. These advances mean that the microbiome can now be approached as a modifiable entity to enhance drug efficacy. However, the role of the gut microbiome in drug metabolism remains poorly understood, as do its interactions with host genetics and exogenous factors, a knowledge gap that greatly limits clinical application of approaches that target the microbiome.

This ERC project tackles this pressing issue by defining the impacts of the gut microbiome and genetics on drug metabolism, ultimately enabling personalized approaches that enhance efficacy and safety of already marketed drugs via microbiome modulation. The project will address important technical and clinical challenges in three innovative parts:
1) a population-based cohort study to better understand the interindividual difference in the gut microbiome and to build sophisticated models that take genetic, microbial and lifestyle/health factors into account to improve prediction of drug metabolism
2) pharmacokinetics analyses using innovative, personalized organ-on-a-chip to better understand causality and mechanism
3) an intervention trial using probiotics to achieve greater drug efficacy through modulation of the gut microbiome.
In summary, this project will lay the foundation for major advances in personalized medicine.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During the past two years, the project has achieved several advances in terms of human cohort-based studies and the development of hiPSC-based liver-on-a-chip. The main results include 1) the completion of the Dutch Microbiome Project, for which we systematically assessed the gut microbiome in over 8,000 individuals and evaluation microbial association with many lifestyle, clinical and physical factors, including medication (Nature 2022); 2) We characterized the microbial stability over time and found drug intake (e.g PPI) can influence the microbial stability and a significant increase of microbial antibiotic resistance over time (Cell 2021); 3) A systematic genetics-microbe-diet interaction on plasma metabolome analysis revealed a pronounced effect of the gut microbiome on metabolism (Nature Medicine 2023), and identified novel bacterial genes and pathways for bile acid metabolism (Cell Host Microbes 2022) and GalNAc utilization (Nature 2024). 4) We have achieved significant progress on construction of personalized in-vitro models for drug testing, including gut microbe isolation and in-vitro culture and hiPSC-based liver-on-a-chip. We also published a perspective article on the application of hiPSC-based organ-on-a-chip technologies in personalized medicine (Trends in Genetics 2023) and a review article to discuss the challenges on CYP expression on hiPSC-derived liver-on-a-chip (Frontiers in Pharmacology 2023).

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Several aspects of the project’s progress are innovative and beyond the state of the art:

1) Our developed bioinformatics techniques on bacterial genetic variants analysis have propelled the microbiome research field from the microbial abundance analysis towards assessing genetic diversity at the species level. The generated datasets and developed analysis codes are made publicly available via the EGA database and Github.

2) The development of hiPSC-based liver-on-a-chip is highly innovative, and we have optimized the protocols for hiPSC differentiation, organoid culture, parameter setting for organ-on-a-chip. We have a close contact with the Emulate for technical advancements. Additionally, we consider the possibility of incorporating the Emulate system into an anaerobic chamber to enable the co-culture of gut microbes on hiPSC-based gut-on-a-chip. To facilitate host-microbe interaction analysis, the Groningen Microbiome Hub has been established, and myself as one of the founders and main PIs.

For the upcoming phase of the project, we will further scale up the hiPSC-based liver-on-a-chip technology and conduct drug metabolism testing based on hiPSC-based OoC and the gut microbiome. We have also developed a novel chemoinformatic tool to predict bacterial transformation of orally administrated drugs. The manuscript is currently under preparation. Additionally, we are planning to experimentally validate some of the novel predictions. The probiotics trial has been completed and we expect to complete the analysis on the effect of probiotic treatment on gut permeability and clinical parameters in the coming year.

Progress summary of BugDrug