Periodic Reporting for period 4 - BugTheDrug (Predicting the effects of gut microbiota and diet on an individual’s drug response and safety)
Reporting period: 2022-02-01 to 2023-12-31
The BugTheDrug project sought to address the significant challenge of individual variability in drug response, a concern that impacts not only patients and caregivers, but also strains healthcare systems worldwide. Medications are developed to be processed by the human body – absorbed, metabolised, transported, and ultimately eliminated – to achieve their intended therapeutic effect. These pharmacokinetic properties, assessed during drug development, guide the determination of optimal dosages. Yet, individual differences in genetic makeup can lead to diverse drug responses, with some individuals metabolising drugs slower or less efficiently. Lifestyle factors, including diet and exercise, alongside the gut microbiome, which can extensively metabolise commonly prescribed drugs, further complicate drug response predictability. The composition of gut microbes, varying significantly among individuals due to diet and age, necessitates novel approaches for optimal drug response management.
In response, the BugTheDrug project developed an innovative computational framework that integrates genetic, dietary, and microbial data to predict an individual's drug response. This forward-thinking approach aimed to enable personalised treatment strategies, moving away from a currently pervasive one-size-fits-all mentality. The project achieved its goals through several key objectives:
The creation of novel computational methods to account for the highly complex interdependencies between human, microbial, dietary, and drug metabolism.
The creation of digital models of humans and associated microbes that allow for the personalised prediction of drug responses based on customisable queries and input data, such as genetic makeup, diet, and gut microbiome composition
The application and validation of these novel technologies in the context of colon cancer and Parkinson’s disease.
The project's conclusions underscore its transformative potential in precision health care. The development of digital metabolic twins represents a leap forward in creating personalised health interventions based on mechanism-derived hypotheses. By fostering a vast network of stakeholders from academia, industry, policy, regulators, and society, BugTheDrug has not only paved the way for technological advancements in healthcare, as demonstrated by the total expected 45 scientific manuscripts, but also ensured these innovations are accessible and beneficial to all, as demonstrated by the successful Virtuome programme with focus on community engagement. This initiative has laid a solid foundation for future exploration and expansion, evidenced by securing further funding ensuring the project's lasting impact and evolution.
In response, the BugTheDrug project developed an innovative computational framework that integrates genetic, dietary, and microbial data to predict an individual's drug response. This forward-thinking approach aimed to enable personalised treatment strategies, moving away from a currently pervasive one-size-fits-all mentality. The project achieved its goals through several key objectives:
The creation of novel computational methods to account for the highly complex interdependencies between human, microbial, dietary, and drug metabolism.
The creation of digital models of humans and associated microbes that allow for the personalised prediction of drug responses based on customisable queries and input data, such as genetic makeup, diet, and gut microbiome composition
The application and validation of these novel technologies in the context of colon cancer and Parkinson’s disease.
The project's conclusions underscore its transformative potential in precision health care. The development of digital metabolic twins represents a leap forward in creating personalised health interventions based on mechanism-derived hypotheses. By fostering a vast network of stakeholders from academia, industry, policy, regulators, and society, BugTheDrug has not only paved the way for technological advancements in healthcare, as demonstrated by the total expected 45 scientific manuscripts, but also ensured these innovations are accessible and beneficial to all, as demonstrated by the successful Virtuome programme with focus on community engagement. This initiative has laid a solid foundation for future exploration and expansion, evidenced by securing further funding ensuring the project's lasting impact and evolution.
Researchers have developed the first web resource that combines highly curated biochemical knowledge of human and microbial metabolism with disease and nutritional information. This freely available database is called Virtual Metabolic Human (VMH, https://vmh.life(opens in new window)) provides the research community with important biochemical information, collected from thousands of peer-reviewed scientific publications and books, and connects this information with other scientific databases and resources. Importantly, comprehensive computer models underpin the VMH. This means that the information that can be queried in the online database can also be used to simulate healthy and diseased human metabolism, alone or together with gut microbial metabolism. Similarly, the nutritional information can be used to develop defined diets and use them directly when simulating human metabolism to assess how different foods may influence, for example, the fat accumulation in humans, an important aspect in obesity.
The content of the VMH database is continuously maintained and expanded within this research project. For instance, researchers have recently added a detailed biochemical description of gut microbial bile acid metabolism, which may play a role in many human diseases, including Parkinson's disease.
Researchers are now expanding the information included in the VMH with human and microbial metabolism of over 100 commonly prescribed drugs. This information is again collected from peer-reviewed scientific studies and requires the detailed investigation of gut microbial genomes to identify a microbe's potential to modify drugs and their derivatives. This step is crucial as experimental data for many gut microbes are not available, despite recent advances in understanding the role of gut microbes in human drug metabolism.
Researchers are developing novel computational methods to enable the direct analysis of gut microbe data as well as nutritional and physiological information. These computer methods will be directly connected with the VMH database to allow for cross-reference of computer simulations and currently biochemical knowledge. In addition to including microbial and nutritional information in the computer models, the new computer methods will enable to simulate human and microbial metabolism as well as pharmacokinetic properties of one or more drugs.
The content of the VMH database is continuously maintained and expanded within this research project. For instance, researchers have recently added a detailed biochemical description of gut microbial bile acid metabolism, which may play a role in many human diseases, including Parkinson's disease.
Researchers are now expanding the information included in the VMH with human and microbial metabolism of over 100 commonly prescribed drugs. This information is again collected from peer-reviewed scientific studies and requires the detailed investigation of gut microbial genomes to identify a microbe's potential to modify drugs and their derivatives. This step is crucial as experimental data for many gut microbes are not available, despite recent advances in understanding the role of gut microbes in human drug metabolism.
Researchers are developing novel computational methods to enable the direct analysis of gut microbe data as well as nutritional and physiological information. These computer methods will be directly connected with the VMH database to allow for cross-reference of computer simulations and currently biochemical knowledge. In addition to including microbial and nutritional information in the computer models, the new computer methods will enable to simulate human and microbial metabolism as well as pharmacokinetic properties of one or more drugs.
The BugTheDrug project has made significant strides beyond the existing state of the art in computational biology and personalised medicine. Through the development and enhancement of the VMH database, the project has established a cornerstone for biomedical research, interconnecting otherwise scattered biochemical knowledge in a manner unprecedented before this endeavour. The VMH database serves as a testament to its global impact and utility in the biomedical community. This resource stands out not only for its comprehensive collection of data on human, microbiome, diet, and disease but also for its user-friendly interface that facilitates access to complex datasets and visualisations.
Fundamental to our advancements are the sex-specific and organ-resolved whole-body models, which represent a monumental leap towards the creation of digital metabolic twins. The model's ability to be parameterised with diverse datasets, including physiological, dietary, and omics data, underscores the depth of insight they provide into human metabolism.
Another groundbreaking achievement is the AGORA2 resource, which includes detailed metabolic reconstructions of 7,302 human gut microbes and describes the biotransformation capabilities of microbes for 98 drugs. Such insights are crucial for understanding the role of the microbiome in drug metabolism and human health.
The establishment of the Virtuome summer school and the engagement of a broad community through 114 events have been instrumental in diversifying our stakeholder base. This engagement spans the scientific community, policy makers, charities, industry, patients, and the general public, showcasing our commitment to fostering dialogue across various sectors for achieving positive societal impact.
Together, these achievements not only represent progress beyond the state of the art but also set new benchmarks for the integration of computational modelling with biomedical research, to ultimately contribute towards the creation of Virtual Humans. The project was instrumental in securing complementary funding of over €5 million. This testament to the robust foundation laid for ongoing and future research now enables the continuation and expansion of our work towards establishing Digital Metabolic Twins, marking a significant step forward in personalised healthcare.
Fundamental to our advancements are the sex-specific and organ-resolved whole-body models, which represent a monumental leap towards the creation of digital metabolic twins. The model's ability to be parameterised with diverse datasets, including physiological, dietary, and omics data, underscores the depth of insight they provide into human metabolism.
Another groundbreaking achievement is the AGORA2 resource, which includes detailed metabolic reconstructions of 7,302 human gut microbes and describes the biotransformation capabilities of microbes for 98 drugs. Such insights are crucial for understanding the role of the microbiome in drug metabolism and human health.
The establishment of the Virtuome summer school and the engagement of a broad community through 114 events have been instrumental in diversifying our stakeholder base. This engagement spans the scientific community, policy makers, charities, industry, patients, and the general public, showcasing our commitment to fostering dialogue across various sectors for achieving positive societal impact.
Together, these achievements not only represent progress beyond the state of the art but also set new benchmarks for the integration of computational modelling with biomedical research, to ultimately contribute towards the creation of Virtual Humans. The project was instrumental in securing complementary funding of over €5 million. This testament to the robust foundation laid for ongoing and future research now enables the continuation and expansion of our work towards establishing Digital Metabolic Twins, marking a significant step forward in personalised healthcare.